Meningioma in the elderly

Abstract

Meningiomas are the most common primary intracranial neoplasm, accounting for approximately 40% of all primary brain tumors. The incidence of meningioma increases with age to 50 per 100,000 in patients older than 85. As the population ages, an increasing proportion of meningioma patients are elderly. Much of this increase is accounted for by an increase in incidental, asymptomatic diagnoses, which have a low risk of progression in the elderly. The first-line treatment of symptomatic disease is resection. Fractionated radiotherapy (RT) or stereotactic radiosurgery (SRS) can be considered as primary treatment where surgery is not feasible, or as adjuvant therapy in cases of subtotal resection or high grade histopathology. The role of RT/SRS, particularly following gross total resection of atypical meningioma, is unclear and requires further evaluation. There is an increased risk of perioperative and postoperative morbidity in the elderly and therefore management decisions must be tailored to individual circumstances. Good functional outcomes can be achieved in selected patients and age alone is not a contraindication to intervention. The immediate postoperative course is an important determinant of prognosis. Therefore, careful preoperative evaluation and avoidance of complications are necessary to optimize outcomes.

Key Points.

• Elderly patients comprise a large and growing number of patients with meningioma.

• Resection can provide functional benefit in carefully selected elderly patients and age alone is not a contraindication to surgery.

• The role of radiotherapy and radiosurgery is unclear, especially in the elderly.

Meningiomas are the most common primary intracranial neoplasm, accounting for 38% of all primary tumors of the central nervous system (CNS) in the USA.¹ They occur with an aggregate incidence of 5–12 per 100,000 patient years,^2–4 increasing with age to 25–30 per 100,000 in patients aged 65–69 years and 50 per 100,000 in those aged over 85.^1,5 The overall incidence appears to be increasing as a result of an aging and growing population,⁴ with elderly people accounting for an increasing proportion of newly diagnosed meningiomas. While meningiomas generally have a benign course, involvement of important structures, mass effect, high-grade histology, or treatment can result in significant morbidity.⁶

Maximal safe resection is the first-line treatment for symptomatic presentations in good surgical candidates.⁷ Radiotherapy (RT) can be considered as both an upfront treatment where resection is unfeasible, and as adjuvant therapy in cases with high histopathological grading.^7–9 Stereotactic radiosurgery (SRS) may constitute a viable alternative to resection in carefully selected patients, or adjuvant therapy in cases of subtotal resection (STR).^10,11 However, asymptomatic, incidental lesions account for an increasing proportion of meningiomas^5,12 and thus their management is subject to debate. Elderly patients comprise a more complex population in whom optimal management of meningiomas is frequently unclear in the context of comorbidities, uncertain natural history, and diagnostic challenges. This review explores the epidemiology, assessment, management, and prognosis of meningiomas in the elderly. While approximately 10% of meningiomas arise in the spine,¹³ this review focuses specifically on intracranial meningiomas.

Methods

An anecdotal search of PubMed/MEDLINE was performed for articles including terms “meningioma*,” “elderly,” “age,” “older,” and MeSH terms “meningioma” and “geriatrics.” Articles describing the management, course, prognosis, or characteristics of elderly patients with meningioma were sought for retrieval. A search of review article bibliographies was also performed. A total of 1,003 citations were reviewed, and a total of 210 full-text articles informed this narrative synthesis. Elderly is considered to mean persons aged older than 60 years by the United Nations,¹⁴ but definitions vary across countries and organizations. Given that no clear standard exists, and the true ideal definition is likely population specific, we accepted the definition of the term used in each study.

Epidemiology

The incidence of meningiomas in the population ranges from 5 to 12 per 100,000 patient years across Europe, the United Kingdom, and USA.^1–4,15 This is highly age dependent, ranging from an almost negligible incidence in children to 25–30 per 100,000 in patients aged 65–69.^1,4,5 A supralinear increase with age is observed thereafter (Figure 1), with the incidence doubling to 50 per 100,000 in patients aged over 85 years.^1,5 This elderly population is expected to grow substantially, thus, an increasing number of elderly patients presenting with meningiomas is expected. Approximately 80%–90% of meningiomas are benign (World Health Organization [WHO] Grade 1), 15%–20% are atypical (WHO2) and less than 5% are malignant/anaplastic (WHO3).^1,3,13 It appears that there may be a higher incidence of atypical or malignant meningioma in the elderly; however, this has not been consistently demonstrated and the relative risk appears to be small if present (Figure 1).^5,16–19 Some data suggest that the incidence is approximately 1.2 times higher in African Americans.¹

Figure 1.

Incidence of benign and malignant meningioma with age, using data from the Central Brain Tumor Registry of the United States: (a) the incidence throughout the lifespan, using data published by Ostrom et al.¹; (b) the incidence in elderly patients over 65, using data published by Achey et al.⁵

The incidence of meningiomas in females is approximately twice that of males,^1,4 and the female-to-male ratio appears to increase with age, but is less pronounced in malignant disease (WHO3) (Figure 2).^1,5 Recent epidemiological data suggest that the incidence of meningiomas is increasing over time in the elderly,^5,20 which may be related to increasing life expectancy. This increase appears to be largely driven by an increase in radiological diagnoses of small tumors (ie ≤2 cm), while tissue diagnoses have remained at a relatively constant rate (Figure 3).⁴ This likely reflects an increase in incidental diagnoses in the context of increased availability and utilization of neuroimaging.^12,21–23 Evidence suggests that the majority of these incidentally identified asymptomatic lesions rarely enlarge,^24,25 thus the difference between radiological and histopathological diagnoses may alternatively reflect a shift in practice toward conservative management in these cases.^7,26

Figure 2.

Incidence of meningioma in the elderly, stratified by sex. Data originates from the Central Brain Tumor Registry of the United States from years 2005–2015, published by Achey et al.⁵: (a) the incidence of nonmalignant meningioma; (b)the incidence of malignant meningioma.

Figure 3.

Incidence of radiographically and tissue-diagnosed meningiomas using data originating from the Surveillance, Epidemiology and End Results 18 (SEER 18) dataset, published by Withrow et al.⁴ covering years 2004–2017: (a) the incidence of meningiomas over time stratified by diagnostic modality; (b)the incidence of meningiomas throughout the lifespan stratified by diagnostic modality; (c) the incidence of meningioma in patients older than and younger than 65, stratified by size and diagnostic modality.

Beyond age, risk factors for meningiomas include hormonal factors, exposure to ionizing radiation, and genetic predisposition. Estrogen, progesterone, and androgen receptors are frequently observed in meningiomas,²⁷ and a meta-analysis suggested that the use of estrogen-only hormone therapy (commonly used in postmenopausal women) is associated with an increased risk of meningioma.²⁸ While obesity may also increase risk,²⁹ the mechanism of this increase is unclear. Meningiomas are more likely in patients exposed to prior therapeutic cranial radiation,^30,31 but the association with incidental radiation is less clear.³² Associations with a variety of genetic syndromes have also been described, with neurofibromatosis type 2 being the best characterized.³³ However, genetic risk factors may be less relevant in the elderly population, as lesions tend to present at an earlier age.³³

Clinical Presentation and Diagnostic Challenges

Clinical Presentation

Meningiomas are frequent incidental findings,^4,12,21,25 and their incidental prevalence increases with age.^12,21 The utilization of neuroimaging appears to be drastically increasing in patients older than 65 years,²² as does the volume of small, radiologically diagnosed meningiomas (Figure 3).⁴ While establishing the presence of a meningioma is typically straightforward, many presenting complaints and indications for neuroimaging are unrelated, hence, determining its relationship to symptoms can be difficult.

Seizures are observed in 30% of meningiomas and are approximately 8 times more likely in convexity lesions.³⁴ Seizures may be missed or misattributed, particularly in those with cognitive impairment, communication difficulties, or residual deficits from a prior cerebrovascular event. Determining seizure causality is important, as the relationship between seizure semiology and meningioma typically guides management.⁷ Meningiomas may also present with location-based focal neurologic deficits.⁶ Dysphasia can be observed in lesions of the dominant hemisphere, but less commonly than in gliomas⁶ given their extra-axial location and noninfiltrative behavior. Hearing loss is a potential presentation of a meningioma of the cerebellopontine angle.⁶ These may be less obvious in elderly patients, in whom preexisting deficits from prior cerebrovascular events, presbycusis, or other neurological pathologies are common. Using voxel-wise analysis of magnetic resonance imaging (MRI), it has been observed that convexity meningiomas are more prevalent in the elderly.³⁵ However, this observation should be interpreted with caution. It may be possible that convexity meningiomas have longer interval to development of symptoms in comparison to nonconvexity meningiomas, resulting in a higher incidence of convexity meningioma diagnosis in the elderly population.

Neurocognitive impairment is an increasingly recognized presenting symptom of meningiomas⁷ and is present in a substantial proportion of patients.^36,37 Patients with meningiomas may have decreased executive function, perceptual speed, and verbal fluency compared with healthy controls.^37,38 The background prevalence of mild cognitive impairment in patients aged 60–64 is estimated to be 6.7%, rising to 25.2% in those aged 80–84.³⁹ Thus, meningiomas can frequently be observed in patients with other causes of cognitive decline such as dementia, depression, or delirium, given their prevalence in the elderly population,³⁹ which can make determining causation difficult. It is important to note that small incidental meningiomas are unlikely to be responsible for measurable cognitive deficits.⁴⁰ However, a high index of suspicion for meningioma as a possible cause of any cognitive impairment should be maintained in large, otherwise asymptomatic lesions, given that surgical resection may reverse symptoms.^7,36,37,41 The multifactorial etiology of cognitive impairment makes it difficult to determine the relative contribution of any meningioma to symptoms and especially to the likelihood of surgical reversal of such symptoms. Patients with cognitive impairment and a meningioma should be subjected to multidisciplinary evaluation which must include neurosurgery.^7,36,37

Radiological Features

As guidelines endorse conservative management of many meningiomas,⁷ particularly in the elderly, the role of radiological diagnosis is increasing in importance.^5,26 Meningiomas are best appreciated on MRI, where they have a characteristic appearance that is usually diagnostic.⁶ Differential diagnoses include dural-based metastases and solitary fibrous tumour/haemangiopericytoma. Typically, meningiomas are a dural-based extra-axial mass, hypo- to isointense on T1-weighted images and iso- to hyperintense on T2-weighted imaging (Figure 4a,c).⁶ Strong contrast enhancement is usually evident and there is characteristically a dural thickening at the margins, referred to as the “dural tail sign” (Figure 4b).⁶ Perilesional edema is usually assessed on fluid attenuated inversion recovery (FLAIR) sequences. Bone window computed tomography (CT) is useful in evaluating tumoral calcification, hyperostosis of nearby skull, or bony infiltration by tumor (Figure 4d). While meningiomas are the most common lesions consistent with the above radiological appearances, other diagnoses can mimic their radiological appearance.⁴² Elderly patients frequently have a history of malignancy, and dural metastases are an important differential diagnosis.⁴² Craniopharyngiomas or pituitary adenomas may mimic parasellar meningiomas, while vestibular schwannomas may mimic meningiomas in the cerebellopontine angle.^6,42

Figure 4.

Magnetic resonance imaging demonstrating a T1 isointense (a), contrast enhancing (b) dural-based lesion with a dural tail (red arrow). It is hyperintense on T2 FLAIR sequence (c). In addition, a T2 hyperintensity (green arrow) evidencing a lacune is seen in the right hemisphere (b, c), which is reflective of the common scenario of elderly patients with meningioma and comorbid cerebrovascular disease. Bone window of CT scan (d) demonstrates hyperostosis (white arrow) and osseous infiltration. These radiological features are characteristic of meningiomas.

Conversely, meningiomas may present with an uncharacteristic MRI appearance suggestive of an infiltrative lesion.⁶ While this may be more common in atypical or malignant meningiomas,^42,43 and significant edema may predict atypical histology,⁴³ routine MRI imaging alone is insufficient in predicting histological grade. Positron emission topography (PET) imaging using ligands specific for meningioma may be useful where there is uncertainty,⁴² but is not currently employed routinely. Radiological diagnoses in the elderly may be further complicated by contraindications to MRI such as implantable cardiac defibrillators or renal impairment limiting the use of intravenous contrast.

Management

Elderly patients are predisposed to comorbidities and frailty, which may influence management options. Depending on symptomatology, or lack thereof, an observational or active therapeutic approach may be adopted.

Conservative Management

The rising frequency of incidental, asymptomatic meningiomas,^4,12 and evidence demonstrating their benign course, has contributed to a shift toward conservative management of many lesions.^4,7,24–26 This is supported by evidence suggesting that most small, asymptomatic meningiomas will never enlarge^7,23–25 while surgery for asymptomatic lesions carries risk of functional deterioration and adverse events, particularly in the elderly.^44–46

Currently, there is insufficient evidence to accurately personalize radiological follow-up for incidental meningiomas. Guidelines recommend yearly MRI surveillance for the first 5 years, with an increasing interval thereafter in the absence of change.⁷ Several features have been associated with a lower risk of progression including size ≤3^23,47 or ≤4 cm,^47,48 presence of calcifications,^47–49 female sex,^24,48 T2 hypointensity,^24,48 and lack of peritumoral edema.^23,24,48 A prognostic model which attempts g to risk stratify incidental meningiomas²⁴ aims to facilitate personalization of radiological surveillance. Data collection is currently ongoing for a multicenter validation.⁵⁰ Surveillance can be carried out using only T2-weighted sequences^7,51; however, T1 postcontrast sequences remain the gold standard for follow-up⁷ unless there are patient-specific concerns regarding gadolinium administration.

Elderly patients may be less likely to experience progression,^48,52 though this finding is potentially related to shorter follow-up and perhaps less intensive surveillance. When progression occurs, the majority of meningiomas exhibit slow growth.^23,47,48 However, conversely, there may be a higher prevalence of atypical histology with rapid growth in elderly patients,^16,18,19 particularly in very large lesions.⁵³ There are currently no guidelines for intervention in patients who are being monitored with serial imaging. This is partly due to the potential for slow growth with minimal or no symptoms, hence it is difficult to define specific criteria.⁴⁶ The relative growth rate, rather than the absolute volume change, should guide decisions for intervention.^7,46 Evidence of growth over time, particularly rapid growth,⁴⁷ should prompt suspicion for atypical histology⁷ when resection becomes a priority. In patients unsuitable for surgery, novel PET ligands may, in future, facilitate a radiological diagnosis of meningioma.⁴² Small, asymptomatic lesions with low-risk radiological features may not require further surveillance in very elderly patients as rapid growth is very unlikely⁴⁷ and slow growth may be unlikely to reach a clinically significant volume within the patient’s lifetime.

Surgery

There are no randomized controlled trials (RCTs) which seek to compare the benefits of surgical removal to observation or to radiation. However, surgical resection is the gold standard of treatment for large meningiomas, symptomatic lesions, and rapidly growing tumors under surveillance.⁷ Resection relieves mass effect and many of the symptoms associated with it and is frequently curative, particularly in WHO1 meningiomas. In general, the principle of surgery is maximal safe resection⁷ with preservation or improvement of neurological function. Maximal resection is desired as recurrence is less likely when gross total resection (GTR) is achieved.^7,9,54,55 Gross total resection is also an independent predictor of survival.⁵⁵ Extent of resection of meningiomas is typically defined by the Simpson grading system (Table 1).⁵⁶ The growth potential of residual meningioma is unclear, but the relative growth rate appears to be less than 15% per annum.⁵⁷

Table 1.

Simpson grading system for extent of resection of meningiomas, adopted from Simpson.⁵⁶

Grade	Description
1	Complete resection, including dural attachment and abnormal bone
2	Complete resection, with coagulation of the dural attachment
3	Complete resection, without resection or coagulation of the dural attachment
4	Subtotal resection
5	Biopsy only

Elderly patients are more likely to have poorer functional status and higher comorbidity indices preoperatively,^18,58 and prolonged operative duration may be a risk factor for complications and mortality in the elderly^59,60 (Table 2). An STR strategy, typically defined as Simpson grade IV (Table 1), may therefore be beneficial via reduction in operative time, especially as there may not be a survival benefit to GTR in the elderly.^5,63 Subtotal resection may sufficiently relieve symptoms and clinically significant recurrence may be unlikely within the patient’s lifetime in the very elderly. The degree of resection in an STR strategy is determined by the anesthetic risk to the patient, goals of care, premorbid functional status, tumor location, vascularity, and proximity to critical structures, but generally consists of sufficient resection to alleviate mass effect while minimizing operative duration and risk to critical structures. Proximity to critical structures or skull base location is a risk factor for postoperative decline in the elderly,⁶² which may be partially mitigated when GTR is not attempted. Age should not be the sole determinant of the extent of resection. In current practice, GTR is frequently achieved in the elderly⁵ and age does not appear to be strongly associated with the likelihood of GTR.⁸⁷

Table 2.

Summary of important literature findings.

Findings	References
Epidemiology
Incidence increases with age, from 25–30 per 100,000 at 65–69 years to 50 per 100,000 in patients over 85 years	1,5
Atypical or malignant histology may be more frequent in the elderly	5,16–19
Benign meningioma is approximately twice as common in females in the elderly population, but malignant meningioma incidence is approximately equal in females and males	1,5
Clinical presentation and diagnosis
Incidental, asymptomatic meningiomas account for a large and increasing proportion of cases in the elderly	4,12
Neurocognitive impairment is an important symptom present in a large number of patients, which is often responsive to treatment	7,36,37
Management
Most incidental meningiomas will never require treatment and should be managed conservatively	7,23–25
Progression of incidental meningiomas may be less likely in the elderly	48,52
Resection of asymptomatic disease in the elderly carries significant risk of morbidity	44,45
Elderly patients have poorer functional status and higher comorbidity burden preoperatively	18,58,61
Prolonged operative duration may be a risk factor for postoperative decline in the elderly	59,60
Proximity to critical structures or skull base location may be a risk factor for postoperative decline in the elderly	62
Gross total resection may not confer a survival benefit in elderly patients	5,63
Elderly patients are at higher risk of perioperative and postoperative adverse events, the majority of which are medical. Careful patient selection and preoperative care may minimize this risk.	18,53,62,64–70
Comorbidities, frailty and baseline performance status are stronger predictors of poor outcome than age	58,63,65,71–75
Surgical resection can produce significant functional improvement, even in very elderly patients	41,58,63–65,67,68,70–72,76–78
Modern conformational RT and SRS appear to have low toxicity and high rates of local control in elderly patients	11,79,80
SRS or RT may have similar survival outcomes to resection in selected patients	81–83
There may not be a survival benefit to adjuvant RT following resection of WHO3 meningioma in the elderly	5,84,85
Prognosis
Overall survival is decreased in elderly patients compared with the younger population	5,13,63,66,72,86
Progression-free survival may be comparable to younger patients following successful resection	17,76
The majority of excess mortality in the elderly may be accounted for by decline in the immediate postoperative period	72
Poor prognostic factors in the elderly include increased comorbidity burden, frailty, poor baseline performance status and skull base location	58,62,65,73,75
WHO2 and WHO3 have a poor prognosis in the elderly	61,84,86

SRS = stereotactic radiosurgery, RT = radiotherapy, WHO = World Health Organization

Elderly patients are at higher risk of peri- and postoperative adverse events,^{18,53,62,64–67} and the majority of these complications appear to be medical.^64,67 Postoperative complications significantly influence survival and functional course in the elderly.^66,71,72,88 It is important to note that comorbidities, frailty, and poor baseline performance status may be stronger predictors of adverse events than age,^73,74 and age alone is often not associated with complications in multivariable models adjusted for these factors.^58,65,73,75 Poor preoperative functional status is also an important risk factor for further functional deterioration.^63,72,75 Intervention for meningioma is rarely emergent and thus time can be taken to medically optimize patients. Multidisciplinary evaluation for patients with medical concerns, careful patient selection, minimally invasive approaches, and optimized perioperative care may reduce this excess risk and produce outcomes similar to younger cohorts.^{41,58,63–65,67–70,72,76–78} Increased consideration of these factors may explain a lower rate of adverse events in elderly patients in more recent surgical series.⁶⁵ Multiple scoring systems have been proposed to aid in preoperative risk stratification of elderly patients, but there is insufficient evidence of their validity to support their routine use.⁸⁹

An objective assessment of preoperative cognitive and functional status, along with anesthetic risk, is important in this population, both to aid in decision-making and in monitoring the effect of treatments delivered. Multiple well-validated clinical tools are available for the assessment of cognitive status, including the relatively brief Montreal Cognitive Assessment⁹⁰ and more extensive Addenbrooke’s Cognitive Examination (ACE),⁹¹ among many others. Functional assessments, such as the Barthel Index,⁹² are also valuable. The use of these tools aids in the identification of meningioma-associated cognitive impairment and the objective assessment of response to treatment. There is currently weak evidence regarding the response of meningioma-associated cognitive impairment to treatment.^36,37 Routine use of objective indices of cognitive function will facilitate the objective assessment of cognitive and functional improvement with treatment in future studies.

Preoperative anesthetic risk can be assessed using the widely used American Society of Anesthesiologists⁹³ physical status scale. Pulmonary complications are an important risk in the elderly cohort, the risk of which can be assessed using a validated tool such as the ARISCAT.⁹⁴ The use of these tools is essential to assessing baseline comparability of patient cohorts across and within future studies.

Postoperative Management

In elderly patients, the immediate postoperative period appears to be a significant determinant of long-term outcome⁷² and thus optimizing recovery is of significant benefit. Enhanced recovery after surgery (ERAS) protocols have gained significant attention in both the general surgical⁹⁵ and neurosurgical⁹⁶ literature. The basis of ERAS is to improve outcomes by minimizing hospital stay, reducing immediate postoperative morbidity and pain, and encouraging early mobilization and return to premorbid functioning by attenuating the postoperative stress response.⁹⁷

ERAS interventions, including regional anesthetic techniques, early postoperative mobilization, and day-case surgery, have been evaluated in patients undergoing surgery for meningioma, including the elderly.^98,99 While their true efficacy is unknown in neurosurgical patients, most ERAS interventions are safe and may optimize early recovery and thus improve outcomes.

Radiosurgery and Fractionated Radiotherapy

Fractionated RT or SRS can be considered in cases of high-grade histology, STR, unresectable lesions, and in some patients unsuitable for surgery.^7,8 As a primary treatment, SRS and conformal RT are frequently employed in skull base or optic nerve sheath meningiomas where resection is considered unfeasible.^8,100,101 SRS is generally preferred over fractionated RT where feasible, but fractionated RT should be considered in larger lesions as this reduces the risk of severe reactive edema.¹⁰² Fractionated RT may additionally be warranted to optimize coverage where there is significant infiltration or extension to critical structures.⁸¹ Modern conformational techniques are well tolerated and are associated with low toxicity,^8,82,103 even in elderly patients.^11,79,80 Rates of local control exceed 90%–95% in modern series^8,82,103 and outcomes appear to be comparable to surgical intervention in selected patients.^10,81 This makes RT an attractive primary treatment option in the elderly, particularly for skull base lesions given their association with increased postsurgical morbidity in this cohort.⁶² It is important to note, however, that there is currently no RCT evidence comparing primary radiosurgery to surgical resection. There is insufficient evidence to support the use of primary SRS as first-line management, but it should be considered in select patients. In the elderly population, it may have utility in difficult lesions or small meningiomas in difficult patients, that is, comorbid patients at higher risk of perioperative complications. RT additionally removes the need for a major surgical procedure, and this may be an important factor where other differential diagnoses, such as dural-based metastases, need to be excluded. A potential concern in patients undergoing RT for meningioma is cognitive impairment, particularly in the context of comorbid dementia or cognitive impairment. While cranial RT is traditionally associated with cognitive decline, this is likely dose dependent,¹⁰⁴ and there is some evidence to suggest the doses used for the treatment of meningioma have minimal impact on cognition.¹⁰⁵

The IMPASSE study reported superior progression-free survival (PFS) in incidental meningiomas managed with primary SRS compared with active surveillance,¹⁰⁶ without increased risk of neurological deficits. These results will prompt debate on whether SRS should be routinely offered at diagnosis to patients with asymptomatic meningioma, or when tumor growth is observed, particularly in elderly patients in whom surgical resection may be high risk. It is important to highlight that there was no histopathological diagnosis for most patients and the inclusion of higher grade meningiomas or meningioma mimics (ie solitary fibrous tumors, dural-based metastases) cannot be excluded. It is important to note that PFS exceeded 75% at 2 years and 50% at 5 years in the observation group and thus its generalizability to the elderly population, in whom life expectancy is shorter and the impact of progression less clear, is uncertain. However, the observed alteration to the growth trajectory is promising and an RCT is needed to define the optimal management of incidental meningiomas.

As an adjuvant therapy, the utility of RT is predominantly in cases of incomplete resection, especially those with atypical or malignant histology. Following STR of WHO1 meningiomas, adjuvant RT is generally unnecessary^7,81 as rapid progression is rare. However, RT can be considered, either as adjuvant or salvage treatment, in patients with recurrent WHO1 tumor.¹⁰⁷ It can also be used as adjuvant treatment in patients with tumors in complex locations, that is, cavernous sinus, who remain symptomatic following STR or in whom proximity to critical structures warrants further treatment.⁸¹ RT may also be employed following deliberate STR.⁷ As discussed above, STR may limit operative duration and reduce the risk of complications in the elderly. RT may facilitate further local control in this scenario without compromising on tissue diagnosis. RT has also been shown to deliver significant PFS for patients with recurrent WHO1 meningioma following any extent of surgical resection.¹⁰⁸

Adjuvant RT is standard practice following STR of WHO2 meningiomas.⁷ However, its role following GTR of WHO2 meningiomas is a subject of debate.¹⁰⁹ While there is conflicting evidence to suggest that it improves local control and PFS,^110–113 there is currently no strong evidence of an overall survival benefit.^7,113 Patients older than 55 years may have a higher risk of recurrence following GTR of WHO2 meningioma.¹¹⁴ Although there is no definitive evidence to support RT in preventing recurrence in younger patients with completely resected WHO2 meningiomas. There is a similar lack of published evidence to support the role of RT in elderly patients with completely resected WHO2 meningiomas. Given this equipoise, decisions regarding the role of adjuvant RT should be made on a case-by-case basis accounting for age, preferences, life expectancy, and risk of toxicity. The European Association of Neuro-Oncology recommends adjuvant RT following STR⁷ despite the risk of toxicity due to the high rate of progression in residual WHO2 lesions.¹¹⁵ The role of adjuvant RT following GTR for WHO2 lesions remains unclear.¹⁰⁹ Practice varies according to patient, neurosurgeon, and oncologist preferences.¹¹⁶ The ROAM/EORTC 1308 trial, a phase III multicenter RCT, aims to answer the question of the need for RT following complete resection of WHO2 meningioma.¹¹⁷ A similar study, NRG-BN003, is ongoing in the USA.

WHO3 meningiomas are locally aggressive with poor PFS and overall survival,^13,61,118 particularly in the elderly.^5,84,85 Adjuvant RT is typically recommended,⁷ and appears to have a significant survival benefit in most patients.^118–120 In the elderly, however, the survival benefit of adjuvant RT in the context of WHO3 meningioma may be limited to patients with STR, as RT was shown to convey no survival benefit following GTR.^5,84

Overall, there is no strong evidence of a survival benefit of RT specifically in the elderly in most cases.^5,84,85 Furthermore, some data suggests that the addition of RT to resection is in fact associated with decreased survival in the elderly following GTR of nonmalignant meningiomas.⁵ While this is likely to be confounded by a variety of patient factors and may not extrapolate to modern radiosurgery, it is difficult to infer a survival benefit in the elderly from the available data. Thus, decisions regarding adjuvant SRS/RT should be made on an individual basis based on symptoms, histological subtype, patient preferences, goals of care, performance status, and extent of primary resection.

Prognosis

In untreated patients with asymptomatic disease, the prognosis is generally excellent even in the elderly, given that most will never require intervention.^24,25 The survival implications, if any, of asymptomatic disease are unclear. Recent apparent increases in the prevalence of asymptomatic meningiomas⁴ likely reflect increased detection rather than a true increase in incidence. The true incidence may be higher even than current data suggests, given that incidental meningiomas are found on 2%–3% of autopsies.¹²¹ Accordingly, this suggests that the majority of meningiomas in the population never become symptomatic and thus the survival impact of incidental meningiomas in the elderly is likely to be very small.

Despite a benign course and 5-year survival rates exceeding 90%, even WHO1 lesions are associated with substantial excess mortality compared to the disease-free population,^1,54,86 though this appears to be improving over time.^86,122 However, it is difficult to determine to what degree this is attributable to the disease itself given that some risk factors for developing meningioma are also associated with decreased life expectancy. Increasing age at diagnosis is associated with progressive shortening of overall survival in the elderly when all meningioma grades are considered,^{5,13,63,66,72,86} but the specific impact of low-grade meningiomas on overall survival is not well described.⁵ PFS in the elderly is likely to be comparable to younger patients if successful resection is possible^17,76 and thus the reduced overall survival may not be tumor related.

Evidence suggests that most excess mortality in the elderly is related to postoperative decline and adverse events in the first postoperative year.⁷² Thus, the immediate postoperative course is likely a significant determinant of prognosis. Risk factors for postoperative decline, and therefore for decreased survival,^66,88 in the elderly include increased medical comorbidity, frailty, and poor baseline performance status.^58,65,73,75 Tumor location is a further key consideration and the risk of postoperative decline may be higher in elderly patients with skull base lesions,⁶² while GTR is also more difficult to achieve, operative duration may be longer and the risk of iatrogenic postoperative deficits higher.¹²³ In future, the increasing use of RT as primary treatment may allow more selective surgical management of skull base lesions and further improve survival in the elderly. GTR is an important prognostic factor in general,⁵⁵ but may be less important in elderly patients.⁵ Survival following primary treatment with SRS or conventional RT is poorly described in the elderly, but may be comparable to surgical intervention in selected patients.^81–83

The prognosis of higher grade meningiomas is substantially worse, and 5-year overall survival rates may be as low as 76% and 44% for WHO2 and 3, respectively, even after resection and RT.^61,86 In one study of elderly patients with WHO3 meningioma, overall survival at 5 years was just 35%, with median survival of 38 months.⁸⁴ Data from the Central Brain Tumor Registry in the USA suggests a median survival of 40 months in patients aged 65–69 with malignant meningioma, which falls to just 25 months in patients aged 80–84 and 15 months in patients aged older than 85.⁵

Limitations

The most prominent limitation of this review is the quality of primary literature regarding both meningiomas in general and in the elderly. Despite the prevalence of meningioma, most studies are observational and there is a lack of randomized evidence to guide practice. Recommendations regarding the role of SRS and RT are difficult to make as there is little prospective evidence and no RCTs comparing primary irradiation to resection. Survival data regarding these primary treatment modalities are particularly limited. This is of special interest in the elderly population, as SRS offers a promising alternative to surgery which may be of significant benefit. The natural history of meningioma, particularly incidental findings and residual disease following STR, is uncertain and appears to vary substantially across patients. Further understanding of the natural history of meningioma in the elderly and factors associated with progression would substantially aid clinical practice. Another important limitation is the narrative structure of this review. No systematic, critical assessment of study quality was performed and there is no statistical synthesis, which limits the strength of any inference from our findings and conclusions.

Future Directions

It is possible that the variability in the course of meningiomas across elderly patients is due to variation in molecular composition.^33,124 Some studies suggest, both directly¹²⁵ and indirectly,³⁵ that meningiomas may have differing molecular alterations in the elderly. This may have implications for risk stratification,^124,126 management and prognosis, and even yield systemic therapies in future.¹²⁷ Given the differences in baseline function, medical comorbidities, goals of treatment, and life expectancy, future studies should consider including prespecified subgroup analyses of elderly patients to provide much needed evidence informing their care.

Conclusion

Elderly patients with meningiomas comprise a growing volume of patients in clinical practice. Incidental, asymptomatic disease is increasingly identified, but can be managed with radiological surveillance and has a good prognosis. Surgical intervention is the first-line therapy for symptomatic meningiomas in good surgical candidates and can often improve functional status in carefully selected patients. SRS and advanced conformal RT techniques are important management options in the elderly, particularly for WHO2, residual and recurrent tumors, and in patients where risks of surgery are deemed to be too high. There is a need for improved preoperative diagnosis of meningioma grade, especially for important prognostic factors such as brain invasion and necrosis. Age alone is not a contraindication to intervention in elderly patients with good baseline function and a low medical comorbidity burden.

Funding

No financial support was provided for this research.

Conflict of interest statement. The authors have no conflict of interests to declare.

Supplement sponsorship. This supplement was sponsored by a generous donation from Mr. Paul Mielnik and his family to help raise awareness and advance the care of patients with meningiomas worldwide.

>Authorship statement. Concept and design: MA, MF, MJ. Literature search, screening, and review: MA, JH. Writing: MA, JH, MF, MJ. Review and revision of manuscript: MA, JH, MF, MJ. All authors reviewed the final manuscript prior to submission.