Version May 2024
INTRODUCTION — Meningiomas account for approximately one-third of primary central nervous system tumors (table 1 and figure 1). Surgery and/or radiation therapy (RT) constitutes the initial therapeutic approach. Furthermore, surgery and/or RT are able to control disease in some patients with recurrence.
Despite the appropriate use of surgery and RT for initial management and management of recurrent disease, there is a subset of patients in whom disease cannot be controlled with these approaches. Experience with systemic therapy is limited, and most data are from observational studies. Although a number of agents have been studied, none have an established role in prolonging progression-free or overall survival [1].
The available data for systemic therapy are reviewed here. Topics dealing with other aspects of meningioma management include:
●(See "Epidemiology, pathology, clinical features, and diagnosis of meningioma".)
●(See "Management of known or presumed benign (WHO grade 1) meningioma".)
●(See "Management of atypical and malignant (WHO grade 2 and 3) meningioma".)
HORMONAL THERAPY — Epidemiologic evidence suggests that there is a link between hormonal factors and the development or progression of meningiomas. Progesterone and androgen receptors are expressed on approximately two-thirds of meningiomas and estrogen receptor is expressed on approximately 10 percent [2]. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Hormonal factors'.)
Inhibition of these receptors has not been demonstrated to alter the natural history of recurrent meningiomas:
●Progesterone receptor inhibition – Small studies with the progesterone receptor inhibitor mifepristone suggested that this agent resulted in objective improvement in 25 to 30 percent of patients with unresectable meningioma [3-5]. However, a multicenter cooperative group phase III trial failed to demonstrate any benefit from treatment with mifepristone [6]. In this trial, 180 patients were randomly assigned to either mifepristone or placebo. There was no improvement in median progression-free survival (PFS; 10 versus 12 months). The lack of activity in this trial may have been due to loss of expression of progesterone receptor in patients with advanced disease [2].
●Estrogen receptor inhibitors – Two studies have evaluated tamoxifen in patients with inoperable meningiomas, without definitive evidence of clinical activity [7,8]. In the larger of these, a Southwest Oncology Group study, 21 patients were treated; only one partial response was observed [7]. The poor response rate may reflect the low rate of expression of estrogen receptor in patients with meningioma [2].
●Androgen receptor inhibitors – No formal clinical studies have been reported with antiandrogens. Experience with a limited number of patients has not demonstrated useful clinical activity [2].
CHEMOTHERAPY — A variety of chemotherapy agents has been studied in small series, including hydroxyurea [9], temozolomide [10], and combinations such as cyclophosphamide, doxorubicin, and vincristine [11]. Results with these approaches have not provided evidence of significant activity [2].
The most extensively studied agent is hydroxyurea. Early studies reported imaging evidence of tumor shrinkage or seemingly prolonged stable disease [2]. However, these observations were not confirmed in a phase II study conducted by the Southwest Oncology Group (S9811) [9]. There were no objective responses in the 29 patients with measurable, biopsy-proven benign meningiomas, although the median progression-free survival (PFS) was 27 months and the three-year PFS rate was 43 percent. Whether this represents an effect on the natural history of benign meningiomas is unclear.
Trabectedin, an antineoplastic drug with activity in some forms of sarcoma, did not improve progression-free or overall survival compared with local standard of care in a multicenter phase II randomized trial in Europe [12].
SOMATOSTATIN ANALOGS — Somatostatin receptors are expressed in approximately 90 percent of meningiomas [2]. Although case reports initially suggested that therapy targeted to this pathway might have therapeutic usefulness for patients with recurrent, unresectable meningiomas [13-15], subsequent trials have not shown clear benefit.
A prospective pilot study treated 16 patients with a long-acting formulation of the somatostatin analog octreotide [16]. All patients had recurrent, progressive meningioma and at least six months had passed since prior radiation therapy (RT). All of the meningiomas expressed somatostatin receptors as demonstrated by a radiolabeled octreotide scan. Partial responses were observed in five patients (31 percent) and another five patients had stable disease. The median survival was eight months.
A subsequent prospective, two-stage phase II trial of octreotide in patients with recurrent high-grade meningioma was stopped early due to lack of efficacy, after only nine patients were enrolled [17].
Another somatostatin analog, pasireotide (SOM230C), was evaluated in a multicenter, phase II trial in patients with recurrent, progressive meningioma [18]. There did not appear to be significant activity. No responses were observed; progression-free survival (PFS) at six months was 15 percent for grade 2 and 3 meningiomas and 50 percent for grade 1 tumors.
MOLECULARLY TARGETED AGENTS — An increasing understanding of the cell signaling pathways has led to the identification of other pathways and potential targets for therapeutic intervention [2]. Several of these approaches are being evaluated in meningioma patients requiring systemic therapy. These include:
●Platelet-derived growth factor – Platelet-derived growth factor (PDGF) stimulates tumor cell growth in a number of tumors. PDGF receptors are commonly expressed on the cell surface of meningiomas. Imatinib, an inhibitor of the PDGF receptors, has been evaluated in phase II studies either alone [19] or in combination with hydroxyurea [20]. No objective responses or prolongation in progression-free survival (PFS) were identified by imaging in either study.
●Epidermal growth factor – Epidermal growth factor receptor (EGFR) is overexpressed on more than 60 percent of meningiomas [2]. The EGFR tyrosine kinase inhibitors gefitinib and erlotinib were evaluated in two multicenter studies [21]. No objective responses were observed and the studies concluded that these agents did not have clinically useful activity.
●Angiogenesis inhibition – Meningiomas are vascular tumors, suggesting that inhibition of angiogenesis might be a clinically useful approach [2]. Bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor (VEGF), has been associated with disease stabilization in case reports of patients with recurrent and refractory meningiomas [22,23]. In a phase II multicenter trial of bevacizumab monotherapy that included 42 patients with progressive meningioma of any grade and eight other nonparenchymal tumors, the majority of patients achieved stable disease as a best response [24]. PFS at six months (PFS-6) was 93 percent for grade 1 meningiomas, 85 percent for grade 2 meningiomas, and 51 percent for grade 3 meningiomas. Median overall survival for grade 1, 2, and 3 meningiomas was 35, 27, and 12 months, respectively. These outcomes reflect an improvement compared with a historical PFS-6 benchmark of approximately 25 percent for recurrent/refractory meningiomas [25], although confidence is limited by disease heterogeneity and lack of prospective randomized trials. Nonetheless, bevacizumab was well tolerated in the phase II trial, with expected rates of hypertension and proteinuria and no treatment-related deaths [24]. The anti-edema effects of bevacizumab may help to reduce steroid toxicities in patients with symptomatic edema, although this has also not been well studied prospectively.
In a multicenter, phase II trial of sunitinib in 36 heavily pretreated patients with high-grade meningioma (30 atypical and 6 anaplastic), PFS at six months was 42 percent, meeting the primary endpoint [26]. Median PFS was five months, and median overall survival was 25 months. Overall toxicity included one grade 5 intratumoral hemorrhage, two grade 3 and one grade 4 intracranial/intratumoral hemorrhages, one grade 3 and one grade 4 thrombotic microangiopathy, and one grade 3 gastrointestinal perforation. PFS was longer in patients whose tumors expressed vascular endothelial growth factor receptor 2 (VEGFR2; median PFS 6.4 versus 1.4 months, p = 0.005). This study, along with case reports, suggests that sunitinib may have activity in recurrent grade 2 and 3 meningiomas, although it is not very well tolerated and predictors of response are not yet well understood [26,27].
Other agents being investigated to target angiogenesis include vatalanib [28].
●Pi3K/Akt/mTOR pathway – Most meningiomas show evidence of upregulation or overexpression of the Pi3K/Akt/mTOR pathway. Preclinical data indicate that inhibition of mechanistic target of rapamycin (mTOR) with agents such as everolimus may be an effective strategy [29,30]. In a phase II study of octreotide plus everolimus in 20 patients with recurrent/refractory meningiomas, the six-month PFS was 55 percent, and the majority of tumors (78 percent) experienced >50 percent reduction in the rate of growth at three months [31]. Everolimus has also been combined with bevacizumab in a small prospective trial that was stopped early due to slow accrual [32].
GENOTYPE-DIRECTED THERAPY — Next-generation sequencing of meningiomas has revealed that approximately 8 percent of grade 1 meningiomas have AKT1 mutations, 5 percent have smoothened (SMO) mutations, and over 50 percent have NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (NF2) mutations [33,34]. AKT1 and SMO mutations are primarily identified in skull base meningiomas. Trials with agents targeting these mutations are ongoing [35]. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Molecular pathogenesis'.)
IMMUNOTHERAPY — As in many other cancer types, there is increasing interest in modulation of local immune responses in meningioma. At least one study has found evidence of increased programmed death ligand 1 (PD-L1) expression in archival anaplastic meningioma specimens [36], prompting trials of anti-programmed cell death 1 (PD-1) therapies in patients with refractory grade 2 and 3 tumors.
In a phase II trial of 25 patients with recurrent atypical or anaplastic meningioma, the PD-1 inhibitor nivolumab was associated with one radiographic response, which was ongoing at 4.5 years [37]. Six-month progression-free survival and overall survival were 42 percent and 31 months, respectively. No molecular or clinical predictors of response could be identified, although sample numbers were low and few tumors had evidence of high mutational burden.
Some meningiomas are found to have evidence of high mutational tumor burden, high-frequency microsatellite instability (MSI-H), and/or mismatch repair (MMR) deficiency on sequencing that may increase the likelihood of responsiveness to immunotherapy. In a study that included over 1000 meningioma samples, 2.5 percent of tumors had a high tumor mutational burden, including six samples (0.6 percent), all high-grade tumors, with detectable inactivating mutations in MMR-related genes [38]. One patient with an MSH2-deficient meningioma experienced a dramatic and durable response to nivolumab.
Although rare, such genetic changes are important to recognize in patients with recurrent/refractory meningioma for the purposes of clinical trial eligibility as well as approved therapies. As an example, pembrolizumab is approved for use in the United States for patients with MSI-H or MMR-deficient advanced solid tumors that have progressed following prior treatment and for which there are no satisfactory alternative treatment options. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)
Of note, patients with tumor-associated MSI-H or MMR deficiency have an increased risk of Lynch syndrome cancer predisposition and should be referred for genetic counseling and germline genetic assessment for Lynch syndrome, regardless of family history [39]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Microsatellite instability testing'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)
SUMMARY AND RECOMMENDATIONS
●Role of systemic therapy – There is no established systemic therapy that has been shown to effectively treat recurrent meningioma or to increase survival. Whenever possible, such patients should be enrolled into formal clinical protocols.
●Options for recurrent tumors – For patients who are not eligible for inclusion on a protocol and are not candidates for re-irradiation or further surgery, options include hydroxyurea, octreotide, and a vascular endothelial growth factor receptor (VEGFR) inhibitor. Selection is individualized; for patients with symptomatic edema or steroid toxicities, bevacizumab may be favored based on its concurrent anti-edema effects. (See 'Chemotherapy' above and 'Somatostatin analogs' above and 'Molecularly targeted agents' above.)
●Immunotherapy – Some meningiomas are found to have evidence of high mutational tumor burden, high-frequency microsatellite instability (MSI-H), and/or mismatch repair (MMR) deficiency on sequencing that may increase the likelihood of responsiveness to immunotherapy. (See 'Immunotherapy' above.)
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