Medical management of meningioma in the era of precision medicine

Free access

Surgery is curative for most meningiomas, but a minority of these tumors recur and progress after resection. Initial trials of medical therapies for meningioma utilized nonspecific cytotoxic chemotherapies. The presence of hormone receptors on meningioma ushered in trials of hormone-mimicking agents. While these trials expanded clinical understanding of meningioma, they ultimately had limited efficacy in managing aggressive lesions. Subsequent detection of misregulated proteins and genomic aberrancies motivated the study of therapies targeting specific biological disturbances observed in meningioma. These advances led to trials of targeted kinase inhibitors and immunotherapies, as well as combinations of these agents together with chemotherapies. Prospective trials currently recruiting participants are testing a diverse range of medical therapies for meningioma, and some studies now require the presence of a specific protein alteration or genetic mutation as an inclusion criterion. Increasing understanding of the unique and heterogeneous nature of meningiomas will continue to spur the development of novel medical therapies for the arsenal against aggressive tumors.

ABBREVIATIONS AKT = alpha serine/threonine-protein kinase; EGFR = epidermal growth factor receptor; OS = overall survival; PDGF = platelet-derived growth factor; PFS = progression-free survival; PFS6 = PFS at 6 months; TGF = tumor growth factor; VEGF = vascular endothelial growth factor.

Abstract

Surgery is curative for most meningiomas, but a minority of these tumors recur and progress after resection. Initial trials of medical therapies for meningioma utilized nonspecific cytotoxic chemotherapies. The presence of hormone receptors on meningioma ushered in trials of hormone-mimicking agents. While these trials expanded clinical understanding of meningioma, they ultimately had limited efficacy in managing aggressive lesions. Subsequent detection of misregulated proteins and genomic aberrancies motivated the study of therapies targeting specific biological disturbances observed in meningioma. These advances led to trials of targeted kinase inhibitors and immunotherapies, as well as combinations of these agents together with chemotherapies. Prospective trials currently recruiting participants are testing a diverse range of medical therapies for meningioma, and some studies now require the presence of a specific protein alteration or genetic mutation as an inclusion criterion. Increasing understanding of the unique and heterogeneous nature of meningiomas will continue to spur the development of novel medical therapies for the arsenal against aggressive tumors.

Meningiomas are the most common primary central nervous tumors in adults, comprising more than a third of all brain tumors. Most are WHO grade I, while 15%–20% are considered high grade (WHO grade II or III). While grade I meningiomas largely express an indolent course, high-grade meningiomas are associated with poor prognoses: 10-year overall survival (OS) ranges from 53%–79% for patients with WHO grade II lesions to 14%–34% for those with grade III tumors. Patients with meningioma refractory to conventional surgery or radiation have limited pharmacotherapeutic options.72

Clinical trials for meningioma are challenged not only by a dearth of targets, but also by several qualities of the tumor’s growth pattern and epidemiology. First, the relatively indolent nature of WHO grade I meningiomas and the wide variability in the natural history of grade II meningiomas challenge our ability to define consistent outcome measures within a reasonable time frame. The amount of time necessary to reflect true disease control or progression may exceed that budgeted for a typical clinical trial. Second, the relative efficacy of surgery and adjuvant radiation for meningiomas constrains the burden of progressive meningiomas, especially WHO grade I subtypes, which might be studied in clinical trials. These constraints have frequently prompted the accrual of tumors of different grades and with prior treatments into the same trial to allow sufficient power for the end points, which may then confound the interpretation of results.

Additionally, approaches for measuring meningioma growth vary across studies of tumor progression, with some investigators utilizing maximum diameter; others, maximum area; and still others, three-dimensional volumetric analysis. The lack of consistent clinical end points across studies has limited comparisons between trials and raised calls for standardization of trial techniques.

Medical management of meningioma has continued to evolve in the last 2 decades, mirroring the expansion of therapeutic strategies in human cancers. Studies of nonspecific agents have given way to trials that leverage our understanding of specific molecular alterations and the immune environment. These discoveries have motivated trials of novel molecular inhibitors and immunotherapies. In the present review, we summarize the medical management strategies studied for meningioma to date and avenues for future therapeutic development in light of biological insights.

Cytotoxic Chemotherapy

Cytotoxic chemotherapy has generally been reserved for meningiomas refractory to both surgery and radiotherapy (Table 1). A cyclophosphamide, doxorubicin, and vincristine regimen for anaplastic meningioma had modest results despite severe toxicities, with the majority of recipients displaying a stable radiological response and median OS of 5.3 years.9 Irinotecan, a topoisomerase I inhibitor, and temozolomide, a DNA alkylator, resulted in 6% and 0% progression-free survival (PFS) at 6 months (PFS6), respectively, for refractory WHO grade I meningioma in phase II trials.14,15

TABLE 1.

Clinical studies of cytotoxic chemotherapy for meningioma

Authors & YearRegimenMechanismStudy DesignNo. of PtsPrior Op/RT/STWHO Grade*Best Radiographic Response*PFSMedian OS
NAIIIIIISDMRPRCRPDMedianPFS6      
Schrell et al., 1997HydroxyureaRRIRetrospective44/3/NA030111200NANANA
Newton et al., 2000HydroxyureaRRIRetrospective17NA0161011000580 wksNANA
Mason et al., 2002HydroxyureaRRIProspective2020/8/NA01631121007NANANA
Rosenthal et al., 2002HydroxyureaRRIRetrospective1515/1/NA01050110004NANANA
Newton et al., 2004HydroxyureaRRIProspective1212/6/NA08403100813 mosNANA
Fuentes et al., 2004HydroxyureaRRIProspective4828/NA/0151810NA1302021NANANA
Hahn et al., 2005Hydroxyurea, radiationRRIRetrospective2123/0/NA41322192000NANANA
Weston et al., 2006HydroxyureaRRIProspective65/NA/NA150030001NANANA
Chamberlain & Johnston, 2011HydroxyureaRRIRetrospective6060/60/NA0600021000394 mos10%NA
Chamberlain, 2012HydroxyureaRRIRetrospective3535/35/NA00221315000202 mos3%NA
Reardon et al., 2012Hydroxyurea, imatinibRRI, PDGFR inhibitorPhase II217/0/NA0894NANANANANA7 mos62%66 mos
Kim et al., 2012HydroxyureaRRIRetrospective1313/NA/NA085010000377 mosNANA
Karsy et al., 2016Hydroxyurea, verapamilRRIPhase I/II77/5/NA0250100068 mos85%35 mos
Mazza et al., 2016Hydroxyurea, imatinibRRI, PDGFR inhibitorPhase II1515/11/00291400004 mosNA6 mos
Chamberlain et al., 2006IrinotecanTopoisomerase I inhibitorPhase II1616/16/NA016001201034.5 mos6%7 mos
Chamberlain et al., 1996Cyclophosphamide, doxorubicin, vincristineCombinatory therapyPhase II1414/14/NA000141202004.6 yrsNA5.3 yrs
Chamberlain et al., 2004TemozolomideDNA alkylatorPhase II1616/16/NA016001300035 mos0%7 mos

CR = complete response; MR = minimal response; NA = not available; PD = progressive disease; PDGFR = platelet-derived growth factor receptor; PR = partial response; Pts = patients; RRI = ribosomal reductase inhibitor; RT = radiation therapy; SD = stable disease; ST = systemic therapy.

Data missing for some cases; therefore, values do not reflect total number of patients for each study.

Hydroxyurea, a ribonucleotide reductase inhibitor, offered initial promise in a small case series in which a positive radiographic response was demonstrated in 3 of 4 recurrent meningioma patients who had received the drug.64 Further retrospective and prospective studies of hydroxyurea revealed that patients most commonly display a stable response, followed by progressive disease, and that median PFS on hydroxyurea ranges from 2 to 77 months depending on the study population.10,13,29,40,48,62,74

Subsequent clinical trials that assessed the safety and efficacy of combination therapies that included hydroxyurea are discussed further in Combinatorial Pharmacological Therapies below.

Hormone-Directed Therapy

Meningioma has been associated with the dysregulation of a number of hormonal axes. Hormone exposure has been implicated in the development of meningioma as evidenced by a female preponderance among patients, tumor growth during pregnancy, and the risk reduction seen in menopause and after oophorectomy.

Tamoxifen, an anti-estrogen agent, did not demonstrate efficacy in two phase II trials, with the majority of patients developing progressive disease.23,47 In contrast, the anti-progesterone agent mifepristone was associated with modest positive responses in a minority of patients in several retrospective and prospective single-arm trials.25,26 These results motivated a phase III randomized controlled trial assessing the impact of mifepristone on OS and PFS in progressive or recurrent meningioma.33 While no statistical differences were found between the two treatment arms, the low patient enrollment prevented stratification by tumor grade. Moreover, meningiomas of different grades may differentially express sex hormone receptors and may have obscured potentially salient results from this trial.

Meningiomas demonstrate activation of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. The GH/IGF-1 axis is endogenously inhibited by somatostatin, motivating the study of somatostatin analogs in trials. Meningiomas preferentially express somatostatin receptor type 2 (SST2), which can bind the hormone octreotide to decrease cell proliferation.24 Response to octreotide is correlated to high SST and Merlin levels in vitro.24

An initial retrospective analysis on the efficacy of the somatostatin analog octreotide as therapy for 3 refractory meningioma cases suggested its potential to maintain stable disease.19 Additionally, a retrospective study of octreotide in 8 progressive WHO grade I meningiomas demonstrated 100% PFS at 48 months.65 However, other phase II trials that recruited higher proportions of patients with grade II–III meningiomas demonstrated a median PFS ranging from 4 to 5 months.34,68

A phase II trial of pasireotide, another somatostatin analog formulation, showed possible therapeutic benefit in high-grade meningioma.55 Notably, patients with high-grade meningioma, all of whom had undergone prior surgery and radiotherapy and most of whom had received chemotherapy, had a median OS of 2.0 years. Radiolabeled [DOTA0,Tyr3]-octreotide (DOTATOC) therapy, which targets somatostatin receptors, was tested in a phase II trial and demonstrated stable disease in a majority of progressive meningioma cases and a mean OS of 8.6 years from the initiation of treatment; however, the tumor grade distribution was not reported in this study.46

Non-Hormonal Targeted Therapies

The molecular specificity of targeted therapies differentiates them from traditional chemotherapy in providing precise attacks on protein targets. Current therapies act on a range of cellular receptors, signal transduction molecules, cell cycle regulators, and other vital molecules that were initially identified by aberrant protein expression. Targeted therapy for meningioma will necessitate foundational knowledge of these interrelated mechanisms. Antagonists of these pathways have been trialed in meningioma and are discussed below (Table 2).

TABLE 2.

Clinical studies of targeted therapy for meningioma

Authors & YearRegimenMechanismStudy DesignNo. of PtsPrior Op/RT/STWHO Grade*Best Radiographic Response*PFSMedian OS
NAIIIIIISDMRPRCRPDMedianPFS6      
Norden et al., 2009Erlotinib, gefitinibEGFR TKIPhase II2525/21/10089880001710 wks28%23 mos
Wen et al., 2009ImatinibPDGFR TKIPhase II2222/20/7012559000102 mos29.4%NA
Horak et al., 2012ImatinibPDGFR TKIRetrospective9NA01267000216 mos66.7%42 mos
Kaley et al., 2015SunitinibVEGFR + PDGFR TKIPhase II3636/35/NA003062501185.2 mos42%25 mos
Lou et al., 2012BevacizumabAnti–VEGF antibodyRetrospective1414/11/9155311010217.9 mos86%NA
Nayak et al., 2012BevacizumabAnti–VEGF antibodyRetrospective1515/15/7006913200026 wks43.8%15 mos
Nunes et al., 2013BevacizumabAnti–VEGF antibodyRetrospective15NA15NANANA14010020 mos93%NA
Alanin et al., 2015BevacizumabAnti–VEGF antibodyRetrospective7NANANANANA20500NANANA
Shih et al., 2016Bevacizumab, everolimusAnti–VEGF antibodyPhase II1716/12/3147515000122 mos69%23.8 mos
Raizer et al., 2014VatalanibVEGFR + PDGFR TKIPhase II2525/24/11121481401NA67 mos60%26 mos

TKI = tyrosine kinase inhibitor; VEGFR = VEGF receptor.

Data missing for some cases; therefore, values do not reflect total number of patients for each study.

Vascular Endothelial Growth Factor

Aberrant angiogenesis is a shared characteristic and therapeutic target in many cancers. Vascular endothelial growth factor (VEGF) is a potent activator of angiogenesis with expression levels that correlate with meningioma grade.43 It is also associated with phenotypic characteristics including peritumoral edema and necrosis.22,43 Vascular endothelial growth factor signaling further cross-talks with platelet-derived growth factor (PDGF) signaling, another process that has been explored in the treatment of refractory meningiomas, as discussed below.45

Targeted anti-angiogenic therapy is a promising avenue for meningioma because of robust pharmaceutical development and VEGF expression in meningioma. In two recent retrospective case series, bevacizumab, a monoclonal antibody against VEGF-A, has shown efficacy in maintaining stable disease in meningiomas refractive to multiple treatment modalities.45,52 In one of these studies, bevacizumab led to a median PFS of 17.9 months and PFS6 of 85.7% among 14 patients with WHO grade I–III meningiomas.45 A retrospective review of bevacizumab for NF2-associated vestibular schwannomas and meningiomas revealed a radiographic response, defined as at least 20% volumetric shrinkage, in 29% of the meningiomas for a median duration of 3.7 months.56 These responses were generally short-lived, however, as median PFS was 15 months.

Platelet-Derived Growth Factor

Models of meningioma highlight the important role of PDGF in tumor development and transformation. Antibodies against PDGF variants inhibit meningioma growth in vitro, and the induction of PDGFβ expression in mouse arachnoid is sufficient to generate meningioma.58,69 The expression level of certain PDGF and PDGF receptor (PDGFR) subtypes correlates with tumor grade.75 The PDGFR inhibitor regorafenib has shown increased survival in in vivo testing using an orthotopic mouse model.70 Imatinib mesylate inhibits PDGFR as well as c-Kit and c-Abl, rendering the drug a potential treatment for refractory meningioma. A phase II trial testing imatinib showed modest results, however, with more cases demonstrating radiological progression rather than stable disease.73 A retrospective case series of tumors with positive immunohistological staining for PDGFR demonstrated a median PFS and PFS6 of 16 months and 66.7%, respectively.32

Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor with activity against the receptors for both VEGF and PDGF and reduces meningioma cell DNA synthesis, viability, and migration in vitro.3 A phase II trial of sunitinib for high-grade meningioma refractory to surgery and radiotherapy yielded a median PFS of 5.2 months and median OS of 25 months.38 Of interest, a case report on sunitinib for a recurrent, rapidly growing WHO grade II skull base meningioma documented a marked reduction of tumor volume that caused cerebrospinal fluid leakage.59 Vatalanib is another multi-targeted receptor tyrosine kinase inhibitor that has exhibited modest therapeutic efficacy in a phase II trial for refractory meningioma; grade II cases in the trial had a 7-month median PFS and 26-month median OS.60

Epidermal Growth Factor

Epidermal growth factor (EGF) and the EGF receptor (EGFR) represent other therapeutic targets. Higher expression levels are associated with benign meningiomas.51 A phase II trial of erlotinib or gefitinib, two targeted EGFR inhibitors, for recurrent meningioma demonstrated a median PFS of 10 weeks and PFS6 of 28%.63 The limited efficacy of EGFR inhibitors may be partially explained by differing EGFR expression levels of the trial participants.

Other Pathways

Other pathways involved in cellular growth, cell cycle regulation, transcriptional regulation, and apoptosis have been implicated in meningioma tumorigenesis and growth. Tumor growth factor (TGF) α expression is associated with recurrence and is negatively associated with survival.44 Expression of TGFβ increases activity of the SMAD signaling pathway.35 In addition, the expression of TGFβ receptor III is associated with higher-grade meningioma.36

Cyclins and cyclin-dependent kinases (CDKs) regulate cell cycle progression and contribute to the hallmark over-proliferation associated with cancer. Cyclin D1 expression is associated with an increased tumor grade and recurrence in meningioma.16 A screen for compounds to identify in vitro tumor growth inhibitors identified silvestrol as an inhibitor that putatively acts through cyclin downregulation that induces G2/M cell cycle arrest.57

Histone deacetylase (HDAC) inhibitors exert cytostatic effects on replicating cells by hyper-acetylating DNA. The HDAC inhibitor AR-42 induces meningioma apoptosis in vitro.8 It has also caused tumor regression in a xenograft mouse model of meningioma.8 A truncated form of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) that cannot initiate apoptotic signaling is correlated with meningioma grade.42

Molecularly Targeted Therapies From Genomic Analyses

Next-generation sequencing technology has yielded insights into potential oncogenic drivers of meningioma. Identified mutations include AKT1, SMO, KLF4, TRAF7, PIK3CA, SUFU, BAP1, SMARCB1/E, POL2RA, and others, in addition to the well-characterized NF2.1,7,17,66 Screening tumors prior to adjuvant therapy may improve the tailoring of individual regimens and trial stratification. BAP1 mutations highlight additional benefits of genomic screening, including those for possible syndromic patients.

PI3K/AKT/mTOR Pathway

The phosphoinositol-3 kinase (PI3K) pathway transduces growth factor signals and is upregulated in many cancers. Activation of PI3K leads to the phosphorylation and activation of alpha serine/threonine-protein kinase (AKT), which directly activates mammalian target of rapamycin (mTOR). AKT1 and PI3KCA mutations were identified in 9% and 7% of meningiomas, respectively, which are largely WHO grade I tumors.1,28,50 AKT1-mutant meningiomas demonstrate a proclivity for the anterior fossa skull base (19%).

AKT1 mutations, observed nearly exclusively in non-NF2 altered tumors, have generated particular excitement due to the presence of inhibitors currently in clinical trial. A case of metastatic, highly refractory meningioma that demonstrated ex vivo AKT inhibitor sensitivity had stable disease up to 1 year after initiating AKT inhibitor therapy with AZD5363.71 The role of AKT1 inhibition in the treatment of recurrent or progressive meningioma is currently in clinical trial (see below).

SMO

Mutations in SMO have been detected in about 6% of non-NF2 altered meningiomas, with the majority of SMO-altered tumors found at the skull base, particularly at the olfactory groove.6,17 Up to 28% of olfactory groove meningiomas harbor SMO mutations, and this molecular signature may also portend a poorer prognosis among WHO grade I olfactory groove tumors.6 A phase II trial is underway to explore the efficacy of SMO inhibition in recurrent or progressive meningioma.

BAP1

Breast cancer type 1 susceptibility protein (BRCA1)–associated protein-1 (BAP1) is a tumor suppressor that acts via deubiquitinase activity on nucleosomes, and BAP1 inactivating mutations have been identified in meningiomas with rhabdoid morphology.66 BAP1-mutant meningiomas have been found to be at least WHO grade II and clinically aggressive. The presence of BAP1 mutations confers an elevated risk for multiple types of cancer, so knowledge of their expression could modify an individual’s tumor screening and surveillance. Enhancer of zeste homolog 2 (EZH2) inhibitors and their homologs have demonstrated in vitro inhibition of BAP1-mutant mesotheliomas, which have elevated EZH2 mRNA levels. The EZH2 inhibitor tazemetostat is currently undergoing clinical trial in BAP1-deficient relapsed or refractory malignant mesothelioma (NCT02860286, http://www.clinicaltrials.gov). Enhancer of zeste homolog 2 is similarly upregulated in high-grade meningioma and may present an opportunity for targeted inhibition.31

Immunotherapy

Immunotherapy in refractory meningioma dates to initial experiences with interferon (IFN)-α after it was shown to reduce meningioma growth by 70%–100% in vitro.41 A phase II pilot study testing IFN-α on 6 recurrent meningioma cases showed a positive response to treatment with stable disease or a slight regression.37 Another phase II trial on 35 WHO grade I meningiomas refractory to surgery, radiation, and chemotherapy demonstrated a favorable median PFS of 7 months and PFS6 of 54%.12 A similar trial on high-grade meningiomas demonstrated a median PFS of only 3 months and PFS6 of 17%.11

Despite these initially grim results, several lines of evidence support a role for immunotherapy in meningioma.5 First, these tumors recruit immune populations, especially monocytes and cytotoxic T cells, with higher concentrations of macrophages in higher-grade tumors.27 Second, half of the mutations found in meningioma are predicted to be neo-antigenic with a higher number observed in high-grade tumors.4 Third, meningiomas exist outside the blood-brain barrier and may be modulated by the systemic immune response. Fourth, and most salient for therapeutics, high-grade meningiomas with higher expressions of the immune checkpoint markers programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1) are associated with worse survival, independent of tumor grade, extent of resection, and prior recurrence.30 Programmed cell death protein 1 is a cell surface receptor on T cells and binds PD-L1 on antigen-presenting cells and tumors cells to inhibit T-cell activation. Antibodies directed against the PD-1/PD-L1 axis strengthen the immune response and have achieved objective responses in several cancers. Anaplastic meningioma cells highly express PD-L1, suggesting that anti–PD-1/PD-L1 inhibitors may offer clinical efficacy for these tumors.

A report of the PD-1 inhibitor nivolumab for lung cancer in a patient with concurrent meningioma demonstrated a 24% radiographic volume reduction in the meningioma.20 Trials of nivolumab (NCT03173950, http://www.clinicaltrials.gov) and another PD-1 inhibitor, pembrolizumab (NCT03279692, http://www.clinicaltrials.gov), for meningioma are currently recruiting participants.

Combinatorial Pharmacological Therapies

Targeted therapies have great potential in personalized medicine by allowing each patient’s mutagenic profile to guide their treatment. An inherent limitation to this paradigm is the “one mutation, one drug” assumption. Intratumoral genomic heterogeneity renders subpopulations of tumor cells immune to therapies targeted to alterations found in neighboring cell populations, resulting in the subsequent outgrowth of these resistant clones. Combinatorial therapies mitigate this problem by targeting multiple pathways simultaneously. The intratumoral genomic heterogeneity observed in recurrent meningioma underlies the need for therapeutic approaches that efficaciously target different subpopulations.

Authors of recent studies have examined the safety and efficacy of combinatorial therapy in meningioma with promising results. In a phase II trial of hydroxyurea and imatinib for patients with progressive or recurrent meningioma, the majority of cases demonstrated stable disease, though no cases showed a positive radiological response.61 The combination was well tolerated and PFS6 for all cases was 61.9%. A randomized phase II trial testing the same combinatorial therapy was prematurely concluded because of slow enrollment, although all patients who enrolled demonstrated stable disease.49 A phase I/II trial of hydroxyurea and verapamil, a calcium-channel antagonist that enhances hydroxyurea’s cytostatic effect in in vitro and in vivo models of meningioma, demonstrated side effects in 86% of patients and a median PFS and PFS6 of 8 months and 85%, respectively, in refractory meningioma.21

Current Trials

Currently, there are 8 active, enrolling trials assessing novel medical strategies for meningioma, focusing on cytotoxic chemotherapy, targeted therapy, combinatorial therapy, and immunotherapy (Table 3). These include phase 0 trials of AR-42 (NCT02282917) and the mTOR inhibitor everolimus (NCT01880749, not recruiting). AR-42 will gauge the efficacy of epigenomic manipulation in meningioma treatment, while everolimus will target the mTOR pathway, which has been shown to be overactive in some meningiomas. Currently enrolling phase II trials include the cyclin/CDK inhibitor ribociclib (NCT02933736); the hedgehog pathway inhibitor vismodegib and the focal adhesion kinase inhibitor GSK2256098 (NCT02523014); the MEK1 inhibitor selumetinib (NCT03095248); the PD-1 inhibitors nivolumab (NCT03173950) and pembrolizumab (NCT03279692); and a combinatorial regimen consisting of everolimus and octreotide (NCT02333565, status unknown).

TABLE 3.

Active, enrolling trials of medical therapies for meningioma registered on clinicaltrials.gov

Official Study TitleDrugPhaseNo. of ParticipantsSponsorCompletion DateTrial Registration No.
Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and MeningiomaAR-42020Massachusetts Eye and Ear Infirmary, Johns Hopkins University, Mayo Clinic, Stanford University, Ohio State University, Nationwide Children’s HospitalAugust 2018NCT02282917
Combination of Everolimus and Octreotide LAR in Aggressive Recurrent MeningiomasEverolimus, octreotideII20Assistance Publique Hopitaux de MarseilleJanuary 2018NCT02333565
Ribociclib (LEE011) in Preoperative Glioma and Meningioma PatientsRibociclib0/II48St. Joseph’s Hospital and Medical CenterDecember 2018NCT02933736
A Study of Nivolumab in Adult Participants With Recurrent High-Grade MeningiomaNivolumabII25Dana-Farber Cancer InstituteAugust 2018NCT02648997
Vismodegib and FAK Inhibitor GSK2256098 in Treating Patients With Progressive MeningiomasVismodegib, GSK2256098II69Alliance for Clinical Trials in Oncology, National Cancer Institute, GlaxoSmithKline, Genentech Inc., Brain Science FoundationAugust 2019NCT02523014
Phase II Trial of Pembrolizumab in Recurrent or Residual High Grade MeningiomaPembrolizumabII26Massachusetts General Hospital, Merck Sharp & Dohme Corp.March 2021NCT03279692
Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors (SEL-TH-1601)SelumetinibII34Children’s Hospital Medical Center, AstraZenecaMay 2020NCT03095248
Immune Checkpoint Inhibitor Nivolumab in People With Select Rare CNS CancersNivolumabII180National Cancer InstituteDecember 2021NCT03173950

Prior trials have demonstrated that no individual agent or class of agents is likely to produce a favorable response in all recurrent and progressive meningiomas. Rather, different therapeutics will probably be more efficacious for certain tumors depending on the genomic makeup of the tumor and the local immune microenvironment among other factors. The enrolling trials on ribociclib, vismodegib, and selumetinib incorporate genomic data for inclusion criteria, which may provide guidance in predicting biological subsets of meningiomas that will respond favorably.

Future Directions

Expanding knowledge of meningioma biology is powering the development of novel therapeutics to challenge this disease. Genomics and epigenetic signatures may also improve prognostication and trial stratification. Evolving quantitative radiomic characterizations of meningioma may provide additional tumor stratification tools and upfront prediction of tumor behavior on initial diagnosis. Finally, acknowledging the cellular heterogeneity of meningioma conferred by cancer stem cells provides a parallel avenue for therapeutic discoveries in multidrug-resistant meningioma.

Conclusions

Few options exist to medically manage refractory and progressive cases of meningioma. Advances in molecular biology and genomics have led to the development of novel molecular inhibitors that can target aberrantly expressed oncogenic and immunomodulatory molecules. Emerging trials for meningioma are beginning to integrate genomic inclusion criteria, with hope to refine future clinical outcomes within the precision medicine paradigm.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: all authors. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Dunn. Administrative/technical/material support: all authors. Study supervision: all authors.

Supplemental Information

Previous Presentations

Portions of this paper were presented in poster format at the 2016 New England Neurosurgical Society conference.

References

  • 1

    Abedalthagafi MBi WLAizer AAMerrill PHBrewster RAgarwalla PK: Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro Oncol 18:6496552016

  • 2

    Alanin MCKlausen CCaye-Thomasen PThomsen CFugleholm KPoulsgaard L: Effect of bevacizumab on intracranial meningiomas in patients with neurofibromatosis type 2 — a retrospective case series. Int J Neurosci 126:100210062015

  • 3

    Andrae NKirches EHartig RHaase DKeilhoff GKalinski T: Sunitinib targets PDGF-receptor and Flt3 and reduces survival and migration of human meningioma cells. Eur J Cancer 48:183118412012

  • 4

    Bi WLGreenwald NFAbedalthagafi MWala JGibson WJAgarwalla PK: Genomic landscape of high-grade meningiomas. NPJ Genom Med 2:152017

  • 5

    Bi WLWu WWSantagata SReardon DADunn IF: Checkpoint inhibition in meningiomas. Immunotherapy 8:7217312016

  • 6

    Boetto JBielle FSanson MPeyre MKalamarides M: SMO mutation status defines a distinct and frequent molecular subgroup in olfactory groove meningiomas. Neuro Oncol 19:3453512017

  • 7

    Brastianos PKHorowitz PMSantagata SJones RTMcKenna AGetz G: Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 45:2852892013

  • 8

    Burns SSAkhmametyeva EMOblinger JLBush MLHuang JSenner V: Histone deacetylase inhibitor AR-42 differentially affects cell-cycle transit in meningeal and meningioma cells, potently inhibiting NF2-deficient meningioma growth. Cancer Res 73:7928032013

  • 9

    Chamberlain MC: Adjuvant combined modality therapy for malignant meningiomas. J Neurosurg 84:7337361996

  • 10

    Chamberlain MC: Hydroxyurea for recurrent surgery and radiation refractory high-grade meningioma. J Neurooncol 107:3153212012

  • 11

    Chamberlain MC: IFN-α for recurrent surgery- and radiation-refractory high-grade meningioma: a retrospective case series. CNS Oncol 2:2272352013

  • 12

    Chamberlain MCGlantz MJ: Interferon-alpha for recurrent World Health Organization grade 1 intracranial meningiomas. Cancer 113:214621512008

  • 13

    Chamberlain MCJohnston SK: Hydroxyurea for recurrent surgery and radiation refractory meningioma: a retrospective case series. J Neurooncol 104:7657712011

  • 14

    Chamberlain MCTsao-Wei DDGroshen S: Salvage chemotherapy with CPT-11 for recurrent meningioma. J Neurooncol 78:2712762006

  • 15

    Chamberlain MCTsao-Wei DDGroshen S: Temozolomide for treatment-resistant recurrent meningioma. Neurology 62:121012122004

  • 16

    Cheng GZhang LLv WDong CWang YZhang J: Overexpression of cyclin D1 in meningioma is associated with malignancy grade and causes abnormalities in apoptosis, invasion and cell cycle progression. Med Oncol 32:4392015

  • 17

    Clark VEErson-Omay EZSerin AYin JCotney JOzduman K: Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339:107710802013

  • 18

    Fuentes SChinot ODufour HPaz-Paredes AMétellus PBarrie-Attarian M: [Hydroxyurea treatment for unresectable meningioma.] Neurochirurgie 50:4614672004 (Fr)

  • 19

    García-Luna PPRelimpio FPumar APereira JLLeal-Cerro ATrujillo F: Clinical use of octreotide in unresectable meningiomas. A report of three cases. J Neurosurg Sci 37:2372411993

  • 20

    Gelerstein EBerger AJonas-Kimchi TStrauss IKanner AABlumenthal DT: Regression of intracranial meningioma following treatment with nivolumab: Case report and review of the literature. J Clin Neurosci 37:51532017

  • 21

    Gerlinger MRowan AJHorswell SMath MLarkin JEndesfelder D: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:8838922012

  • 22

    Goldman CKBharara SPalmer CAVitek JTsai JCWeiss HL: Brain edema in meningiomas is associated with increased vascular endothelial growth factor expression. Neurosurgery 40:126912771997

  • 23

    Goodwin JWCrowley JEyre HJStafford BJaeckle KATownsend JJ: A phase II evaluation of tamoxifen in unresectable or refractory meningiomas: a Southwest Oncology Group study. J Neurooncol 15:75771993

  • 24

    Graillon TRomano DDefilles CSaveanu AMohamed AFigarella-Branger D: Octreotide therapy in meningiomas: in vitro study, clinical correlation, and literature review. J Neurosurg 127:6606692017

  • 25

    Grunberg SMWeiss MHRussell CASpitz IMAhmadi JSadun A: Long-term administration of mifepristone (RU486): clinical tolerance during extended treatment of meningioma. Cancer Invest 24:7277332006

  • 26

    Grunberg SMWeiss MHSpitz IMAhmadi JSadun ARussell CA: Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. J Neurosurg 74:8618661991

  • 27

    Grund SSchittenhelm JRoser FTatagiba MMawrin CKim YJ: The microglial/macrophagic response at the tumour-brain border of invasive meningiomas. Neuropathol Appl Neurobiol 35:82882009

  • 28

    Gunel M: Meningioma driver mutations determine their anatomical site of origin. Neurosurgery 63 (Suppl 1):1852016 (Abstract)

  • 29

    Hahn BMSchrell UMSauer RFahlbusch RGanslandt OGrabenbauer GG: Prolonged oral hydroxyurea and concurrent 3d-conformal radiation in patients with progressive or recurrent meningioma: results of a pilot study. J Neurooncol 74:1571652005

  • 30

    Han SJReis GKohanbash GShrivastav SMagill STMolinaro AM: Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma. J Neurooncol 130:5435522016

  • 31

    Harmancı ASYoungblood MWClark VECoşkun SHenegariu ODuran D: Integrated genomic analyses of de novo pathways underlying atypical meningiomas. Nat Commun 8:144332017

  • 32

    Horak PWöhrer AHassler MHainfellner JPreusser MMarosi C: Imatinib mesylate treatment of recurrent meningiomas in preselected patients: a retrospective analysis. J Neurooncol 109:3233302012

  • 33

    Ji YRankin CGrunberg SSherrod AEAhmadi JTownsend JJ: Double-blind phase III randomized trial of the antiprogestin agent mifepristone in the treatment of unresectable meningioma: SWOG S9005. J Clin Oncol 33:409340982015

  • 34

    Johnson DRKimmel DWBurch PACascino TLGiannini CWu W: Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma. Neuro Oncol 13:5305352011

  • 35

    Johnson MDOkediji EWoodard A: Transforming growth factor-beta effects on meningioma cell proliferation and signal transduction pathways. J Neurooncol 66:9162004

  • 36

    Johnson MDShaw AKO’Connell MJSim FJMoses HL: Analysis of transforming growth factor β receptor expression and signaling in higher grade meningiomas. J Neurooncol 103:2772852011

  • 37

    Kaba SEDeMonte FBruner JMKyritsis APJaeckle KALevin V: The treatment of recurrent unresectable and malignant meningiomas with interferon alpha-2B. Neurosurgery 40:2712751997

  • 38

    Kaley TJWen PSchiff DLigon KHaidar SKarimi S: Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma. Neuro Oncol 17:1161212015

  • 39

    Karsy MHoang NBarth TBurt LDunson WGillespie DL: Combined hydroxyurea and verapamil in the clinical treatment of refractory meningioma: human and orthotopic xenograft studies. World Neurosurg 86:2102192016

  • 40

    Kim MSYu DWJung YJKim SWChang CHKim OL: Long-term follow-up result of hydroxyurea chemotherapy for recurrent meningiomas. J Korean Neurosurg Soc 52:5175222012

  • 41

    Koper JWZwarthoff ECHagemeijer ABraakman RAvezaat CJBergström M: Inhibition of the growth of cultured human meningioma cells by recombinant interferon-alpha. Eur J Cancer 27:4164191991

  • 42

    Koschny RKrupp WXu LXMueller WCBauer MSinn P: WHO grade related expression of TRAIL-receptors and apoptosis regulators in meningioma. Pathol Res Pract 211:1091162015

  • 43

    Lee SHLee YSHong YGKang CS: Significance of COX-2 and VEGF expression in histopathologic grading and invasiveness of meningiomas. APMIS 122:16242014

  • 44

    Linggood RMHsu DWEfird JTPardo FS: TGF alpha expression in meningioma—tumor progression and therapeutic response. J Neurooncol 26:45511995

  • 45

    Lou ESumrall ALTurner SPeters KBDesjardins AVredenburgh JJ: Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series. J Neurooncol 109:63702012

  • 46

    Marincek NRadojewski PDumont RABrunner PMüller-Brand JMaecke HR: Somatostatin receptor-targeted radiopeptide therapy with 90Y-DOTATOC and 177Lu-DOTATOC in progressive meningioma: long-term results of a phase II clinical trial. J Nucl Med 56:1711762015

  • 47

    Markwalder TMSeiler RWZava DT: Antiestrogenic therapy of meningiomas—a pilot study. Surg Neurol 24:2452491985

  • 48

    Mason WPGentili FMacdonald DRHariharan SCruz CRAbrey LE: Stabilization of disease progression by hydroxyurea in patients with recurrent or unresectable meningioma. J Neurosurg 97:3413462002

  • 49

    Mazza EBrandes AZanon SEoli MLombardi GFaedi M: Hydroxyurea with or without imatinib in the treatment of recurrent or progressive meningiomas: a randomized phase II trial by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Cancer Chemother Pharmacol 77:1151202016

  • 50

    Mei YBi WLGreenwald NFAgar NYBeroukhim RDunn GP: Genomic profile of human meningioma cell lines. PLoS One 12:e01783222017

  • 51

    Narla SUppin MSSaradhi MVSahu BPPurohit AKSundaram C: Assessment of expression of epidermal growth factor receptor and p53 in meningiomas. Neurol India 62:37412014

  • 52

    Nayak LIwamoto FMRudnick JDNorden ADLee EQDrappatz J: Atypical and anaplastic meningiomas treated with bevacizumab. J Neurooncol 109:1871932012

  • 53

    Newton HBScott SRVolpi C: Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up. Br J Neurosurg 18:4954992004

  • 54

    Newton HBSlivka MAStevens C: Hydroxyurea chemotherapy for unresectable or residual meningioma. J Neurooncol 49:1651702000

  • 55

    Norden ADLigon KLHammond SNMuzikansky AReardon DAKaley TJ: Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma. Neurology 84:2802862015

  • 56

    Nunes FPMerker VLJennings DCaruso PAdi Tomaso EMuzikansky A: Bevacizumab treatment for meningiomas in NF2: a retrospective analysis of 15 patients. PLoS One 8:e599412013

  • 57

    Oblinger JLBurns SSHuang JPan LRen YShen R: Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation. Exp Neurol 299:2993072018

  • 58

    Peyre MSalaud CClermont-Taranchon ENiwa-Kawakita MGoutagny SMawrin C: PDGF activation in PGDS-positive arachnoid cells induces meningioma formation in mice promoting tumor progression in combination with Nf2 and Cdkn2ab loss. Oncotarget 6:32713327222015

  • 59

    Raheja AColman HPalmer CACouldwell WT: Dramatic radiographic response resulting in cerebrospinal fluid rhinorrhea associated with sunitinib therapy in recurrent atypical meningioma: case report. J Neurosurg 127:9659702017

  • 60

    Raizer JJGrimm SARademaker AChandler JPMuro KHelenowski I: A phase II trial of PTK787/ZK 222584 in recurrent or progressive radiation and surgery refractory meningiomas. J Neurooncol 117:931012014

  • 61

    Reardon DANorden ADDesjardins AVredenburgh JJHerndon JE IICoan A: Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma. J Neurooncol 106:4094152012

  • 62

    Rosenthal MAAshley DLCher L: Treatment of high risk or recurrent meningiomas with hydroxyurea. J Clin Neurosci 9:1561582002

  • 63

    Sanford MScott LJ: Gefitinib: a review of its use in the treatment of locally advanced/metastatic non-small cell lung cancer. Drugs 69:230323282009

  • 64

    Schrell UMRittig MGAnders MKoch UHMarschalek RKiesewetter F: Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea. J Neurosurg 86:8408441997

  • 65

    Schulz CMathieu RKunz UMauer UM: Treatment of unresectable skull base meningiomas with somatostatin analogs. Neurosurg Focus 30(5):E112011

  • 66

    Shankar GMAbedalthagafi MVaubel RAMerrill PHNayyar NGill CM: Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro Oncol 19:5355452017

  • 67

    Shih KCChowdhary SRosenblatt PWeir AB IIIShepard GCWilliams JT: A phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma. J Neurooncol 129:2812882016

  • 68

    Simó MArgyriou AAMacià MPlans GMajós CVidal N: Recurrent high-grade meningioma: a phase II trial with somatostatin analogue therapy. Cancer Chemother Pharmacol 73:9199232014

  • 69

    Todo TAdams EFFahlbusch RDingermann TWerner H: Autocrine growth stimulation of human meningioma cells by platelet-derived growth factor. J Neurosurg 84:8528591996

  • 70

    Tuchen MWilisch-Neumann ADaniel EABaldauf LPachow DScholz J: Receptor tyrosine kinase inhibition by regorafenib/sorafenib inhibits growth and invasion of meningioma cells. Eur J Cancer 73:9212017

  • 71

    Weller MRoth PSahm FBurghardt ISchuknecht BRushing EJ: Durable control of metastatic AKT1-mutant WHO Grade 1 meningothelial meningioma by the AKT inhibitor, AZD5363. J Natl Cancer Inst 109:142017

  • 72

    Wen PYQuant EDrappatz JBeroukhim RNorden AD: Medical therapies for meningiomas. J Neurooncol 99:3653782010

  • 73

    Wen PYYung WKLamborn KRNorden ADCloughesy TFAbrey LE: Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08). Neuro Oncol 11:8538602009

  • 74

    Weston GJMartin AJMufti GJStrong AJGleeson MJ: Hydroxyurea treatment of meningiomas: a pilot study. Skull Base 16:1571602006

  • 75

    Yang SYXu GM: Expression of PDGF and its receptor as well as their relationship to proliferating activity and apoptosis of meningiomas in human meningiomas. J Clin Neurosci 8 (Suppl 1):49532001

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Correspondence Ian F. Dunn: Brigham and Women’s Hospital, Boston, MA. idunn@partners.org.

INCLUDE WHEN CITING DOI: 10.3171/2018.1.FOCUS17754.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

References

1

Abedalthagafi MBi WLAizer AAMerrill PHBrewster RAgarwalla PK: Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro Oncol 18:6496552016

2

Alanin MCKlausen CCaye-Thomasen PThomsen CFugleholm KPoulsgaard L: Effect of bevacizumab on intracranial meningiomas in patients with neurofibromatosis type 2 — a retrospective case series. Int J Neurosci 126:100210062015

3

Andrae NKirches EHartig RHaase DKeilhoff GKalinski T: Sunitinib targets PDGF-receptor and Flt3 and reduces survival and migration of human meningioma cells. Eur J Cancer 48:183118412012

4

Bi WLGreenwald NFAbedalthagafi MWala JGibson WJAgarwalla PK: Genomic landscape of high-grade meningiomas. NPJ Genom Med 2:152017

5

Bi WLWu WWSantagata SReardon DADunn IF: Checkpoint inhibition in meningiomas. Immunotherapy 8:7217312016

6

Boetto JBielle FSanson MPeyre MKalamarides M: SMO mutation status defines a distinct and frequent molecular subgroup in olfactory groove meningiomas. Neuro Oncol 19:3453512017

7

Brastianos PKHorowitz PMSantagata SJones RTMcKenna AGetz G: Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 45:2852892013

8

Burns SSAkhmametyeva EMOblinger JLBush MLHuang JSenner V: Histone deacetylase inhibitor AR-42 differentially affects cell-cycle transit in meningeal and meningioma cells, potently inhibiting NF2-deficient meningioma growth. Cancer Res 73:7928032013

9

Chamberlain MC: Adjuvant combined modality therapy for malignant meningiomas. J Neurosurg 84:7337361996

10

Chamberlain MC: Hydroxyurea for recurrent surgery and radiation refractory high-grade meningioma. J Neurooncol 107:3153212012

11

Chamberlain MC: IFN-α for recurrent surgery- and radiation-refractory high-grade meningioma: a retrospective case series. CNS Oncol 2:2272352013

12

Chamberlain MCGlantz MJ: Interferon-alpha for recurrent World Health Organization grade 1 intracranial meningiomas. Cancer 113:214621512008

13

Chamberlain MCJohnston SK: Hydroxyurea for recurrent surgery and radiation refractory meningioma: a retrospective case series. J Neurooncol 104:7657712011

14

Chamberlain MCTsao-Wei DDGroshen S: Salvage chemotherapy with CPT-11 for recurrent meningioma. J Neurooncol 78:2712762006

15

Chamberlain MCTsao-Wei DDGroshen S: Temozolomide for treatment-resistant recurrent meningioma. Neurology 62:121012122004

16

Cheng GZhang LLv WDong CWang YZhang J: Overexpression of cyclin D1 in meningioma is associated with malignancy grade and causes abnormalities in apoptosis, invasion and cell cycle progression. Med Oncol 32:4392015

17

Clark VEErson-Omay EZSerin AYin JCotney JOzduman K: Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339:107710802013

18

Fuentes SChinot ODufour HPaz-Paredes AMétellus PBarrie-Attarian M: [Hydroxyurea treatment for unresectable meningioma.] Neurochirurgie 50:4614672004 (Fr)

19

García-Luna PPRelimpio FPumar APereira JLLeal-Cerro ATrujillo F: Clinical use of octreotide in unresectable meningiomas. A report of three cases. J Neurosurg Sci 37:2372411993

20

Gelerstein EBerger AJonas-Kimchi TStrauss IKanner AABlumenthal DT: Regression of intracranial meningioma following treatment with nivolumab: Case report and review of the literature. J Clin Neurosci 37:51532017

21

Gerlinger MRowan AJHorswell SMath MLarkin JEndesfelder D: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:8838922012

22

Goldman CKBharara SPalmer CAVitek JTsai JCWeiss HL: Brain edema in meningiomas is associated with increased vascular endothelial growth factor expression. Neurosurgery 40:126912771997

23

Goodwin JWCrowley JEyre HJStafford BJaeckle KATownsend JJ: A phase II evaluation of tamoxifen in unresectable or refractory meningiomas: a Southwest Oncology Group study. J Neurooncol 15:75771993

24

Graillon TRomano DDefilles CSaveanu AMohamed AFigarella-Branger D: Octreotide therapy in meningiomas: in vitro study, clinical correlation, and literature review. J Neurosurg 127:6606692017

25

Grunberg SMWeiss MHRussell CASpitz IMAhmadi JSadun A: Long-term administration of mifepristone (RU486): clinical tolerance during extended treatment of meningioma. Cancer Invest 24:7277332006

26

Grunberg SMWeiss MHSpitz IMAhmadi JSadun ARussell CA: Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. J Neurosurg 74:8618661991

27

Grund SSchittenhelm JRoser FTatagiba MMawrin CKim YJ: The microglial/macrophagic response at the tumour-brain border of invasive meningiomas. Neuropathol Appl Neurobiol 35:82882009

28

Gunel M: Meningioma driver mutations determine their anatomical site of origin. Neurosurgery 63 (Suppl 1):1852016 (Abstract)

29

Hahn BMSchrell UMSauer RFahlbusch RGanslandt OGrabenbauer GG: Prolonged oral hydroxyurea and concurrent 3d-conformal radiation in patients with progressive or recurrent meningioma: results of a pilot study. J Neurooncol 74:1571652005

30

Han SJReis GKohanbash GShrivastav SMagill STMolinaro AM: Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma. J Neurooncol 130:5435522016

31

Harmancı ASYoungblood MWClark VECoşkun SHenegariu ODuran D: Integrated genomic analyses of de novo pathways underlying atypical meningiomas. Nat Commun 8:144332017

32

Horak PWöhrer AHassler MHainfellner JPreusser MMarosi C: Imatinib mesylate treatment of recurrent meningiomas in preselected patients: a retrospective analysis. J Neurooncol 109:3233302012

33

Ji YRankin CGrunberg SSherrod AEAhmadi JTownsend JJ: Double-blind phase III randomized trial of the antiprogestin agent mifepristone in the treatment of unresectable meningioma: SWOG S9005. J Clin Oncol 33:409340982015

34

Johnson DRKimmel DWBurch PACascino TLGiannini CWu W: Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma. Neuro Oncol 13:5305352011

35

Johnson MDOkediji EWoodard A: Transforming growth factor-beta effects on meningioma cell proliferation and signal transduction pathways. J Neurooncol 66:9162004

36

Johnson MDShaw AKO’Connell MJSim FJMoses HL: Analysis of transforming growth factor β receptor expression and signaling in higher grade meningiomas. J Neurooncol 103:2772852011

37

Kaba SEDeMonte FBruner JMKyritsis APJaeckle KALevin V: The treatment of recurrent unresectable and malignant meningiomas with interferon alpha-2B. Neurosurgery 40:2712751997

38

Kaley TJWen PSchiff DLigon KHaidar SKarimi S: Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma. Neuro Oncol 17:1161212015

39

Karsy MHoang NBarth TBurt LDunson WGillespie DL: Combined hydroxyurea and verapamil in the clinical treatment of refractory meningioma: human and orthotopic xenograft studies. World Neurosurg 86:2102192016

40

Kim MSYu DWJung YJKim SWChang CHKim OL: Long-term follow-up result of hydroxyurea chemotherapy for recurrent meningiomas. J Korean Neurosurg Soc 52:5175222012

41

Koper JWZwarthoff ECHagemeijer ABraakman RAvezaat CJBergström M: Inhibition of the growth of cultured human meningioma cells by recombinant interferon-alpha. Eur J Cancer 27:4164191991

42

Koschny RKrupp WXu LXMueller WCBauer MSinn P: WHO grade related expression of TRAIL-receptors and apoptosis regulators in meningioma. Pathol Res Pract 211:1091162015

43

Lee SHLee YSHong YGKang CS: Significance of COX-2 and VEGF expression in histopathologic grading and invasiveness of meningiomas. APMIS 122:16242014

44

Linggood RMHsu DWEfird JTPardo FS: TGF alpha expression in meningioma—tumor progression and therapeutic response. J Neurooncol 26:45511995

45

Lou ESumrall ALTurner SPeters KBDesjardins AVredenburgh JJ: Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series. J Neurooncol 109:63702012

46

Marincek NRadojewski PDumont RABrunner PMüller-Brand JMaecke HR: Somatostatin receptor-targeted radiopeptide therapy with 90Y-DOTATOC and 177Lu-DOTATOC in progressive meningioma: long-term results of a phase II clinical trial. J Nucl Med 56:1711762015

47

Markwalder TMSeiler RWZava DT: Antiestrogenic therapy of meningiomas—a pilot study. Surg Neurol 24:2452491985

48

Mason WPGentili FMacdonald DRHariharan SCruz CRAbrey LE: Stabilization of disease progression by hydroxyurea in patients with recurrent or unresectable meningioma. J Neurosurg 97:3413462002

49

Mazza EBrandes AZanon SEoli MLombardi GFaedi M: Hydroxyurea with or without imatinib in the treatment of recurrent or progressive meningiomas: a randomized phase II trial by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Cancer Chemother Pharmacol 77:1151202016

50

Mei YBi WLGreenwald NFAgar NYBeroukhim RDunn GP: Genomic profile of human meningioma cell lines. PLoS One 12:e01783222017

51

Narla SUppin MSSaradhi MVSahu BPPurohit AKSundaram C: Assessment of expression of epidermal growth factor receptor and p53 in meningiomas. Neurol India 62:37412014

52

Nayak LIwamoto FMRudnick JDNorden ADLee EQDrappatz J: Atypical and anaplastic meningiomas treated with bevacizumab. J Neurooncol 109:1871932012

53

Newton HBScott SRVolpi C: Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up. Br J Neurosurg 18:4954992004

54

Newton HBSlivka MAStevens C: Hydroxyurea chemotherapy for unresectable or residual meningioma. J Neurooncol 49:1651702000

55

Norden ADLigon KLHammond SNMuzikansky AReardon DAKaley TJ: Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma. Neurology 84:2802862015

56

Nunes FPMerker VLJennings DCaruso PAdi Tomaso EMuzikansky A: Bevacizumab treatment for meningiomas in NF2: a retrospective analysis of 15 patients. PLoS One 8:e599412013

57

Oblinger JLBurns SSHuang JPan LRen YShen R: Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation. Exp Neurol 299:2993072018

58

Peyre MSalaud CClermont-Taranchon ENiwa-Kawakita MGoutagny SMawrin C: PDGF activation in PGDS-positive arachnoid cells induces meningioma formation in mice promoting tumor progression in combination with Nf2 and Cdkn2ab loss. Oncotarget 6:32713327222015

59

Raheja AColman HPalmer CACouldwell WT: Dramatic radiographic response resulting in cerebrospinal fluid rhinorrhea associated with sunitinib therapy in recurrent atypical meningioma: case report. J Neurosurg 127:9659702017

60

Raizer JJGrimm SARademaker AChandler JPMuro KHelenowski I: A phase II trial of PTK787/ZK 222584 in recurrent or progressive radiation and surgery refractory meningiomas. J Neurooncol 117:931012014

61

Reardon DANorden ADDesjardins AVredenburgh JJHerndon JE IICoan A: Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma. J Neurooncol 106:4094152012

62

Rosenthal MAAshley DLCher L: Treatment of high risk or recurrent meningiomas with hydroxyurea. J Clin Neurosci 9:1561582002

63

Sanford MScott LJ: Gefitinib: a review of its use in the treatment of locally advanced/metastatic non-small cell lung cancer. Drugs 69:230323282009

64

Schrell UMRittig MGAnders MKoch UHMarschalek RKiesewetter F: Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea. J Neurosurg 86:8408441997

65

Schulz CMathieu RKunz UMauer UM: Treatment of unresectable skull base meningiomas with somatostatin analogs. Neurosurg Focus 30(5):E112011

66

Shankar GMAbedalthagafi MVaubel RAMerrill PHNayyar NGill CM: Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro Oncol 19:5355452017

67

Shih KCChowdhary SRosenblatt PWeir AB IIIShepard GCWilliams JT: A phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma. J Neurooncol 129:2812882016

68

Simó MArgyriou AAMacià MPlans GMajós CVidal N: Recurrent high-grade meningioma: a phase II trial with somatostatin analogue therapy. Cancer Chemother Pharmacol 73:9199232014

69

Todo TAdams EFFahlbusch RDingermann TWerner H: Autocrine growth stimulation of human meningioma cells by platelet-derived growth factor. J Neurosurg 84:8528591996

70

Tuchen MWilisch-Neumann ADaniel EABaldauf LPachow DScholz J: Receptor tyrosine kinase inhibition by regorafenib/sorafenib inhibits growth and invasion of meningioma cells. Eur J Cancer 73:9212017

71

Weller MRoth PSahm FBurghardt ISchuknecht BRushing EJ: Durable control of metastatic AKT1-mutant WHO Grade 1 meningothelial meningioma by the AKT inhibitor, AZD5363. J Natl Cancer Inst 109:142017

72

Wen PYQuant EDrappatz JBeroukhim RNorden AD: Medical therapies for meningiomas. J Neurooncol 99:3653782010

73

Wen PYYung WKLamborn KRNorden ADCloughesy TFAbrey LE: Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08). Neuro Oncol 11:8538602009

74

Weston GJMartin AJMufti GJStrong AJGleeson MJ: Hydroxyurea treatment of meningiomas: a pilot study. Skull Base 16:1571602006

75

Yang SYXu GM: Expression of PDGF and its receptor as well as their relationship to proliferating activity and apoptosis of meningiomas in human meningiomas. J Clin Neurosci 8 (Suppl 1):49532001

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 235 235 68
PDF Downloads 594 594 120
EPUB Downloads 0 0 0

PubMed

Google Scholar