Meningiomas: Overview and New Directions in Therapy

Nancy Wang, MD; Matthias Osswald, MD

Disclosures

Semin Neurol. 2018;38(1):112-120. 

In This Article

Treatment

The lack of prospective, randomized clinical trials leads to an absence of recommendations with an evidence level A in the European Association of Neuro-Oncology guidelines for the diagnosis and treatment of meningiomas.[92] Treatment decisions are typically guided by tumor size, location, symptoms, age, and health status. Radiographically presumed asymptomatic meningiomas with no mass effect that are discovered incidentally may be observed and treated at the time of symptom onset, sustained growth, or encroachment of sensitive structures.[92,93] For observation, MRIs and clinical follow-ups should typically be done annually after an initial interval of 6 months.[92] Standard therapy otherwise consists of surgery and/or radiation, and systemic therapies should be considered in refractory cases, although data to support the latter are generally lacking.

Surgery and Radiation

Complete surgical excision of the tumor, surrounding dural attachment, and involved bone is recommended for symptomatic or progressively enlarging meningiomas.[77] For tumors in locations difficult to access surgically or in patients who are poor surgical candidates due to age and other comorbidities, either fractionated external beam radiation or, for smaller tumors, stereotactic radiosurgery (SRS) is recommended.[92,93] Adjuvant radiotherapy is obligatory for WHO grade III tumors and should be considered for WHO grade II tumors, particularly ones that are incompletely resected.[92] Radiotherapy can also be considered in incompletely resected WHO grade I meningiomas.[92] In the setting of tumor recurrence, surgery should be considered if accessible, with radiation as an alternative option.[92–94] Endovascular embolization is not generally recommended but can be used in selected cases preoperatively.[92]

Although adjuvant radiotherapy in anaplastic meningiomas has been shown to improve outcomes, data on atypical meningiomas have mainly supported improved local control and time to progression/recurrence.[95] A large retrospective study found that adjuvant radiotherapy following surgery of atypical meningiomas was associated with improved overall survival (OS) only in patients who underwent subtotal resection but not gross total resection.[96] The benefits of radiation should be weighed against the potential risks, with a 3.4 to 16.7% rate of treatment-related toxicity including cerebral necrosis, neurocognitive impairment, hypopituitarism, and radiation-induced tumors.[95]

Two large phase II trials evaluating the efficacy and optimum dose of radiotherapy have recently finished accrual. In the Radiation Therapy Oncology Group 0539 trial (NCT00895622), patients with low-risk meningioma were observed clinically, whereas patients with intermediate- or high-risk disease received radiotherapy. The study used 54 Gy for atypical meningioma following gross total resection, and 60 Gy in the case of subtotal resection, recurrent WHO grade II tumors, and all WHO grade III tumors. The European Organization for Research and Treatment of Cancer (EORTC) trial 22042–26042 (NCT00626730) similarly evaluated radiotherapy in postsurgical patients diagnosed with WHO grade II or III meningiomas: patients who were Simpson stage 1 to 3 received 60 Gy, whereas patients who were Simpson stage 4 to 5 received an additional 10-Gy boost. Results from both of these trials are pending at the present time. A randomized phase III trial is currently underway to evaluate the role of radiation versus observation following surgical resection of atypical meningiomas (ROAM/EORTC-1308).[97]

SRS has also been studied as an alternative to external beam radiation for residual or recurrent tumor < 35 mm in diameter in patients who are poor surgical candidates due to medical comorbidities or tumor location.[25,98–100] Five-year local control rates range from 86 to 99% for grade I meningiomas, with toxicity observed in 2.5 to 13% of patients, primarily symptomatic edema or injury to adjacent cranial nerves.[101,102] Recurrence rates after SRS in WHO grade II and III lesions are significantly higher, with 5-year progression-free survival (PFS) of 59 and 13%, respectively.[103] It is important to note that edema may be a more common adverse effect of SRS than external beam radiotherapy.[104] Several small retrospective studies have also found that proton therapy appears to be safe and effective in the treatment of meningioma.[105,106]

Systemic Therapy

Systemic therapy is currently only recommended in the setting of recurrent meningioma when additional surgery and radiation are not possible. Prospective data have not supported the majority of agents studied.

The best-studied chemotherapy agent has been hydroxyurea. In a case series, hydroxyurea led to a reduction in tumor size in three of four patients.[107] Several other small retrospective studies showed stable disease or modest responses in patients with recurrent or unresectable meningiomas.[108–110] More recently, two retrospective case series showed that hydroxyurea produced no radiographic responses in patients with recurrent WHO grade I to III meningiomas.[111,112] A small prospective study of 14 patients with malignant meningiomas treated with surgery followed by radiotherapy and chemotherapy with cyclophosphamide, adriamycin, and vincristine found that 3 patients had partial responses and 11 had stable disease with a median OS of 5.3 years.[113]

Biologics including interferon-α and somatostatin analogues have also been studied. Although two small studies with interferon-α showed promising results, a phase II study of interferon-α in 35 patients with recurrent WHO grade I meningiomas showed no radiographic responses and a median time to progression of 7 months.[114–116] In a study of 16 patients with recurrent meningiomas shown to overexpress somatostatin receptors, therapy with sustained-release somatostatin led to a partial response in 5 patients and stable disease in another 5 patients.[117] In contrast, a prospective phase II trial of octreotide in nine patients with recurrent high-grade meningioma showed no radiographic responses and a best response of stable disease in 33%.[118] A phase II trial of pasireotide, another long-acting somatostatin analogue with higher affinity for somatostatin receptors, was similarly disappointing with no radiographic responses and no improvement in 6 month progression free survival (PFS6) for patients with WHO grade I to III meningiomas.[119] A phase II trial of octreotide in combination with the mTOR inhibitor everolimus is currently enrolling in France (NCT02333565).

Hormonal agents have also been studied given the increased expression of progesterone receptors in meningiomas. A randomized, double-blind phase III trial (SWOG S9005) of mifepristone showed no significant difference in failure-free or OS as compared with placebo.[120] A phase II trial of tamoxifen showed partial or minor responses in 3 of 19 patients, and 6 patients with stable disease.[121]

Studies for targeted therapies thus far have also failed to show significant efficacy. Angiogenesis has been targeted in particular due to the highly vascularized nature of meningiomas and elevated expression of proangiogenic factors.[122] A phase II trial with the small-molecule tyrosine kinase inhibitor sunitinib, which targets VEGF receptor (VEGFR) and PDGF receptor (PDGFR), in WHO grade II and III meningiomas demonstrated a PFS6 of 42% and median OS of 24.6 months.[123] However, 60% of patients experienced grade 3 or 4 toxicities. In retrospective studies, bevacizumab, a monoclonal antibody against VEGF, showed a PFS6 rate of 43.8% in high-grade meningiomas and 86% in WHO grade I to III meningiomas.[124,125] A phase II study of bevacizumab in 40 patients with WHO grade I to III meningiomas showed a best response of partial response in 5% of atypical meningiomas and stable disease in 100, 85, and 82% of grade I, II, and III meningiomas, respectively.[126] The PFS6 was 87% and median OS was 35.6 months. Another phase II study of bevacizumab in combination with everolimus showed a best response of stable disease in 15 of 17 enrolled patients; PFS6 was 69% with median OS of 23.8 months.[127] Vatalanib, a tyrosine kinase inhibitor targeting VEGFR, has also been studied in a phase II trial with a best response of stable disease in 68.2% of patients and PFS6 of 64.3 and 37.5% in grade II and grade III patients, respectively.[128] Overall, strategies targeting VEGF appear to stabilize tumor growth in highly pretreated patients, although additional randomized studies are needed to confirm efficacy.

Imatinib, an inhibitor of PDGFR, has also been studied in patients with recurrent WHO grade I to III meningiomas (North American Brain Tumor Consortium study 01–08). The phase II trial showed no responses with a PFS6 of 29.4%.[129]

Novel Therapies

Recent studies on the molecular and genetic landscape of meningiomas have led to several clinical trials of targeted therapy. For example, a multi-arm nonrandomized phase II trial with vismodegib (for tumors with a SMO/PTCH1 mutation) and focal adhesion kinase (FAK)-inhibitor GSK2256098SMO (for tumors with a NF2 mutation) is currently underway in recurrent meningioma patients, with plans to add an arm for patients with AKT mutations in the future (NCT02523014). Abnormal mTORC1 signaling in NF2-mutant and sporadic (NF2 wild-type) meningioma patients has led to a phase II trial of the mTORC1/2 inhibitor vistusertib for recurrent grade II and III meningiomas (NCT03071874).[130] Phase I trials of everolimus (NCT01880749) and the cyclin-dependent kinase (CDK)-inhibitor ribociclib (NCT02933736) are also currently recruiting.

Increased PD-L1 expression in meningiomas and the remarkable successes of immunotherapy in other malignancies have led to two clinical trials, one of nivolumab (NCT02648997) and another planned trial of pembrolizumab (NCT03016091). Treatment with tumor treating fields (NovoTTF) showed stable disease in a small pilot study of four of six patients with recurrent or progressive grade II or III meningiomas; a phase II trial in combination with bevacizumab is ongoing (NCT02847559).[131] Trabectedin, a novel antineoplastic agent, is also being studied in a phase II trial, given promising in vitro activity against high-grade meningioma cell lines (NCT02234050).[132]

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