Meningioma - Emerging treatments

Angiogenesis inhibitors

These tumours may be highly vascular, and angiogenesis is a possible target for therapy.[87] High microvessel density correlates with unfavourable prognosis, and vascular endothelial growth factor (VEGF) receptors are frequently expressed in meningiomas.[88] One multi-centre retrospective study of the use of bevacizumab for atypical and anaplastic meningiomas demonstrated non-fatal intratumoral haemorrhage in 3 out of 15 patients, with the best radiographical response of stable disease and progression-free survival at 6 months of 43.8%.[89] Another study demonstrated intratumoral haemorrhage in 1 of 14 patients and progression-free survival at 6 months of 86%.[90] Sunitinib is a tyrosine kinase inhibitor that blocks multiple receptors including VEGF and platelet-derived growth factor (PDGF) receptors. Sunitinib has shown cytostatic and anti-migratory effects on meningioma cell cultures.[91] One phase 2 trial demonstrated progression-free survival at 6 months of 42% in atypical and anaplastic meningiomas.[92] Overall, this demonstrates great promise.[93] Vatalanib is another tyrosine kinase inhibitor that inhibits both VEGF and PDGF receptors and has shown modest therapeutic efficacy against refractory meningioma.[94] The National Comprehensive Cancer Network guidelines recommend sunitinib, bevacizumab, or bevacizumab plus everolimus, as options for systemic therapy in patients with recurrent meningioma refractory to surgery or radiation.[46] However, these regimens for meningioma are considered experimental, and further controlled studies are needed.[53]

Cytotoxic agents

Cytotoxic agents are commonly used in the treatment of cancer because of their ability to preferentially damage cells with rapid turnover. Commonly used agents such as doxorubicin, dacarbazine, hydroxycarbamide, ifosfamide, irinotecan, trabectedin, and temozolomide have been tried in the treatment of meningiomas; however, results from these trials have demonstrated overall poor efficacy.[83][95] A regimen of doxorubicin, vincristine, and cyclophosphamide for anaplastic meningioma has resulted in a likely increase in overall survival.[96]

Hormonal therapy

It has long been known that meningiomas express oestrogen and progesterone receptors and respond to antihormonal therapy in tissue culture. The majority of benign meningiomas express progesterone receptors and, less frequently, oestrogen receptors. A double-blind phase 2 randomised trial of mifepristone in the treatment of unresectable meningiomas demonstrated the medication was well tolerated but did not impact failure-free or overall survival.[97] In addition to mifepristone, tamoxifen has also been used but data regarding the efficacy of these medications are limited. Although the expression of oestrogen receptors is less consistent, tamoxifen, an anti-oestrogen agent, has been shown to induce transient stabilisation or minor response in the majority of a small series of patients with recurrent unresectable meningiomas.[98] Inhibitors of growth hormone (GH) (pegvisomant) and insulin-like growth factor (fenretinide) have also been studied because of the ubiquitous expression of GH receptors in meningioma cells. Somatostatin receptors are also present on most meningioma cells and may be used as a target of inhibition of tumour growth in vitro. Some small pilot trials with somatostatin receptors have demonstrated stabilisation or response to treatment in a minority of patients with recurrent meningiomas.[99][100][101][102] Others have shown little benefit.[103]

Interferon alfa

Interferon alfa is an immune therapy that inhibits growth of meningioma cells both in vitro and in vivo in experimental systems. Early work suggested stabilisation of disease in several patients treated with interferon alfa-2b with unresectable recurrent or malignant meningiomas.[104][105][106] These results suggest that it can produce long-lasting remissions in some patients with rapidly progressing atypical and malignant meningiomas and may represent a further treatment option for patients with recurrent or unresectable tumours. One phase 2 study of World Health Organization grade 1 meningiomas demonstrated that interferon alfa is relatively well tolerated and modestly effective, but no patient demonstrated neuroradiographically partial or complete response.[107] One retrospective case series found limited efficacy in patients with recurrent high-grade meningiomas.[108]

Calcium-channel blockers

Much experimental evidence exists for the independent growth-inhibitory effects of calcium-channel blockers, such as verapamil or diltiazem, on meningioma growth. There is some evidence supporting the adjuvant use of these agents with hydroxycarbamide, but not all studies have shown efficacy.[109][110][111][112][113]