Medical Management of Meningiomas: Current Status, Failed Treatments, and Promising Horizons

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Key points

  • Meningiomas have the propensity for aggressive recurrence and resistance to traditional therapy.

  • Only alpha-interferon, somatostatin receptor agonists, and vascular endothelial growth factor inhibitors are currently recommended for medical treatment of meningiomas.

  • Novel therapeutic approaches and combinations may be a useful method in the treatment of aggressive meningiomas.

Mutations in meningioma

Many recent studies have helped define the mutational background of meningiomas, aiding in understanding the pathophysiology of meningiomas and suggesting new therapeutic targets. Deletion of neurofibromin 2 (NF2, also known as Merlin and moesin-, ezrin-, radixin [ERM]-like protein), which is found on chromosome 22q12, is a well-characterized mutation in sporadic meningioma found in upwards of 50% to 60% of patients.12 The NF2 protein is a member of the 4.1 ERM family of proteins localized to

Angiogenic pathway inhibitors

Expression of VEGF A can be seen in 79% of meningiomas and correlates with microvascular density and increased tumor grade.35, 36, 37 Expression of hypoxia-inducible factor-1, a significant regulator of VEGF expression and hypoxia regulation, is also commonly seen in meningiomas.38 Reductions in peritumoral edema and radiation necrosis have also been seen with VEGF inhibitors, suggesting a potential role of antiangiogenesis inhibitors as targeted therapy in meningioma.39, 40

The efficacy of the

Tyrosine kinase receptor inhibitors

Targeting tyrosine kinase inhibitors (TRKIs), including imatinib (targeting PDGFR)49 and erlotinib50, 51 and gefitinib51 (both targeting EGFR), has been tried with minimal success in meningiomas. PFS-6 for TRKIs ranged from 28% to 44% and median PFS from 8 weeks to 5 months in prospective studies. Imatinib was evaluated in the North American Brain Tumor Consortium (NABTC) study 01-08 in a group of 22 individuals with recurrent grade I and II meningiomas.49 The results suggested that imatinib

Hydroxyurea

Hydroxyurea has been widely studied in the treatment of meningioma, grades I through III. It was initially developed as a ribonucleotide reductase inhibitor inhibiting cell cycle for the treatment of myeloproliferative diseases and chronic myelogenous leukemia.4 In meningioma, hydroxyurea has shown a range in median PFS of 10 to 80 weeks and PFS-6 of 3% to 10%.52, 53, 54, 55, 56, 57, 58, 59, 60, 61 These studies are limited by their retrospective design and small sample sizes. The use of

Hormone receptor targeted agents

The incidence of meningiomas in women has been shown to be twice as high as that in men, suggesting a hormonal influence on tumor pathogenesis.1 Evaluation of meningiomas has shown a significant level of progesterone receptors but limited expression of estrogen receptors.66 Several studies have evaluated the role of hormone receptor targeting agents in the treatment of meningioma. In an initial evaluation of megestrol in a series of 9 patients with meningiomas (8 grade I, 1 grade III), stable

Chemotherapeutic agents

Another avenue of investigation has considered treatment of meningiomas with traditional cytotoxic chemotherapeutic agents. Use of combined cyclophosphamide, Adriamycin (doxorubicin), and vincristine (CAV therapy) after surgery and radiation as initial treatment of grade III meningioma was evaluated in a small cohort of 14 patients, demonstrating a median PFS of 4.6 years, PFS-6 of 6%, and radiographically stable disease in 12 of 14 patients.78 Another approach evaluated the alkylating agent

Somatostatin analogues

Somatostatin analogues, including octreotide, Sandostatin LAR, and pasireotide, have been evaluated in the treatment of meningioma.8, 84, 85, 86, 87, 88, 89 Somatostatin, also known as growth hormone–inhibiting hormone, is secreted by the ventromedial nucleus of the hypothalamus and inhibits multiple pituitary, gastrointestinal, and pancreatic hormones. Meningiomas have been known to highly express somatostatin receptors.8 One study evaluated 16 patients with recurrent meningioma treated with

Immunomodulation

Several studies have shown that treatment of meningioma with interferon-α has a therapeutic effect.10, 91, 92 Interferon-α binds to the interferon-α/β receptor and is involved in cell resistance to viral infection but has been investigated as a cancer adjuvant therapy. The most recent study evaluated interferon-α in 35 cases of refractory grade I meningioma after standard therapies and showed a PFS-6 of 17%, suggesting limited activity.93

Emerging approaches

Several newer approaches in the treatment of meningioma have sought novel therapeutic targets. One strategy involved targeting meningiomas with growth hormone receptor antagonists because of their high expression of growth hormone receptors.94 In vitro targeting with growth hormone antagonists can inhibit meningioma cell proliferation.94 Furthermore, targeting of growth hormone receptors with pegvisomant via an in vivo flank model was shown to significantly reduce tumor volume, serum IGF-1

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