Key points

Introduction

Meningiomas are mostly benign tumors in adults that arise from the arachnoidal cap cells intracranially and in the spine with an incidence of 7.44:100,000. Most meningiomas are World Health Organization (WHO) grade I (80%); however, atypical grade II (15%–20%) and anaplastic grade III (1%–3%) tumors are relatively common and show a greater propensity for recurrence and therapeutic resistance. Changes introduced in the 2007 WHO guidelines have led to an increase in the relative percentage of grade II and III meningiomas. Risk factors for meningioma include older age, a variety of genetic mutations and family disorders, ionizing radiation, head trauma, and sex. Current therapeutic modalities include maximal safe gross total resection (GTR) followed by radiotherapy for higher-grade or recurrent lesions. The Simpson grade, evaluating the degree of surgical resection, continues to be a viable tool for predicting survival and recurrence rates. WHO grade II meningiomas show 5-year local control rates of 78% to 100% and 5-year progression-free survival (PFS) rates of 74% to 100% with GTR and radiotherapy. WHO grade III meningiomas show 5-year PFS rates of 15% to 57% and 5-year overall survival (OS) of 47% to 61% with GTR and radiotherapy. Although surgery and radiotherapy have been widely studied in the treatment and control of meningiomas, chemotherapeutic and targeted drugs have limited clinical efficacy.

The current National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines, www.nccn.org ) recommend radiological evaluation with biopsy if needed, as first-line steps in the evaluation of meningioma ( Fig. 1 ). After radiographic or biopsy-proven diagnosis, asymptomatic meningiomas are recommended for surgery if they are accessible and large (≥30 mm) or there is a concern regarding a potential neurologic consequence but can otherwise be observed. Surgery is also recommended for lesions that are symptomatic and accessible at any size or stage. After surgery, radiotherapy is recommended as a standard for WHO grade III lesions but is optional for WHO grade I or II lesions. For low-grade lesions, follow-up with MRI is recommended at 3, 6, and 12 months, then every 6 to 12 months for another 5 years, and less frequently beyond 5 years. Higher-grade lesions are monitored more closely. For recurrent meningiomas not amenable to surgery or radiation therapy, the current NCCN Guidelines recommend only 3 classes of chemotherapeutic agents as medical treatments in meningiomas because clinical trials have shown partial benefits. These agents include α-interferon, somatostatin receptor agonists, and vascular endothelial growth factor (VEGF) inhibitors.

NCCN guidelines version 1.2015: meningiomas. ( A ) Guidelines for the treatment of newly diagnosed meningioma. For small, asymptomatic lesions, observation is generally recommended after clinical and radiographic evaluation. For larger asymptomatic lesions, surgical resection is typically recommended, particularly when they are located in more accessible areas or there are potential neurologic consequences to a conservative approach. Depending on tumor grade, subsequent radiotherapy (RT) may also be recommended. Tumors that are symptomatic are referred for surgical resection when feasible. These patients are monitored closely after surgery and may undergo RT depending on tumor grade and level of resection. CSF, cerebrospinal fluid. ( B ) Guidelines for the treatment of recurrent meningioma. After treatment, patients are followed at 3, 6, and 12 months with contrast-enhanced MRI. After 1 year, the MRIs are repeated every 6 to 12 months for 5 years and then every 1 to 3 years. The management of recurrence depends on individual factors, personalized to the patient. For instance, surgical treatment followed by RT may be used if the recurrence is accessible, whereas RT or chemotherapy, or observation, may be recommended if the lesion is surgically inaccessible. ^a Multidisciplinary input for treatment planning if feasible. ^b The median growth rate for meningiomas is 4 mm per annum. ^c WHO Grade I = benign meningioma; WHO Grade II = atypical meningioma; WHO Grade III = malignant (anaplastic) meningioma. ^d RT can be either external-beam or stereotactic radiosurgery (SRS). ^e Principles of brain tumor radiation therapy: WHO grade I meningiomas may be treated by fractionated conformal radiotherapy with doses of 45 to 54 Gy. For WHO grade II meningiomas undergoing radiation, treatment should be directed to gross tumor (if present) and surgical bed + a margin (1–2 cm) to a dose of 54 to 60 Gy in 1.8 to 2.0 Gy fractions. Consider limiting margin expansion into the brain parenchyma if there is no evidence of brain invasion. WHO grade III meningiomas should be treated as malignant tumors with treatment directed to gross tumor (if present) and surgical bed + a margin (2–3 cm) receiving 59.4 to 60 Gy in 1.8 to 2.0 Gy fractions. WHO grade I meningiomas may also be treated with SRS doses of 12 to 16 Gy in a single fraction when appropriate. ^f Less frequent follow-up after 5 to 10 years. ^g More frequent imaging may be required for WHO grade III meningiomas and for meningiomas of any grade that are treated for recurrence or with chemotherapy. ^h Interferon-α (category 2B), somatostatin analogue (if octreotide scan positive), sunitinib (category 2B).

( Adapted from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ^® ) for Central Nervous System Cancers V.1.2015. © 2015 National Comprehensive Cancer Network, Inc. The NCCN Guidelines ^® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org . NATIONAL COMPREHENSIVE CANCER NETWORK ^® , NCCN ^® , NCCN GUIDELINES ^® , and all other NCCN Contents are trademarks owned by the National Comprehensive Cancer Network, Inc.)

The focus of the recent prospective RTOG 0539 trial, which has closed enrollment, is to evaluate the best current care for meningiomas ( www.rtog.org ). Patients were categorized into groups based on the risk of recurrence, and PFS will be assessed at 3 years. The low-risk group includes patients with Simpson grade I–III resections or Simpson grade IV–V resections and grade I tumor; these patients are observed after surgical treatment. The intermediate group includes patients with WHO grade II or recurrent WHO grade I lesions that are treated with planned conformal radiotherapy or intensity-modulated radiotherapy (IMRT; 54 Gy in 30 fractions). The high-risk group includes patients with WHO grade III or recurrent WHO grade II tumors who were treated with planned IMRT (60 Gy in 30 fractions). The results of this prospective study will aid in elucidating the therapeutic efficacy of various treatment approaches. Furthermore, the use of medical treatments can be compared as additive treatments to these approaches.

A recent meta-analysis of 47 publications evaluating various treatment options in meningioma concluded that significant heterogeneity of inclusion and response criteria made evaluation of effective treatments more challenging but suggested that PFS-6 was easily extractable from most studies and could be compared across treatment types. For WHO I meningiomas, the weighted average PFS-6 was 29%, whereas the average for WHO II/III meningiomas was 26%. Furthermore, this analysis indicated that a PFS-6 of greater than 40% for grade I meningiomas and greater than 30% for grade II/III meningiomas would reasonably suggest that a treatment had therapeutic efficacy. These results provide a starting point for powering studies and evaluating clinically meaningful impacts of diverse treatment options.

In this review, various medical therapies that have been evaluated in meningiomas ( Table 1 ) are discussed. Many of these agents have had limited success, with results hindered by small study sizes and heterogenous inclusion criteria. Despite these limitations, previous trials have helped in the ongoing design of the next generation of clinical trials and combination therapies to improve on meningoma treatment.

Table 1

Summary of studies evaluating medical treatments in meningiomas

Reference	Agent	Mechanism	n	WHO Grade				Median PFS	PFS-6
				N/A	I	II	III
Kim et al, 2012	Hydroxyurea	Ribonucleotide reductase inhibitor	—	—	—	—	—	—	—
Schrell et al, 1997	Hydroxyurea	Ribonucleotide reductase inhibitor	4	—	3	—	—	—	—
Newton et al, 2000	Hydroxyurea	Ribonucleotide reductase inhibitor	17	—	16	3	1	80 wk	—
Mason et al, 2002	Hydroxyurea	Ribonucleotide reductase inhibitor	20	—	16	3	1	—	—
Rosenthal et al, 2002	Hydroxyurea	Ribonucleotide reductase inhibitor	15	—	10	5	—	—	—
Loven et al, 2004	Hydroxyurea	Ribonucleotide reductase inhibitor	12	—	8	4	—	13 mo	—
Hahn et al, 2005	Hydroxyurea with radiotherapy		21	4	13	2	2	—	—
Weston et al, 2006	Hydroxyurea	Ribonucleotide reductase inhibitor	6	1	5	—	—	—	—
Chamberlain & Johnston, 2011	Hydroxyurea	Ribonucleotide reductase inhibitor	60	—	60	—	—	4 mo	10%
Chamberlain, 2012	Hydroxyurea	Ribonucleotide reductase inhibitor	35	—	—	22	13	2 mo	3%
Chamberlain et al, 2004	Temozolomide	Alkylating agent	16	—	16	—	—	5 mo	0%
Chamberlain et al, 2006	Irinotecan	Topoisomerase 1 inhibitor	16	—	16	—	—	4.5 m	6%
Chamberlain, 1996	Cyclophosphamide + Adriamycin (doxorubicin) + vincristine (CAV)	Cytotoxic chemotherapy	14	—	—	—	14	4.6 y	—
Kaba et al, 1997	Interferon-α	Immunomodulation	6	—	2	1	3	—	—
Muhr et al, 2001	Interferon-α	Immunomodulation	12	2	6	1	3	—	—
Chamberlain & Glantz, 2008	Interferon-α	Immunomodulation	35	—	35	—	—	7 mo	54%
Lamberts et al, 1992	Mifepristone (RU486)	Antiprogesterone	12	—	—	—	—	—	—
Grunberg et al, 1991	Mifepristone (RU486)	Antiprogesterone	14	2	7	3	2	—	—
Grunberg et al, 2006	Mifepristone (RU486)	Antiprogesterone	28	4	22	—	2	—	—
Touat et al, 2014	Mifepristone (RU486)	Antiprogesterone	3	—	3	—	—	—	—
de Keizer & Smit, 2004	Mifepristone (RU486)	Antiprogesterone	2	—	—	—	—	—	—
Grunberg & Weiss, 1990	Megestrol acetate	Progesterone receptor agonist	9	—	8	—	1	—	—
Jaaskelainen et al, 1986	Medroxy-progesterone acetate	Synthetic progesterone	5	—	4	—	1	—	—
Markwalder et al, 1985	Tamoxifen	Antiestrogen	6	—	—	—	—	—	—
Goodwin et al, 1993	Tamoxifen	Antiestrogen	21	—	—	—	—	15.1 mo	—
Runzi et al, 1989	Octreotide	Somatostatin analogue	1	1	—	—	—	—	—
Garcia-Luna et al, 1993	Octreotide	Somatostatin analogue	3	—	2	—	1	—	—
Jaffrain-Rea et al, 1998	Octreotide	Somatostatin analogue	1	—	—	—	—	—	—
Johnson et al, 2011	Octreotide	Somatostatin analogue	11	—	3	3	5	17 wk	—
Chamberlain et al, 2007	Sandostatin LAR	Somatostatin analogue	16	—	8	3	3	5 mo	44%
Norden et al, 2015	Pasireotide LAR	Somatostatin analogue	26	—	9	17	—	20 wk	29%
Simo et al, 2014	Octreotide	Somatostatin analogue	9	—	—	5	4	4.23 mo	44%
Wen et al, 2009	Imatinib	PDGFR TKI	23	—	12	5	5	2 mo	29.40%
Raizer et al, 2010	Erlotinib	EGFR TKI	1	—	—	1	—	—	—
Norden et al, 2010	Erlotinib or gefitinib	EGFR TKI	25	—	8	9	8	10 wk	28%
Reardon et al, 2012	Imatinib and hydroxyurea	PDGFR TKI + ribonucleotide reductase inhibitor	21	—	8	9	4	7 mo	61.90%
Raizer et al, 2010	Vatalanib (PTL-787)	VEGFR + PDGFR TKI	21	—	—	14	7	—	37.50%
Raizer et al, 2014	Vatalanib (PTL-787)	VEGFR + PDGFR TKI	25	—	2	14	8	6.5 mo	37.50%
Kaley et al, 2015	Sunitinib	VEGFR + PDGFR TKI	36	—	—	30	6	5.2 mo	42%
Puchner et al, 2010	Bevacizumab	Anti-VEGFR antibody	1	—	—	—	1	—	—
Goutagny et al, 2011	Bevacizumab	Anti-VEGFR antibody	1	1	—	—	—	—	—
Wilson & Heth, 2012	Bevacizumab + paclitaxel	Anti-VEGFR antibody	1	—	1	—	—	15 mo	—
Lou et al, 2012	Bevacizumab	Anti-VEGFR antibody	14	1	5	5	3	17.9 mo	85.70%
Nayak et al, 2012	Bevacizumab	Anti-VEGFR antibody	15	—	—	6	9	26 wk	43.80%
Nunes et al, 2013	Bevacizumab	Anti-VEGFR antibody	15	—	—	—	—	15 mo	—

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