Asymptomatic tumors. In an epidemiologic study, only 25% of meningiomas were symptomatic. Three quarters of the meningiomas were found incidentally on imaging study or postmortem (Radhakrishnan et al 1995). Asymptomatic meningiomas averaging 2.15 cm (range=.5 cm to 5 cm) were followed for an average of 32 months, and none of 57 patients became symptomatic during the follow-up period. In 2 other studies of asymptomatic patients, 4 of 35 and 1 of 12 patients showed tumor growth, with 2 of the 47 patients becoming symptomatic (Braunstein and Vick 1997; Go et al 1998). Forty-five patients had follow-up imaging studies, and 35 of these patients showed no growth during an average follow-up of 29 months. Ten patients showed growth ranging from .2 cm over 15 years to 1 cm over 12 months, with an average growth of .24 cm per year. A study by Yoneoka and colleagues of asymptomatic patients had 9 of 37 patients (24.3%) enlarging with annual growth rate greater than 1 cm3 per year (Yoneoka et al 2000). Another study finds the average annual growth rate to be 0.796 cm3 per year and recommends conservative nonsurgical management for asymptomatic meningioma (Nakamura et al 2003). In a fourth study of 43 patients with 51 brain tumors, 32 tumors in 28 patients showed no growth. Nineteen tumors (37%) in 16 patients had a mean growth rate of 4 mm/yr, with average tumor size increase from 18.5 to 30 mm (Herscovici et al 2004). The authors of all these studies concluded that a patient with asymptomatic meningiomas can be followed with noninvasive imaging studies at intervals, and only requires operation if there is significant growth, or if the patient becomes symptomatic or is likely to become symptomatic (Olivero et al 1995; Radhakrishnan et al 1995; Braunstein and Vick 1997; Go et al 1998; Yoneoka et al 2000). Asymptomatic meningioma has a much higher operative morbidity in patients older than 70 years of age (Kuratsu et al 2000). Some authors felt a more aggressive surgical approach was appropriate in patients less than 60 years (Herscovici et al 2004).
Embolization. Transarterial embolization is a standard treatment in the preoperative management of meningiomas (Dowd et al 2003).
Surgery. Surgery is the treatment of choice for symptomatic meningiomas. Preoperative management includes the administration of anticonvulsants, dexamethasone, and occasionally preoperative embolization in highly vascular tumors. The goal of embolization is to achieve distal loading of the vascular bed to produce confluent tumor necrosis prior to surgery, in order to expand the spectrum of tumors that can be operated on safely (Probst et al 1999). Intratumoral hydrogen peroxide was used as a hemostatic agent in 75 patients, shortening operating room time, decreasing blood loss, and decreasing the need for tumor embolization (Lichtenbaum et al 2006). If there is significant brain edema, dexamethasone should be given for 1 to 2 weeks prior to surgery. The primary aim is gross total resection, with improvement or preservation of neurologic function. At the time of initial surgery, a layer of arachnoid membrane separates the tumor from the brain parenchyma, cranial nerves, and blood vessels. When the neurosurgeon operates within that plane during the resection, the chances of damage to neural and vascular structures are reduced (DeMonte and Al-Mefty 1995). Debulking the tumor from the inside will often allow collapse of the tumor with continued visualization of the arachnoidal membrane. Following meningioma removal, the involved dura and bone must also be removed. CT with bone windows will allow imaging of hyperostotic bone that should be removed (DeMonte and Al-Mefty 1995). Tuberculum sellae meningiomas are difficult to remove because the tumor stretches the optic nerves, obscuring the distinction between tumor and optic nerves. These tumors may involve both optic nerves. Medial sphenoid ridge meningiomas (parasellar) are difficult to remove completely, because they invade the cavernous sinus or extend along the clivus. Parasagittal meningiomas often cannot be removed completely when they invade the sagittal sinus posteriorly.
External beam radiation therapy. External beam radiation therapy has been used for the treatment of meningiomas when only a subtotal resection could be performed. The median treatment dose was 54 gray for both benign and malignant meningiomas, with the upper end of the dose range to 59 gray for benign meningiomas, and 69 gray for malignant meningiomas. The 5-year progression-free survival for patients with benign meningiomas was 98% when CT or MRI was used for treatment planning. The 5-year progression-free survival for malignant meningiomas was slightly less than 50%. Morbidity was 3.6%, with 2 patients developing cerebral radiation necrosis, and 3 patients developing visual loss (Goldsmith et al 1994; Kokubo et al 2000). In optic nerve, tuberculum sellae, and medial sphenoid ridge meningiomas, the risk of damage to optic nerves is greater following radiation therapy because of their proximity to the radiated field. In another series following subtotal resection, irradiated patients had a 32% progression rate versus 60% in nonirradiated patients. The median time to recurrence in the irradiated group was 125 months versus 66 months in the nonirradiated group (Barbaro et al 1987). The 10-year survival rate of patients with 38 inoperable meningiomas following radiation therapy was 46%, with 38% of patients having an improvement in neurologic performance (Glaholm et al 1990). Benign meningioma, partially resected (8 patients), or recurrent benign meningioma (29 patients) were treated with a combination of photon and proton radiation with a 100% and 88%, 5-year and 10-year recurrence-free survival (Wenkel et al 2000).
Proton beam radiation has been used alone for skull-base meningiomas with radiologic control in 16 of 18 patients with a median radiologic of 31 months. Two patients failed marginally (Vernimmen et al 2001).
Following gross total resection, patients with malignant meningiomas should be considered for radiation as well as patients with recurrent benign meningiomas on recurrence or after resection of recurrence (Solan and Kramer 1985; Taylor et al 1988). Patients with benign meningiomas who received radiation therapy following resection had a local control rate of 89%, versus 30% with surgery alone (Taylor et al 1988). At the Karolinska Institute, 56% of 45 patients with meningiomas treated with fractionated radiotherapy between 1975 and 1995 developed serious complications (Mathiesen et al 2003). We would expect this to be markedly decreased with focal conformal radiation therapy.
A more recent retrospective review also points out a potential role of radiotherapy in atypical meningiomas following gross total resection. In their experience, they had improved local control in patients who received postoperative radiotherapy, though a prospective trial is required to better delineate the role in gross totally-resected atypical meningiomas (Komotar et al 2012).
Stereotactic radiosurgery. Currently, stereotactic radiosurgery is used primarily as adjunctive therapy in the management of meningiomas that have been previously resected, especially in the more aggressive subtypes such as atypical or anaplastic meningiomas. Meningiomas located at the skull base can prove difficult to resect entirely secondary to their anatomical location, and stereotactic radiosurgery may be used adjunctively to treat residual tumor postsurgically. Overall, in a meta-analysis of stereotactic radiosurgery in the management of meningiomas, stereotactic radiosurgery has a stabilization rate of 89%, with a low complication rate of 7% (Pannullo et al 2010).
The role of stereotactic radiosurgery and the dose used in the treatment of meningiomas are evolving. Gamma knife radiosurgery and LINAC radiosurgery are both reported on favorably. In patients with benign meningiomas LINAC radiosurgery was used to treat 210 with local control 100% at 1 and 2 years and 93 to 97.9% control at 5 years. Atypical tumors had 100% control at 1 year, 92% at 2 years, and 77% at 5 years with malignant meningiomas being 100% at 1 and 2 years and 19% at 5 years (Friedman et al 2005; Kollova et al 2007; Lee et al 2007). Thirteen (62%) patients had temporary radiation complications, and 5 had permanent complications, all with malignant meningiomas treated with high-dose fractionated radiotherapy also. In a second series of 200 skull base meningiomas treated with gamma knife radiosurgery, 99 patients were treated with a combination of neurosurgical dissection and radiosurgery and 101 patients with radiosurgery alone. Tumor volumes averaged 6.5 cm and doses ranged from 7 to 25 Gy (median 12 Gy). Progression-free survival to the total group was 98.5% at 5 years, and 97.2% at 10 years. Transitory radiation induced edema occurred in 2 patients with temporary clinical worsening (1%). One patient had permanent vision deterioration and 1 patient an unrelated stroke. Three patients had tumor progression with clinical worsening. The overall complication rate was 2.5% with 1% permanent (Kreil et al 2005). In 3 series stereotactic radiosurgery was the first choice treatment for cavernous sinus meningioma (Lee et al 2002; Nicolato et al 2002; Pollock and Stafford 2005). In 1 of these series, the 5-year actuarial tumor control rate was 96.9% ± 3% (Lee et al 2002). Other patients in each of the above series were treated with adjuvant radiosurgery after initial surgery with disease control in a lesser percentage than those treated with radiosurgery as the primary modality.
In recurrent cavernous sinus meningiomas, tumor control was obtained in all 34 patients, with 56% of patients having tumor shrinkage. The median follow-up period was 26 months (Duma et al 1993). In a series of 28 cavernous sinus meningiomas, after surgery in 22 meningiomas, and photon radiation and radiosurgery in 28, 8 years progression-free survival was 81% with overall survival 96% (Maguire et al 1999). In 12 patients with recurrent atypical or malignant meningiomas, radiosurgery was used to treat 30 tumors with 13 lesions showing progression in the treated field after a mean follow-up of 43.5 months. Recurrence rate was dose dependent with 64% of lesions receiving less than 20 Gy recurring and only 25% when the tumor received greater than 20 Gy (Kano et al 2007). The dose required for malignant meningiomas is greater than for benign meningiomas. Obviously the recurrence rate is much higher with aggressive meningiomas as compared to benign meningiomas following radiosurgery.
A recent retrospective review was performed, comparing outcomes of skull base meningiomas treated with either stereotactic radiosurgery, hypofractionated stereotactic radiotherapy, or fractionated stereotactic radiotherapy. The reviewers did not find a significant difference in clinical or radiographic response to the different treatment techniques (Han et al 2012). Therefore, the appropriate technique should be chosen based on location and size of tumor and tailored to the individual patient.
Interstitial brachytherapy. Thirteen skull-base meningiomas were initially treated with high-activity iodine-125 seeds, with 9 of 11 patients without calcification having a complete response, and the 2 with calcification having a partial response (Kumar et al 1991). How these results compare with stereotactic radiosurgery or with new skull-base surgery techniques has not been determined.
Conventional cytotoxic chemotherapy has no role in the treatment of benign meningiomas and has significant morbidity without significant efficacy in the more aggressive grades and in recurrent disease.
Hydroxyurea has had relatively more success, propelling it to become a standard chemotherapeutic agent in patients with recurrent meningiomas based on several studies. In 1997, 4 patients with meningiomas were treated with hydroxyurea at a daily dose of 20 mg/kg with a 15% to 60% reduction in 3 benign meningiomas. The fourth patient treated following gross total resection of a malignant meningioma had no recurrence (Schrell et al 1997). In a larger study, 17 patients had unresectable or residual meningioma; 11 of 17 who had actively growing meningiomas were treated with hydroxyurea, and the result was that 14 of 16 evaluated patients were stable for 20 to more than 144 weeks (median 80 weeks). Two patients had progressive disease after 10 weeks, and 3 responders progressed at 20 to 56 weeks (Newton et al 2001). More recently, Chamberlain published a retrospective case series of 35 patients with recurrent atypical or anaplastic meningioma treated with hydroxyurea at progression. In his series, no radiographic response was seen, 43% of patients had disease stability, and 57% showed progression at first radiographic evaluation, suggesting perhaps hydroxyurea is not as efficacious as originally hypothesized (Chamberlain 2012).
The role of chemotherapy in the treatment of malignant meningioma is still to be defined (Chamberlain 1996). Temozolomide has been tried in patients with refractory meningiomas previously treated with surgery and radiation without effect. Somatostatin has also been studied. Somatostatin receptors are present on most meningiomas. Receptor activation is associated with antiproliferative effect in vitro. This effect is thought to be due to an inhibitory effect on cyclic adenosine monophosphate formation. In a study of 16 patients with recurrent meningiomas who were given a sustained-release somatostatin, 31% showed a partial radiographic response and 44% achieved progression-free survival at 6 months (Sioka and Kyritsis 2009).
Hormonal therapy. Tamoxifen (40 mg/m2 twice daily for 4 days, then 10 mg/m2 twice daily), an antiestrogen, was used to treat 19 patients with unresectable or refractory meningiomas. Progression occurred in 10 patients, temporary disease stabilization in 6 patients, and minor response in 3 patients (Goodwin et al 1993).
The antiprogestational agent RU-486 (200 mg daily) has been used to treat recurrent benign meningiomas after failure of surgery and radiation therapy. Twenty-eight patients were treated with long-term RU-486 for a median of 35 months. Eight patients had minor responses including improved visual field exam or imaging studies. Endometrial hyperplasia was noted in several patients (Grunberg et al 2006).
Recurrent meningiomas frequently have overexpressed somatostatin receptors on their tumor cells. Somatostatin has been shown to inhibit the growth of meningioma in some in vitro studies. Sandostatin LAR, a long acting somatostatin analogue, was given to 16 patients at monthly intervals with proven recurrent meningioma. Somatostatin receptors were demonstrated using Indium 111 octreotide. Most patients (75%) had previous surgery, radiotherapy, and chemotherapy. Four partial responses were seen with 5 patients having stable disease. Forty-four percent of patients were progression free at 6 months with median overall survival of 7.5 months. Toxicity was minimal. This may offer a new treatment for patients with recurrent meningioma with increased somatostatin receptors (Chamberlain et al 2007).
Interferon-alpha has demonstrated activity-inhibiting meningioma cell growth in vitro in several studies. Disease stability with interferon-alpha treatment in recurrent grade I meningiomas was demonstrated in 74% of 35 patients treated. Although a radiographic response was not seen, stability was achieved with a 6-month PFS of 54%, suggesting some clinical activity in these tumors (Chamberlain and Glantz 2008).
Given that epidermal growth factor receptor is overexpressed in meningiomas, it was postulated that inhibitors of EGFR could potentially be used in the treatment of recurrent meningiomas that have failed surgery, radiation, and chemotherapy. A phase II trial of erlotinib or gefitinib, both EGFR inhibitors, was published in 2009 (Norden et al 2010). Twenty-five patients with benign (32%), atypical (36%), and malignant (32%) meningiomas were given either gefitinib or erlotinib. There was, however, no statistically significant activity against recurrent meningiomas.
Bevacizumab is currently being investigated as potential therapy, particularly for malignant meningiomas, which are well known to produce high levels of vascular endothelial growth factor. Published case reports indicate remission of meningiomas following treatment with bevacizumab for recurrence following surgery and radiation therapy (Puchner et al 2010). This prompted retrospective reviews looking at the efficacy of bevacizumab in recurrent meningiomas, including a review looking at atypical and anaplastic meningiomas treated with bevacizumab at 4 institutions; the treatment was found to be well tolerated, but the best response was disease stability (Nayak et al 2012). There is an ongoing phase 2 study looking at the activity of bevacizumab in meningioma patients.
Similar to EGFR and VEGF, PDGF (platelet-derived growth factor) receptors are prevalently expressed in meningiomas; imatinib has been examined for treatment of meningiomas due to this finding. A retrospective study looked at outcomes in patients whose recurrent meningioma was identified to harbor expression of PDGF receptors; the patients were subsequently treated with imatinib mesylate. While no radiographic response was seen, 7 of 9 patients demonstrated disease stability in response to treatment after 3 months of therapy; the patients also demonstrated PFS-6 of 66.7% (Horak et al 2012). This study prompted further ongoing studies looking at imatinib treatment in selected patients with recurrent meningioma.
It is well known that tumor cells can alter the expression of proteins in the extracellular matrix in order to promote tumor progression. Studies have shown that there is an increased level of extracellular proteins, fibronectin, and tissue transglutaminase 2 (TG2) in glioblastomas and meningiomas. A study published in 2008 explored the small molecule KCC009, a TG2 inhibitor in the treatment of meningiomas (Yuan et al 2008). This study showed that by inhibiting the binding of TG2 to fibronectin this altered the disposition of the extracellular matrix surrounding the tumor. They also showed that treatment with KCC009 promoted apoptosis and enhanced radiation sensitivity in cultured meningioma cells and in meningioma tumor explants. This implies that perhaps in patients not appropriate for surgery, inhibition of TG2 can possibly be used in conjunction with radiation to enhance death of meningioma cells (Yuan et al 2008).
Current research is investigating the use of lopinavir in the inhibition of meningioma growth. Lopinavir is an HIV-1 protease inhibitor. Initial in vitro studies have suggested that lopinavir may arrest the cell cycle, thus, inhibiting growth (Johnson et al 2011). Further studies are needed to investigate its use as adjunctive therapy.
Ongoing studies are investigating various medical agents in the treatment of recurrent, inoperable, or radiation-refractory meningiomas as this continues to be a great unmet need in the field of neuro-oncology. At this point in time, most studies are focused at the use of targeted or molecular agents, as these appear to be well-tolerated and efficacious in theory, though the clinical efficacy has yet to be determined.