Introduction
Meningiomas are the most common primary brain tumor and comprise nearly one-third of all newly diagnosed primary brain tumors.[1] Meningiomas are thought to be arachnoid cap cell–derived and are dural (intracranial extraparenchymal) in location. Meningiomas are most common in the elderly, although they occur at all ages. The median age of patients who present with a meningioma is 70 years. Autopsy studies suggest that as much as 1% of the population has an incidental meningioma, suggesting both the common occurrence of these tumors as well as their not infrequent asymptomatic presentation.
Meningiomas may be either intracranial or intraspinal in location; in both instances, the majority of patients are female (there is a 60:40 female-to-male ratio in intracranial meningioma, and an 80:20 ratio in intraspinal meningioma). The majority of meningiomas are intracranial and parasagittal or falcine in location, but they can be located anywhere in the intracranial compartment, including the skull base and posterior fossa (tentorium or cerebellopontine angle). Intraspinal meningiomas are found predominantly in the thoracic spine.
The National Comprehensive Cancer Network (NCCN) central nervous system (CNS) tumor guidelines separate meningiomas into two categories: asymptomatic and symptomatic.[2] These categories are further subdivided into small meningiomas (defined as < 30 mm in maximum unidimensional diameter) and large meningiomas (defined as > 30 mm); this is a practical separation that has relevance (with regard to permissible geometry) for stereotactic radiotherapy administration, discussed below.
Many meningiomas are discovered incidentally by brain imaging in asymptomatic patients. Other patients, however, may present with new-onset headaches or, alternatively, with a sentinel seizure that is most often partial in semiology. Skull-based meningiomas often manifest as cranial nerve dysfunction, whereas posterior fossa meningiomas frequently have gait disorders as a presentation. Intraspinal meningiomas most often present with progressive local back pain, as is commonly the case with all spinal cord tumors.
The World Health Organization (WHO) recognizes three grades of meningioma. WHO grade I, or so-called benign meningiomas, constitute approximately 80% of all meningiomas and have the most favorable long-term survival (median, 12–15 years). WHO grade II meningiomas, termed “atypical meningiomas,” represent 10% to 15% of all meningiomas and have an intermediate long-term survival (8–10 years). WHO grade III meningiomas, also called “anaplastic meningiomas,” are the least common (approximately 5% of all meningiomas) and manifest a comparatively short overall survival (around 5 years). The pathologic division into three grades is clinically relevant, as management and treatment vary based on pathology, as discussed below.
Treatment
Watch and wait
Importantly, not all meningiomas warrant treatment; consequently, a “watch and wait” approach is acceptable in a subset of patients who harbor a presumed meningioma. There have been multiple natural history studies of asymptomatic meningiomas incidentally identified by MRI brain imaging, of which only one-third have grown and warranted treatment over a period of 1 or more years of serial imaging.
Most natural history studies indicate that a radiographically defined meningioma increases in size by 3 to 4 mm per year, on average, a change that does not in itself merit treatment but rather indicates merely that meningiomas do grow over time, although not always in a linear manner. In such a situation-ie, that of an incidentally discovered asymptomatic meningioma-NCCN guidelines recommend repeat imaging at 3 months after the index scan and, if the lesion is found to be stable, repeat MRI (the preferred imaging modality) 6 months later.[3] If again the lesion is found to be stable on the scan, and the patient is stable as well, imaging is then recommended once per year in a neurologically asymptomatic patient. This approach is particularly relevant in elderly patients in whom early treatment may have little benefit based upon actuarial predicted survival. In patients with minimal symptoms referable to the presumed meningioma-for example, in a patient who has had a single seizure and whose propensity for seizures is easily managed with anti-epileptic drugs-a watch and wait management paradigm is equally reasonable. Similarly, in patients who present with headaches but in whom it is unlikely that the headaches are a result of the meningioma, a watch and wait approach would again be a reasonable strategy. The difficulty with a watch and wait policy in the above-mentioned clinical scenarios is that an assumption is made that the dural lesion identified by brain imaging is a meningioma; however, the radiographic differential diagnosis encompasses other entities, including metastatic disease (particularly breast and prostate cancers) and hemangiopericytoma. Additionally-and this is a weakness of active surveillance management of any cancer-there is a presumption of compliance by the patient with a defined clinical and radiographic follow-up schedule, yet compliance with such schedules is often subpar. Lastly, with a watch and wait approach, the grade of the presumed meningioma is never determined pathologically.
Surgery
The standard of care for meningioma remains a complete surgical resection, since essentially all case series demonstrate improved outcomes in patients who have undergone an image-verified complete resection.[1] Importantly, the extent of resection of surrounding dura does not appear as relevant as was once thought (this earlier thinking formed the basis for the Simpson categories of extent of surgical resection). Still, surgical resection needs to be accomplished safely and without perioperative injury to the patient. Increasingly, and particularly in patients with meningiomas in surgically challenging locations (for example, in the skull base), radiotherapy has become a first-line treatment choice. In patients treated with incomplete surgery, adjuvant radiotherapy appears to provide a similar level of tumor control (and patient survival) as that seen with a complete surgical resection. Nonetheless, the rate of recurrence in even completely resected meningiomas remains high and increases with length of follow-up (nearly a 25% incidence of recurrence at 30 years post-surgery), suggesting that serial brain imaging and clinical follow-up is relevant. In instances of recurrent meningioma, repeat surgery, if this can again be accomplished safely and completely, appears to be of benefit. Consequently, it is common for recurrent meningiomas in surgically accessible locations, such as parafalcine or falcine lesions, to be treated with two or more surgeries.
Key Points in the Management of Meningioma
- Not all meningiomas require treatment, and a subset may be managed by active surveillance.
- Three World Health Organization (WHO) grades have been defined, and treatment is in part dependent on the pathologic grade.
- Treatment, when indicated, entails maximal safe surgical resection, which, if completed in WHO grade I (benign meningioma) and grade II (atypical meningioma) tumors, is sufficient upfront treatment. By contrast, in WHO grade III tumors (anaplastic meningioma), fractionated radiotherapy is administered regardless of the degree of resection. Surgically inaccessible meningiomas are most commonly treated with stereotactic radiotherapy as initial therapy.
- Recurrent meningioma may be treated with repeat surgery if this is possible and is likely to be of clinical benefit; post-surgery radiotherapy may be administered if residual disease remains. Stereotactic radiotherapy as a single-modality therapy remains the most common salvage therapy for recurrent meningioma.
- In patients with no further surgery or radiotherapy treatment options, systemic therapy may be used, although data regarding benefit from such therapy are meager. Three agents are commonly employed, most often sequentially, including α-interferon, somatostatin receptor agonists (octreotide long-acting release depot), and vascular endothelial growth factor (VEGF) signaling pathway inhibitors (bevacizumab and sunitinib). There remains a significant unmet need for new systemic therapies for the treatment of meningioma.
Radiotherapy
Radiotherapy may be the initial and only therapy in patients with meningiomas in topographically challenging locations that are not otherwise considered for surgery; it may be used as an adjunctive therapy in incompletely resected meningiomas; or it may be used as a salvage therapy for recurrent and progressive disease.[1] As with other brain tumors, one of two radiotherapies may be administered, and increasingly, both are used in multiple recurring meningiomas. Conventional fractionated (once per day) radiotherapy is used for grade II incompletely resected meningiomas (total dose, 54 Gy) and following resection of any extent of grade III meningiomas (total dose, 60 Gy). By contrast, stereotactic radiotherapy (single or multiple fractions) may be used for small residual disease after resection of a WHO grade I meningioma, as a primary treatment with or without a pathologic diagnosis, or-commonly-as a salvage treatment in instances of recurrent disease.
Chemotherapy/targeted therapy/biologics
The role of systemic anti-meningioma treatment remains to be defined, due to a paucity of literature, few prospective clinical trials, and a lack of standardized response criteria by which to define drug activity.[2,4-13] Currently, and as outlined in the NCCN CNS guidelines, systemic drugs with presumed activity in recurrent meningioma comprise only three classes of agents: α-interferon, somatostatin receptor agonists, and vascular endothelial growth factor (VEGF) signaling pathway inhibitors.[3,7-13] However, the use of systemic therapy for meningioma is reserved for recurrent meningiomas that are refractory to surgery and radiation therapy, when the patient in whom such therapy is believed to be warranted has no alternative treatment options. Trials utilizing hydroxyurea, epidermal growth factor receptor inhibitors, imatinib, and a variety of hormonal therapies (tamoxifen, mifepristone, megestrol) have all demonstrated negligible activity in recurrent meningioma.[2,5,6] There are data for use of α-interferon and somatostatin receptor agonists (ie, octreotide long-acting release depot) in recurrent meningioma, although these data are very modest and predominantly from retrospective case series.[7-10] The use of somatostatin receptor agonists was based on the nearly universal uptake by meningiomas of radioisotope-labeled octreotide, which results from robust expression of somatostatin receptors on meningiomas. Also, octreotide scans are useful in defining extent of disease, both intracranially and, in instances of metastatic disease, systemically. There are evolving and prospective data regarding VEGF signaling pathway inhibitors, both bevacizumab and sunitinib.[11-13] However, a problem with the use of any of these agents is that there is no approved drug with an indication for recurrent meningioma; as a result, obtaining insurer approval can be challenging and costs can be prohibitive for patients.
There continues to be a significant unmet need for systemic therapies active in recurrent meningioma. In part, this reflects a lack of interest by pharmaceutical stakeholders. The European Organisation for Research and Treatment of Cancer is currently evaluating the utility of the marine organism–derived chemotherapy trabectedin in the treatment of surgery- and radiation-refractory meningiomas. A common practice in managing patients with recurrent meningioma in whom systemic therapy is believed warranted is the sequential use of the above-mentioned agents, wherein VEGF signaling pathway inhibitors are often reserved as a last therapy, due primarily to the challenges in obtaining drug use approval. When possible, enrollment in a clinical trial for recurrent meningioma is to be encouraged.
Financial Disclosure:Dr. Chamberlain has served on the advisory boards of Roche-Genentech and Novartis but has not received research funding from either company.
References:
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