A Narrative Review of Targeted Therapies in Meningioma

Lyndon Kim

Disclosures

Chin Clin Oncol. 2020;9(6):76 

In This Article

Abstract and Introduction

Abstract

Meningiomas are the most common primary brain tumors constituting approximately one third of all primary brain tumors. It affects mainly elderly population with increased incidence older than 65 years of age and more woman than man. It usually follows a benign course with a fairly good outcome and the surgery and or radiation therapy remain the standard of care. The prognosis remains excellent for grade I meningiomas with 10-year overall survival greater than 90%. However, although the most of the meningiomas, especially for grade I, can be cured by surgery alone, for grades II and III recurrent meningiomas, they become a clinical challenge as there are no clear standard treatment options available after re-resection or re-irradiation therapy. Prognosis is particularly poor for grade III meningiomas with 10-year overall survival of 33%. Many chemotherapeutic agents and hormonal therapies have been tried with only modest benefits. Recent advances in molecular genetic profiling and diagnostic tools greatly enhanced our understanding of the complex pathways and it opened an opportunity for potential targeted therapies for specific markers. Clinical trial results from sunitinib [multitargeted tyrosine kinase inhibitor (TKI)], bevacizumab (VEGF inhibitor), everolimus (mTOR inhibitor) and bevacizumab revealed some promising tumor response in recurrent meningiomas. Currently, many clinical trials including targeted therapies, antiangiogenic agents and immunotherapies are being investigated or under consideration.

Introduction

Meningiomas are the most common primary brain tumors constituting approximately 37% of these cases. They usually affect the elderly population (65 years old) and have a female preponderance of approximately 2:1 ratio over male (10.83:4.83 per 100,000 persons per year), however, grades II and III occur more often in males. Incidence of meningiomas is 27,000 per year (male:female =7,200:19,800 cases per year) and the prevalence is 170,000 in the United States.[1,2] The tumor is associated with previous ionizing radiation, such as treatment of tinea capitis, atomic bomb survivors and patients who received radiation to the head and neck, and germline mutations in the NF2, SMARCB1, LZTR1 or SMARCE1 genes.[3–6] Multiple studies have evaluated the hormonal risk in woman, cellular phone use, diet and allergy history, head traumas and occupational exposures, all without conclusive results.

Meningiomas can be found incidentally without symptoms and they can be simply followed with serial scans for periodic observation. Most cases that result in symptoms can be treated with surgery and radiation therapy can be added depending on the presence of residual tumor and histologic type and grade. Frequent symptoms and signs include headaches, new onset of seizures, mental status changes, focal weakness, speech difficulty and cranial nerve deficits depending on the location of the tumor. Meningiomas appear extra-axial and vascular on computed tomography (CT) and magnetic resonance imaging (MRI) of brain. Calcifications and bone involvement can be seen on CT scan. MRI scan usually reveals a dural based homogeneously enhancing lesion that has a typical tail sign. Calcification usually confers a benign low grade meningiomas while vasogenic edema are often seen in high-grade meningiomas.

Meningiomas arise from the meninges which is composed of the three protective membranes, dura mater, arachnoid mater, and pia mater, that line the skull and vertebral canal and enclose the brain and spinal cord. Meningiomas are graded based on WHO criteria from grade I, II and III which are further divided into 15 subtypes[7,8] (Figure 1) and mostly, they are considered benign compared to more aggressive tumors such as malignant gliomas.

Figure 1.

Typical mutations by WHO classification and anatomical location (7–11).

Grade I meningiomas which constitute approximately 80% are slow growing tumors that can be potentially curable if gross total resection can be achieved. Ten-year overall survival (OS) rate is around 80–90%. The most common subtypes include meningothelial, fibroblastic, and transitional.[8,12] Psammomatous, angiomatous, microcytic, secretory, lymphoplasmacyte-rich and metaplasia are less common.[8]

Grade II meningiomas are called atypical meningiomas which represent 15–18% of all meningiomas. It is characterized by the increased mitotic activity, presence of brain invasion, or by the presence of at least three of the following morphological criteria; small cells with a high nuclear to cytoplasmic ratio, high cellularity, sheeting, uninterrupted growth pattern, foci of necrosis, or prominent nucleoli. The tumor has mitotic proliferation index of 4–19 per 10 high powered fields compared to <4% in grade I. The tumor is classified as chordoid, clear cell and atypical meningioma.[8] This tumor is still considered as benign and most of these tumors can be closely observed after surgery. Radiation therapy can be an option for symptomatic patients, incomplete resection of tumor, presence of high mitotic proliferation index or brain invasion. Current ongoing NRG Oncology BN-003 clinical trial randomizing observation versus radiation therapy will answer how to best treat these patients.

Grade III meningiomas are called malignant meningiomas and they constitute about 2–4% of all meningiomas. In contrast to lower-grade meningiomas, the incidence is higher in male than female. The prognosis is poor with 10-year PFS of 32.8% (age >75) compared to 87.1% of non-malignant meningiomas (age >40).[13] The tumor is characterized by loss of typical architecture, necrosis and brain invasion and they are classified as papillary, rhabdoid and anaplastic.[8,12] Their mitotic proliferation index is higher than 20% and are difficult to treat as they tend to grow rapidly with frequent recurrences, often less than 5 years. Malignant meningioma with anaplastic features such as sarcoma, carcinoma or melanoma like histology is a rapidly growing tumor that carries a poor prognosis with PFS less than 2–3 years. Most of these patients will require additional treatments such as radiation therapy following surgery.

Approximately, 20%, 40% and 80% of WHO grade I, II and III meningiomas, respectively, will recur after the initial surgical resection. About one third of these patients could not have gross total resection at the initial presentation mainly due to its eloquent location and approximately 70% of these patients will eventually recur.

Recurrent meningiomas can be treated with re-resection if surgery could be an option. If not, these patients can be treated with conventional standard radiation therapy or stereotactic radiosurgery. Most tumors, especially higher-grade, will continue to progress with limited additional treatment options. New novel treatments are desperately needed.

I present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/cco-2020-mbt-01).

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