Meningeal Tumors

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22 Meningeal Tumors

Brian J. Goldsmith, MD, Michael W. McDermott, MD, Susan M. Chang, MD

Epidemiology

Meningiomas constitute approximately 20% of all primary intracranial tumors.¹^,² Reported incidence rates are between 1 and 5 per 100,000,²^–¹⁰ with the range perhaps reflecting differences in study design and population exposure to etiologic factors. The Central Brain Tumor Registry of the United States estimated approximately 8600 new cases of meningioma in the United States in 2002.² Most meningiomas are grossly unifocal. In computed tomography (CT)-era series, multiple synchronous lesions are seen in 40% or fewer of cases,¹¹^–¹⁶ with the majority of authors reporting multiplicity rates between 5 and 9%.¹²^–¹⁵ Intracranial sites for meningioma are listed in order of incidence in Table 22-1. Metastases are extremely rare.¹⁷^,¹⁸ The female/male ratio is approximately 2 : 1 for all meningiomas,^1,^7,⁸ and 1 : 1 for anaplastic meningiomas.¹⁹ The incidence of benign meningioma increases with age, peaking in the seventh decade of life. The incidence of anaplastic meningioma rises to a plateau in the third decade, where it remains relatively constant thereafter.¹⁹ Patients with benign and anaplastic meningioma present at a mean age of 58 ± 15 years (standard error of the mean), and 57 ± 14 years, respectively.¹⁹ In the pediatric population, meningiomas are less common, constituting 1% to 4% of all intracranial tumors. There is no female preponderance as seen with adult meningiomas, and there is a common (24%) association with neurofibromatosis.²⁰^,²¹

Table 22-1 Intracranial Sites of Meningioma

Site	Incidence, %
Cerebral convexity	34
Parasagittal	22
Sphenoid ridge	17
Lateral ventricle	5
Cerebellar convexity	5
Tentorium	4
Tuberculum sellae/parasellar	3
Olfactory groove	3
Intraorbital	2
Cerebellopontine angle	2
Foramen magnum	1
Clivus	1
Other	1

Data from Rohringer, et al: Incidence and clinicopathologic features of meningioma, J Neurosurg 71:665, 1989.

Factors considered for possible causal relationship with meningioma have included radiation, female sex hormones, trauma, and viral infection. Of these, ionizing radiation is an established etiologic factor, and female sex hormones likely contribute to risk. In addition, associations between meningioma and type 2 neurofibromatosis, and between meningioma and breast cancer, have been recognized.

Ionizing Radiation

Several case reports have identified intracranial meningioma in patients with a history of previous scalp irradiation for tinea capitis,²²^–²⁴ suggesting an etiologic role. From 1910 to 1959, an estimated 20,000 children in the United States and 200,000 worldwide received such treatments.²⁵ Ron and associates²⁶ compared the incidence of meningioma in a cohort of 10,834 children treated with ionizing radiation in Israel for tinea capitis with that of a nonirradiated control group. With an estimated 1.5 Gy delivered to the brain surface, the relative risk (RR) was 9.5 times that of the control group (95% confidence interval [CI], 3.5-25.7). The mean interval between irradiation and diagnosis with meningioma was 20 years. Rubinstein and associates²⁷ retrospectively analyzed 201 patients with intracranial meningioma, 43 of whom had received childhood radiation for tinea capitis, and identified several distinctive clinical and histologic features in the irradiated subgroup. A statistically significant (P < .001) difference in location was seen favoring falx cerebri, parasagittal, or convexity regions in the irradiated group, corresponding to the site of scalp treatment. Presentation with seizures was more common in the irradiated group (P < .005), perhaps reflecting the predominantly supratentorial location of the tumors. Histologically, the radiation-associated meningiomas (RAMs) had a significantly higher incidence of (1) high cellularity, (2) pleomorphic nuclei, and (3) numerous giant cells (P < .001). Following resection, recurrence rates were 25% versus 11% (P < .05) in the RAM and non-RAM groups, respectively.²⁷ In a comparison between 16 RAM and 17 non-RAM tumors, Rienstein et al²⁸ found no significant differences in the number of genetic changes and the extent and frequency of chromosomes 1 and 22 losses, suggesting similar molecular pathways for tumorogenesis, regardless of radiation exposure (See “Neurofibromatosis and Genetics”). Of note, radiofrequency electromagnetic field exposure, such as cell phone use, has not been associated with meningioma.²⁹

Female Sex Hormones

Several findings suggest a role of female sex hormones in the etiology and regulation of growth of meningiomas: (1) incidence in women is twice that in men;^1,^7,⁸ (2) relationship between pregnancy and increased rate of meningioma symptom progression³⁰; (3) approximately three quarters of meningiomas are progesterone receptor (PR) positive;³¹^–³⁶ (4) meningioma is less common in women with history of premenopausal bilateral oophorectomy;³⁷ and more common among postmenopausal women with ever use of hormone replacement therapy (RR = 1.7; 95% CI, 1.0-2.8) or long-term (≥10 years) use of long-acting hormonal contraceptives such as subdermal implants, injections, or hormonal intrauterine devices (RR = 2.7; 95% CI, 0.9-7.5).³⁸ Of note, receptor-negative and estrogen receptor (ER)-positive tumors are associated with higher proliferative index, worse histopathology, and more chromosomal abnormalities than PR-positive meningioma.³⁹

Trauma

Head trauma, hypothesized by some to promote tumorogenesis during the increased mitotic activity of the reparative process, has not been convincingly shown to cause meningioma. In a multicenter study of 330 meningioma cases matched to 1132 controls, Preston-Martin and colleagues ⁴⁰ found no statistically significant relationship between trauma and meningioma—results which refute the authors’ earlier observations⁴¹^–⁴³ in Los Angeles County. No increased incidence of meningioma was found in a Mayo Clinic review of 3587 residents of Olmstead County who sustained head trauma between 1935 and 1974 associated with loss of consciousness, amnesia, or skull fracture,⁴⁴ and a case-control study from Schlehofer and colleagues⁴⁵ actually found a history of head trauma protective, with an RR of 0.5.

Viral Infection

Viral antigen and DNA have been found in meningioma by several investigators.⁴⁶^,⁴⁷ It has been hypothesized that infection with papovavirus may promote meningioma by causing the loss of a tumor suppressor gene on chromosome 22.⁴⁸^,⁴⁹ However, the etiologic role of viral infection has not yet been examined epidemiologically.

Neurofibromatosis and Genetics

Losses on 22q are the most frequent genomic alterations observed in meningioma.⁵⁰^,⁵¹ Type 2 neurofibromatosis (bilateral acoustic neurofibromatosis, NF2), characterized cytogenetically by the loss of the NF2 gene from 22q12, is associated with an increased incidence of meningioma.⁵² Based on the most common chromosomal aberrations identified in the various grades of meningioma, a model for progression has been proposed by Weber et al⁵⁰ that initiates the clonal expansion from normal meningeal cells to benign World Health Organization (WHO) Grade I meningioma with loss on 22q, and continues with cumulative genetic alterations on other chromosomes in higher grade tumors (loss on 1p, 6q, 10, 14q, 18q, and gain on 1q, 9q, 12q, 15q, 17q, and 20 in atypical WHO Grade II; followed by loss on 9p and amplification on 17q in anaplastic WHO Grade III). Quantitative measure of accumulation of chromosome change correlates highly with early tumor recurrence.⁵³ Perhaps contradicting stepwise clonal evolution, Al-Mefty et al have demonstrated deletions of 22, 1p, and 14q ab initio in histologically lower grade tumors that later recur and progress to higher grade, suggesting that benign meningioma presenting with complex genetic alterations are potentially aggressive and require closer follow up.⁵⁴

Breast Cancer

Both the risk of developing meningioma in patients who have had breast cancer and the risk of developing breast cancer in patients who have had meningioma are higher than in the general population.⁵⁵ The association may be explained by a hormonal effect or possibly by a shared chromosome 22 abnormality.⁵⁶^–⁵⁸

Pathology

Meningiomas are thought to arise from arachnoidal cap cells that are found on the outer surface of the arachnoidal membrane between the dura and pia mater. Cells of the arachnoidal membrane uniquely display both mesenchymal and epithelial characteristics, capable of fibro-lipo-chondro-osteoblastic differentiation as well as of well-formed desmosomal connections between tumor cells and other structural and histochemical features usually attributed to epithelial neoplasms. Though much meningioma literature is based on legacy classification systems, most neurooncology communities have now adopted the WHO classification.⁵⁹

Conventional histologic subtypes, including meningothelial, fibrous, transitional, psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich, and metaplastic, have no apparent prognostic importance.⁶⁰ By contrast, four rare variants (each constituting <1% of all meningiomas) have characteristically aggressive behavior:

Clear cell, composed of sheets of clear, glycogen-rich, polygonal cells forming only a few vague whorls; often with extensive stromal and perivascular hyalinization; frequently deceptively benign appearance with few mitotic figures.⁶¹

Chordoid, mimicking chordoma with lobular low-power architecture and production of stroma mucosubstances, but with scant reactivity for chordoma-typical epithelial membrane antigen, cytokeratin, and S-100.⁶²

Rhabdoid, usually seen in association with conventional histological subtypes, with increasing prominence with each recurrence; characterized by sheets of loosely cohesive cells with eccentric nuclei and hyaline paranuclear inclusions.⁶³

Papillary, seen both as the predominant morphology and in association with one of the conventional histologic subtypes; characterized by a striking papillary pattern with foci of necrosis, numerous mitotic figures, and local invasiveness.⁶⁴

Since the 1993 WHO revision,⁶² characteristically aggressive hemangiopericytomas and hemangioblastomas have been deemed nonmeningothelial in origin and are no longer classified as meningiomas.

2007 WHO Classification ⁵⁹

Grade I: does not fulfill criteria for grades II (atypical) or III (anaplastic).

Grade II (atypical): Any of the following criteria:

Four or more mitoses per 10 high-power fields

Brain invasion

Three or more of the following:

Increased cellularity

Small cells

Necrosis

Prominent nucleoli

Sheeting architecture

Grade III (anaplastic): Either of the following criteria:

Twenty or more mitoses per 10 high-power fields

Obviously malignant cytologic characteristics such that tumor cell resembles carcinoma, sarcoma, or melanoma.

Clear cell and chordoid histologic subtypes are assigned grade II, and rhabdoid and papillary subtypes are assigned grade III. In the 2007 WHO classification, inclusion of brain invasion as a criterion for atypia is the only significant modification to the former (2000) grading scheme.

Most meningiomas are grade I. From a series of 581 consecutively resected patients from the Mayo Clinic, 81% were grade I and 19% grade II (data modified to reflect 2007 WHO classification).⁶⁵ Grade III meningiomas are rare.

Proliferation indices based on MIB-1 labeling of Ki-67 nuclear protein or PC10 labeling of proliferating cell nuclear antigen (PCNA) are powerful adjuncts that offer additional prognostic information. High indices reflect increased proliferative activity and recurrence potential.⁶⁶^–⁷¹ Identification and quantitative measure of accumulation of chromosome change correlate highly with early tumor recurrence.⁵³^,⁷²

At the time of this chapter’s preparation, the 2007 WHO classification has not yet been examined for prognostic utility in new radiotherapy studies. However, meningioma grade as defined by similar legacy systems,^62,^73,⁷⁴ has been established of clear prognostic importance, with atypia and anaplasia associated with more frequent and earlier recurrence.⁷³^–⁷⁶ For example, postradiotherapy 5-year progression-free survival (PFS) rates of 94% versus 78% for 1993 WHO Grade I versus Grade II (P = .02),⁷⁵ 95% versus 0% for 1993 WHO Grade I versus Grade II/III (P < .01),⁷⁶ and 89% versus 49% for University of California, San Francisco (UCSF) system benign versus malignant (P = .001)⁷³ have been reported.

Clinical Presentation and Diagnostic Evaluation

In practice, the radiation oncologist’s relationship with the meningioma patient often begins in the postoperative setting, after a thorough diagnostic evaluation, optimal resection, and confirmation of histologic diagnosis has been undertaken by the neurosurgeon. Radiotherapy may also be considered for primary management of meningioma, without surgery, when diagnosed by imaging criteria (e.g., homogeneously enhancing, dural-based tumor without rapid growth, and no metastatic disease).

Evaluation begins with a detailed history and physical examination. Presenting complaints and physical findings, listed in order of frequency, are found in Tables 22-2 and 22-3, respectively. Patients with visual complaints should be evaluated with formal visual field and acuity testing before surgery or radiation therapy. Patients with hearing loss should be tested with formal audiometry.

Table 22-2 Presenting Complaints

Complaints	Incidence, %
Headache	37
Personality change/confusion	22
Paresis	19
Generalized seizures	19
Visual impairment	16
Focal seizures	15
Ataxia	15
Aphasia	10
Decreasing level of consciousness	7
Paresthesia	6
Diplopia	3
Vertigo	1
Decreased hearing	1

Data from Rohringer, et al: Incidence and clinicopathologic features of meningioma, J Neurosurg 71:665, 1989.

Table 22-3 Physical Findings

Finding	Incidence, %
Paresis	30
Nonfocal examination	26
Memory deficit	15
Cranial nerve deficit other than CN II	12
Visual field deficit	10
Paresthesia	9
Aphasia	9
Papilledema	8
Decreased visual acuity	6
Altered level of consciousness	5
Nystagmus	3
Decreased hearing	2

Data from Rohringer, et al: Incidence and clinicopathologic features of meningioma, J Neurosurg 71:665, 1989.

Pediatric patients with convexity or parasagittal meningiomas often present with seizures, focal deficits, or signs of increased intracranial pressure (ICP), and those with intraventricular lesions typically present with elevated ICP, hemiparesis, and hemianopia. In addition to these typical presenting signs and symptoms, increasing head circumference as a first sign of meningioma is also seen in children.⁷⁷

Adult patients with spinal meningioma most often present with pain (72%), which usually antedates other symptoms by months to years, followed by sensory loss and weakness, followed by bowel and bladder dysfunction.⁷⁸ Children with spinal meningioma, unlike adults, most often present with extremity weakness (57%), followed by back pain, bowel and bladder dysfunction, and extremity pain. In children, back and extremity pain may be expressed as increased irritability.⁷⁹

CT and magnetic resonance imaging (MRI) with contrast yield information regarding tumor size, location, potential resectability, and proximity to critical neurologic structures. Meningiomas are generally well circumscribed and smooth in contour. Most are homogeneously high density on unenhanced CT scans, 25% to 33% are isodense, about 1% are hypodense, and a few demonstrate mixed attenuation. The majority demonstrate moderate to intense homogeneous enhancement following administration of contrast, with the degree of enhancement dependent on tumor vascularity and extracellular accumulation of the contrast material. Peritumoral edema is seen in 60% of cases, and associated bony changes (destruction or hyperostosis) in 15% to 20%.⁸⁰ The degree of preoperative peritumoral has been reported to correlate positively with probability of brain invasion⁸¹ and postoperative neurologic deficit.⁸²

On MRI, meningiomas are typically isointense with gray matter on both T₁– and T₂-weighted images, and intensely enhanced when contrast is used. A radiographic feature that is suggestive of, but not specific for, meningioma is linear meningeal thickening and enhancement adjacent to a peripherally located cranial mass—the so-called “dural tail sign.”⁸⁰^,⁸³ This has been reported in 60% of meningiomas, but can also been seen in chloroma, lymphoma, and sarcoidosis. The enhancement of the meningioma dural tail usually represents reactive changes and does not necessarily indicate neoplastic involvement.⁸⁴^–⁸⁶ Intratumoral inhomogeneities are often seen on MRI, associated with calcifications, central necrosis, pseudocysts, and vascular spaces. Intratumoral hemorrhage is unusual. Displacement of the gray-white interface, peritumoral edema, and adjacent encephalomalacic changes are better seen with MRI than CT, whereas osseous changes and calcification are better seen with CT than MRI.⁸⁰^,⁸⁷

Meningiomas also show high expression of the somatostatin-receptor subtype 2, enabling visualization with [68Ga]-DOTATOC-PET with very high meningioma to background ratios.⁸⁸ Milker-Zabel et al have demonstrated complementary spatial information in a comparison of planning tumor volume (PTV) obtained with CT-MRI versus CT-MRI-[68Ga]-DOTATOC-PET, with the later smaller than CT-MRI in 35%, similar in 26%, and larger in 39%.⁸⁹

Standard Therapeutic Approaches

Benign meningiomas are well managed with total excision if achievable with minimal morbidity, resulting in 5-, 10-, and 15-year PFS rates of 93%, 80%, and 75%, and 5-, 10-, and 15-year cause-specific survival (CSS) rates of 95%, 93%, and 88%, respectively.⁹⁰ Approximately one in three meningiomas is not fully resectable,⁹¹ however, because of tumor location, size, and proximity to adjacent critical central nervous system (CNS) and vascular structures. In the skull base, total resection is accomplished about half the time⁹¹^,⁹² and is less likely in the setting of previous irradiation, vessel encasement, multiple fossa involvement, and cranial nerve palsies.⁹² Although subtotal resection is an appropriate goal when decompression is expected to result in amelioration of symptoms, it is inadequate as a sole modality, with inferior 5-, 10-, and 15-year PFS of approximately 50%, 40%, and 30%, and CSS of 80%, 66%, and 50%,⁹⁰ respectively.

Fractionated radiotherapy ⁹³ or single fraction radiosurgery,⁹⁴ as primary management without surgery or after subtotal resection of benign meningioma, yields long-term PFS superior to subtotal resection and comparable to total excision, with low morbidity.

Atypical meningioma has an intermediate prognosis, with a 5-year PFS of 59% to 87%.⁶⁵^,⁹⁵ Characteristics associated with higher likelihood of recurrence include subtotal resection,⁹⁵^,⁹⁶ as well as brain invasion,⁶⁵^,⁹⁵ high proliferative indices,⁹⁷ numerous mitoses,⁹⁸ and chromosomal change accumulation^53,^72,⁹⁹ regardless of degree of resection. Adjuvant irradiation is recommended for subtotally resected or brain-invasive atypical meningioma, and should be considered for completely resected tumors with the above high-risk features (Fig. 22-1).¹⁰⁰

FIGURE 22-1 • The atypical and anaplastic meningioma treatment algorithm.

(From Modha A, Gutin PH: Diagnosis and treatment of atypical and anaplastic meningiomas: a review, Neurosurgery 57(3):538–550, 2005.)

Anaplastic meningiomas are likely to recur postoperatively, with a median PFS of 32 months and 5-year PFS rate of 29% to 44%.⁶⁵^,⁹⁵ Adjuvant irradiation for anaplastic tumor is independently associated with an improved PFS rate⁹⁵ and is recommended regardless of degree of resection.⁹⁵^,¹⁰⁰

Fractionated Radiotherapy

Technique

Meningiomas selected for fractionated radiotherapy include well-circumscribed and diffuse/irregular tumors of all sizes and intracranial locations, including those abutting the optic nerve or chiasm. Patients may be irradiated after subtotal resection or recurrence or as primary management without surgery when diagnosed by imaging criteria (e.g., homogeneously enhancing dural-based tumor without rapid growth and no metastatic disease).

Optimal radiation therapy requires meticulous attention to tumor volume as delineated by the neurosurgeon’s description as well as CT and MRI findings. MRI is superior to CT, with its exquisite resolution, absence of bone artifact, intense tumor contrast enhancement, and coronal and sagittal viewing advantages. In a comparison studied by Khoo and colleagues,⁸⁷ however, MRI-defined meningioma volumes were larger but not inclusive of CT-defined volumes, suggesting complementary spatial information and a role for treatment planning with composite CT/MRI volumes. Milker-Zabel et al have also demonstrated complementary tumor imaging with CT/MRI and [68Ga]-DOTATOC-PET,⁸⁹ suggesting composite use of all three modalities when available. Pre- and postoperative studies should be utilized in treatment planning when available. The PTV consists of the clinical tumor volume (CTV) plus a margin of 5 mm for conventional mask immobilization or 2 to 3 mm for stereotactic frame-based immobilization technique.^75,^101,¹⁰² For benign (WHO Grade I) meningioma, the CTV includes the composite gross tumor volume (GTV) in the setting of primary radiotherapy, and residual composite GTV in the adjuvant setting. After surgery, the CTV may be expanded beyond the remaining radiographic GTV to encompass microscopic residua based on the neurosurgeon’s description of intraoperative findings and an appreciation of the preoperative dural base. Because (1) the majority of benign meningioma recurrences following stereotactic fractionated radiotherapy⁷⁵ are not marginal, and (2) microscopic involvement of the adjacent dura is typically confined to the first millimeter or two from the gross tumor,⁸⁴^–⁸⁶ routine inclusion of the entire dural tail in the CTV has not been demonstrated to be necessary. Atypical and anaplastic meningioma also rarely fail marginally when treated with a CTV 10 mm beyond GTV, operative bed, hyperostotic bone, and dural thickening.¹⁰³ For anaplastic tumors the CTV also includes peritumoral edema if present,¹⁰³ or a rim of adjacent normal brain parenchyma if not.

Five-mm set-up error precision is achieved by use of an immobilization system, consisting of a head support, a thermoplastic mask that is molded to the patient’s head, and a frame that locks the mask and head in a reproducible position. Fused CT/MRI computerized treatment planning should be used, with treatment-planning scans obtained with the patient in the treatment position, wearing the immobilization device with radio-opaque fiducials. The use of such careful tumor localization and immobilization techniques has been shown to have greater prognostic importance than tumor size or radiotherapy dose, and has been associated with a 5-year PFS for benign meningioma which is significantly better (98% vs 77%, P = .002) than that achieved without such techniques.⁷³ With the addition of a stereotactic frame and localization system, set-up error is reduced to 2 mm, allowing for a tighter PTV and less normal tissue irradiation.⁷⁵^,¹⁰¹

Optic nerve sheath meningiomas require precision conformal therapy, such as described by Eng and colleagues.¹⁰⁴ The patient is positioned supine with the head rotated laterally, so that the affected optic nerve is approximately perpendicular to the horizontal plane. The appropriate angle of lateral head rotation can be estimated from diagnostic CT scans. In the series from Eng’s group, this value ranged from 15 to 27 degrees. Neck flexion should establish an imaginary vertical line on the lateral simulation film from the center of the orbit to a point just superior to the pituitary fossa. In this position, the patient’s head is immobilized with a head support, thermoplastic mask, and locking frame as just described. The treatment-planning CT scan is then obtained with the patient in this position, wearing the immobilization mask. Three small half-beam blocked fields are set up isocentrically with axes lying in the horizontal plane. Treatment table rotation is used to produce a vertex field and two superior-lateral fields. The superior-lateral fields are angled to avoid the contralateral eye and optic nerve. The beams are split perpendicular to the vertical axis and the anterior half is blocked in order to prevent anterior divergence toward the globe. Differential field weighting is used to optimize the isodose distribution, and the prescribed isodose volume (with 5% or less heterogeneity) should encompass the PTV. Stereotactic technique is particularly appropriate in this setting in order to minimize set-up error and PTV and maximize organ-at-risk (OAR) sparing.¹⁰⁵^,¹⁰⁶

For other intracranial sites, multiple static fields should be selected to minimize dose to the uninvolved CNS tissues (Figs. 22-2 and 22-3). Opposed lateral fields should be avoided in practically all cases to prevent unnecessarily irradiating lateral CNS structures such as the temporal lobes. Intensity-modulated radiotherapy (IMRT), consisting of objective weighting, inverse planning, and fluence modulation, yields target coverage, target conformity, and OAR sparing superior to conventional radiotherapy, particularly for complex tumor volumes, at the expense of larger volumes of normal tissue receiving a low dose (Fig. 22-4).¹⁰⁷^,¹⁰⁸ Careful conformal technique should limit inhomogeneity of dose to less than 10% (ideally less than 5%). No portion of the optic nerve or chiasm should receive greater than 54 Gy at 1.8 Gy per fraction.¹⁰⁹ A dose of 54 Gy at 1.8 Gy per fraction for 5 days a week is generally given to benign (WHO Grade I) meningiomas,⁷³^,⁹³ and for atypical and anaplastic (WHO Grade II and III) lesions, the dose is increased to 59.4 to 61.2 Gy¹⁰³^,¹¹⁰ Dose-response relationships have been demonstrated,^73,^103,^111,¹¹² with 54 Gy and 60 Gy conventionally fractionated yielding a significantly better PFS than lower dose schedules for benign¹¹² and atypical or anaplastic¹⁰³ meningiomas, respectively. Aggressive fractionated radiotherapy beyond 60 Gy is more toxic and has not been demonstrated to improve local control.¹¹⁰^,¹¹³ Anaplastic lesions may be considered for radiosurgery boost following external beam radiotherapy, if the tumor volume is well defined and small.¹¹⁴

FIGURE 22-2 • Axial plane intensity-modulated radiation therapy isodose plan for right cavernous sinus meningioma.

FIGURE 22-3 • Coronal plane intensity-modulated radiation therapy isodose plan for right cavernous sinus meningioma.

FIGURE 22-4 • Intensity-modulated radiation therapy dose volume histogram for right cavernous sinus meningioma.

Outcome

Fractionated radiotherapy as primary management without surgery ^75,^93,¹¹⁵ or after subtotal resection of benign meningioma^73,^75,⁹³ yields a 5-year PFS between 91% and 98%, which is superior to subtotal resection and comparable to total excision, and symptom improvement in 43% to 72% (Table 22-4). (Note that Table 22-4 excludes reports published before 1994, because those series did not use CT- and/or MRI-based targeting and dose planning, in contradistinction to all contemporary single- or multifraction radiation treatments of meningiomas.) Multivariate analyses demonstrate no relationship between PFS and degree of resection or tumor size.^73,^75,^93,¹¹⁶

Table 22-4 Fractionated Radiotherapy for Benign Meningiomas

Mendenhall and colleagues ⁹³ treated 101 patients with skull base meningiomas between 1984 and 2001with fractionated radiotherapy alone (n = 66) or after subtotal resection (n = 35). The median dose was 54 Gy. After median follow-up of 5 years, 5-, 10-, and 15-year PFS rates were 95%, 92%, and 92%, respectively, and the corresponding CSS rates were 97%, 92%, and 92%, respectively, both independent of previous surgery.

Milker-Zabel and coworkers ¹¹⁷ reported the University of Heidelberg’s experience in treating 317 patients (153 benign tumors, 26 atypical tumors, 138 unbiopsied tumors) between 1985 and 2001 with stereotactic fractionated radiotherapy to a median dose of 57.6 Gy. After a median follow-up of 5.7 years, 5- and 10-year PFS rates were 91% and 89%, respectively, for benign and unbiopsied tumors. Pretreatment neurologic deficits improved in 43% of patients and worsened in 8%. Improvement was seen in diplopia in 39 (37%) of 106 patients, exophthalmos in 17 (38%) of 45 patients, trigeminal hypoesthesia or dysesthesia in 20 (24%) of 82 patients, and trigeminal neuralgia in nine (33%) of 27 patients. Twenty-two percent of patients with preexisting cranial nerve deficits experienced complete resolution. A previously published analysis of University of Heidelberg skull base meningiomas⁷⁵ (a subset of those described by Milker-Zabel’s group) found no difference in PFS between primary radiotherapy without surgery and postoperative radiotherapy.

Maire and colleagues ¹¹⁶ have described the Hôpital Saint-André experience with radiotherapy alone for 44 inoperable or unresectable patients between 1981 and 1993. The median dose was 52 Gy. After a median follow-up of 3 years, the crude PFS rate was 93%. When reported in combination with 51 patients treated for other indications (subtotal resection, salvage after recurrence, and total resection with unfavorable histology) overall neurologic performance improved in 72% of patients.

Optic nerve sheath meningioma is frequently irradiated without previous surgery. Narayan and coworkers ¹¹⁵ described 14 such patients treated (12 without surgery) between 1986 and 2001 with three-dimensional conformal fractionated radiotherapy to a median dose of 54 Gy and followed for a median 4 years. The radiographic PFS rate was 100%. Visual acuity significantly improved, remained stable, and worsened in 36%, 50%, and 14% of patients, respectively. Of nine patients with complete baseline and follow-up visual fields testing, all significantly improved.

Goldsmith and colleagues ⁷³ reported on 117 patients irradiated after surgery to a median dose of 54 Gy for benign meningioma. After a median follow-up of 3 years, 5-year PFS rate for patients treated after 1980, when CT or MRI imaging was used for treatment planning, was 98%. Local control of orbital, parasellar, and posterior fossa tumors, notoriously difficult to completely resect and therefore associated with higher recurrence rates in the surgical literature,⁹¹ did not differ significantly from all other sites.

Reflecting the relative rarity of atypical and anaplastic histology, the treatment of higher grade meningiomas is described in studies that include small numbers of patients. The University of Heidelberg series cited above ¹¹⁷ included 26 patients with atypical tumors. Stereotactic fractionated radiotherapy to a median dose of 57.6 Gy yielded 5- and 10-year PFS rates of 89% and 67%, respectively. From the University of Florida, Katz and coworkers¹¹⁰ reported a 45% 5-year PFS rate for 36 atypical and anaplastic tumors combined, after conventionally fractionated radiotherapy (55 to 60 Gy) or accelerated radiotherapy (1.5 Gy twice daily to 60 Gy +/− 12.5-Gy radiosurgery boost), with outcome independent of dose, fractionation, and radiosurgery boost.

Toxicity

Common acute toxicities of fractionated radiotherapy for meningioma are, in general, mild and include fatigue, skin erythema, and varying degrees of dose-related alopecia (which may be transient or permanent). If the external auditory canal and middle ear are not excluded from the prescription volume and irradiated field, an external otitis and serous otitis media may result. Rarely seen are acute transient symptoms suggestive of increased ICP (e.g., headache, nausea, vomiting) and exacerbation of preradiation therapy neurologic deficits.¹¹⁸ The risk of radiation induced edema is low.^73,^93,¹¹⁷

Late effects are dependent on the region irradiated and uncommon when OAR dose tolerances are respected. Chronic otitis ¹¹⁹ and decreased hearing,^75,^119,¹²⁰ have been reported after irradiation of the ear. Retinopathy^73,^120,¹²¹ and optic neuropathy* have been reported after irradiation of the globe to doses above 45 Gy and after irradiation of the anterior visual pathway to doses above 54 Gy, respectively. Cerebral necrosis^73,^74,^103,^113,^119,¹²⁴ and focal neurologic deficits suggestive of late brain injury have been seen, particularly after doses greater than 60 Gy, a dose per fraction greater than 1.8 to 2 Gy, and opposed lateral technique.¹⁰³^,¹¹⁸ Hypopituitarism manifested by hyposecretion of growth hormone, luteinizing hormone, follicle stimulating hormone, corticotropin, and thyrotropin (in order of radiosensitivity) is expected after irradiation of the hypothalamic-pituitary axis region and has been reported after radiation therapy for meningiomas.¹²² Mechanisms of injury and time-dose analyses for radiation injury to the visual apparatus,* brain,¹¹⁸^,¹²⁷ and pituitary gland¹¹⁸^,¹²⁸ are available to the interested reader.

Goldsmith and colleagues ⁷³ reported a crude incidence of radiation complications of 4% (five of 140 patients treated to a wide range of target volumes between 1967 and 1990). Two patients experienced retinopathy, and one experienced optic neuropathy. One of two patients with cerebral necrosis recovered after decompressive craniotomy, and the second died of bronchopneumonia secondary to chronic brain syndrome. As a consequence of the recognition of these complications and a subsequent analysis of optic neuropathy risk,¹⁰⁹ UCSF established an institutional policy to avoid using the high-dose opposed lateral technique and exceeding a maximum dose of 54 Gy to the optic nerve whenever possible.

Mendenhall and coworkers ⁹³ described a crude incidence of late radiation complications of 6% (six of 101 patients treated to a wide range of target volumes between 1984 and 2001). Two patients experienced gradual progressive dementia. One developed edema after radiotherapy as primary management and subsequently underwent resection of the meningioma. Three suffered significant peritumoral edema refractory to steroids, resulting in progressive neurologic compromise and death.

Milker-Zabel and colleagues ¹¹⁷ reported a crude incidence of late grade 3 toxicity of 2.5% (eight of 317 patients treated between 1985 and 1998). Two patients experienced reduced vision, one had trigeminal neuropathy, and five developed intermittent tinnitus.

The future incidence of complications is expected to decline as modern OAR-sparing treatment techniques become uniformly applied.

Single-Fraction Radiosurgery

Technique

Meningiomas selected for stereotactic radiosurgery include discrete, small- to medium-sized tumors (generally 30 to 35 mm) located in sites that can be treated without exceeding tolerance dose constraints of nearby or encompassed critical structures, such as the optic nerves, chiasm and brainstem. Patients may be irradiated after subtotal resection or as primary management without surgery when diagnosed by imaging criteria, (e.g., homogeneously enhancing, dural-based tumor without rapid growth) and when there is little or no surrounding symptomatic vasogenic edema.

For several delivery systems, a stereotactic frame is fixed to the patient’s head under local anesthesia, and imaging is acquired with a stereotactic localizer to define tumor and normal tissue anatomy relative to the frame. Some robotically controlled radiosurgery systems do not require application of a stereotactic frame, but rather rely on thermoplastic mask fixation and plain x-ray/CT scan image coregistration to define stereotactic space for treatment. The necessity of including the entire dural tail within the target volume is unclear. Although recommended by DiBiase and colleagues ¹²⁹ on the basis of univariate association between tail inclusion and local control, this factor was also significantly associated with target conformity and insignificant on multivariate analysis. Patterns of failure were not reported, complicating interpretation. Available data on radiosurgery failure location is conflicting, with Stafford and coworkers⁹⁴ and Rowe and colleagues¹³⁰ describing marginal failure as infrequent (three of 16 cases) and common (12 of 16 cases), respectively. Because microscopic involvement of the dura is typically confined to a distance of 1 to 2 mm beyond the gross tumor,⁸⁴^–⁸⁶ inclusion of the first several millimeters of adjacent dura within the target volume may be sufficient.

Dose prescriptions are based on tumor size, location, and history of previous radiotherapy. At the Mayo Clinic,⁹⁴ tumor margin doses (TMDs) of 16, 18, and 20 Gy have generally been selected for isodose volumes more than 14.1, 4.2 to 14.1, and less than 4.2 cm³, respectively. At the University of Pittsburgh,¹³¹^,¹³² TMDs between 12 and 18 Gy have been used, and lower doses between 12 and 14 Gy have been typical since 1993.¹³²^,¹³³ Shin and coworkers¹³⁴ have reported a local failure rate of 20% associated with TMDs between 10 and 12 Gy versus 0% with a TMD greater than 14 Gy. In the treatment of atypical and anaplastic meningiomas, higher TMDs up to 20 Gy have been employed.¹³⁵ The maximum dose to the optic nerve and chiasm is limited to 8 to 12 Gy to a small portion (Mayo Clinic),¹³⁶ 8 Gy (University of Pittsburgh),¹³⁷ 10 Gy (Medical University Graz),¹³⁸ and 8 Gy (UCSF) (Fig. 22-5).

FIGURE 22-5 • Axial plane radiosurgery isodose plan for left cavernous sinus meningioma.

Outcome

Single-fraction radiosurgery as primary management without surgery ^94,^139,¹⁴⁰ or after subtotal resection⁹⁴^,¹⁴⁰ of benign meningioma yields a 5-year PFS rate between 86% and 98%, which is superior to subtotal resection and comparable to total excision, and symptom improvement in 13% to 42% of patients (Table 22-5).

Table 22-5 Stereotactic Radiosurgery for Benign Meningiomas: Selected Series Since 2000 With 5-Year Progression-Free Survival

Kreil and colleagues ¹³⁸ treated 200 patients with meningioma (99 after surgery with benign histology and 101 without previous surgery) between 1992 and 1999 to a median TMD of 12 Gy, with a median isodose volume of 6.5 cm³. After a median follow-up of almost 8 years, the 5- and 10-year PFS rates were 99% and 97%, respectively. Preexisting neurologic symptoms improved in 42% of patients, with most improvements in visual fields, trigeminal neuralgia, and diplopia.

Stafford and coworkers ⁹⁴ described radiosurgery for 190 patients with meningiomas treated between 1990 and 1998 to a median TMD of 16 Gy, with a median isodose volume of 8.2 cm³. Forty-one percent were treated primarily without surgery and 59% had had at least one previous operation. After a median follow-up of 3 years, benign meningioma 5-year PFS and CSS rates were 93% and 100%, respectively, independent of previous surgery. Preexisting neurologic symptoms (diplopia or facial pain) improved in 8% of patients. Subsequently, Pollock and colleagues¹³⁹ from the same institution compared contemporary patients managed with primary radiosurgery to a mean TMD of 18 Gy (n = 62) or resection (n = 136; 57 Simpson grade 1, 57 grade 2, and 22 grades 3 and 4). After a median follow-up of 5 years, tumor recurrence and/or progression was more frequent in the surgical group (11%) than in the radiosurgical group (2%; P < .05). The 7-year PFS rate achieved with radiosurgery (95%) was equivalent to that after Simpson grade 1 excision (all tumor, attached dura, involved bone: 96%) and superior to anything less than this (Simpson grades 2 and 3-4: 82% and 34%, respectively). Symptoms improved in 13% of patients after resection (visual fields, trigeminal neuralgia, and gait) and 13% of patients after radiosurgery (trigeminal neuralgia, diplopia, facial hypoesthesia, and visual fields). Subsequent tumor treatments were less common after primary radiosurgical management, and there were fewer complications as well. The authors suggested that if the long-term tumor control rates remain high and morbidity remains low, radiosurgery can be considered as the primary form of treatment for small- to medium-sized meningiomas without symptomatic mass effect.

Kondziolka and coworkers ¹⁴¹ reported on the treatment of 872 meningiomas with a mean volume of 7.4 cm³. Fifty-one percent of the patients were treated primarily, and 49% had had at least one previous operation. The mean TMD was 14 Gy. After a median follow-up of 4 years, the 5- and 10-year PFS rates for the primary radiosurgery group were 97% and 87%, respectively, and for the adjuvant radiosurgery benign meningioma group were 91% and 86%, respectively. In the patients treated primarily, 215 (44%) of 488 tumors shrank, 256 (52%) were unchanged, and 19 (4%) enlarged. Recurrences did not typically arise from the dural tail. Eighty-seven (17%) of 502 primarily treated patients neurologically improved, 380 (76%) were unchanged, and 35 (7%) worsened. In the patients treated adjuvantly, 172 (45%) of 384 tumors shrank, 186 (48%) were unchanged, and 26 (7%) enlarged. Twenty-one (5%) of 398 primarily treated patients neurologically improved, 341 (86%) were unchanged, and 36 (9%) worsened. Combining primarily and adjuvantly treated patents, local control probability correlated with tumor volume (P = .01) and multiplicity (P = .03), but not TMD (P = .61).

Malik and colleagues ¹⁴⁰ treated 309 meningiomas (44% without previous surgery, 56% after surgery) with a mean volume of 7.3 cm³ between 1994 and 2000 with single-fraction radiosurgery. The median TMD was 20 Gy, but in 52% of cases part of the tumor received less than the prescribed dose to safeguard neurological, most commonly visual, function. After a mean follow-up of almost 4 years, 5- and 8-year benign meningioma PFS rates were 87% and 75%, respectively. Neither conformity nor the volume of tumor receiving less than 5, 10, or 15 Gy influenced outcome.

Although no randomized trial of radiotherapy treatment techniques for meningiomas has been published, Metellus and coworkers ¹⁴² reviewed their own experience with a small series of cavernous sinus meningioma patients treated with fractionated radiotherapy or radiosurgery at a single institution (Table 22-6). Radiosurgery was performed in accordance with commonly accepted techniques, whereas radiotherapy in this retrospective study involved several different fractionation schemes, including some that are associated with a higher risk of complication. The median follow-up was 88.6 months for the fractionated radiotherapy group and 63.6 months for the radiosurgery group. Selection of treatment modality was based on the availability of radiosurgery (after 1992) or on the lesion size, shape, or proximity to critical structures. Although tumor configuration, size, and Sekhar grade were less favorable in the fractionated radiotherapy group, actuarial PFS and clinical improvement rates were not different between the two treatment groups. The radiographic shrinkage was higher in the radiosurgery group (52.7% versus 29%) and was noted to increase in longer follow-up from a subset of patients previously analyzed out to only 30 months (31% shrinkage at 30 months of mean follow-up). In any case, the degree of postradiation shrinkage does not seem to be correlated with any other outcome variable. The authors concluded that for cavernous sinus meningiomas, fractionated radiotherapy and radiosurgery were both safe and effective techniques for securing long-term tumor control.

Table 22-6 Retrospective Comparison of Fractionated Radiotherapy and Gamma Knife Radiosurgery for Cavernous Sinus Meningiomas

As is the case with fractionated radiotherapy, the higher grade meningioma radiosurgery literature is limited in terms of numbers of patients treated. Harris and colleagues ¹¹⁴ described the University of Pittsburgh experience treating 18 patients with atypical tumors and 12 patients with anaplastic tumors, with mean TMD and isodose volumes of 15 Gy and 15 cm³ for atypical tumors and 16 Gy and 12 cm³ for anaplastic tumors. Twenty-four (80%) of these 30 patients also received fractionated radiotherapy to a mean dose of 54 Gy. Sixteen patients were treated early with adjuvant intent, and 14 were treated late, after radiographic progression. With a median follow-up of 3.8 years, the 5-year PFS rates for atypical and anaplastic meningioma were 83% and 72%, respectively. The median PFS rates were 38 months in the early treatment group versus 13 months in the late group (P = .06). Kondziolka and colleagues¹⁴¹ subsequently updated the University of Pittsburgh experience, reporting on the treatment of 54 atypical and 29 anaplastic meningiomas (which may have included those previously described by Harris and colleagues). With a median follow-up of 2 and 1.3 years for atypical and anaplastic meningiomas, respectively, the 5-year PFS rates were 45% and 13%, respectively.

Kano and coworkers ¹³⁵ treated 10 patients with atypical meningioma after progression to a median TMD of 19 Gy (range: 12 to 20 Gy) with a median isodose volume of 2.9 cm³. On univariate analysis, only TMD was predictive of local recurrence: after a mean follow-up of 43 months, the 5-year PFS rates were 63% for patients treated to 20 Gy TMD versus 29% for patients treated to lower doses (P = .01). Huffmann and colleagues¹⁴³ treated 15 patients with atypical meningioma to a median TMD of 16 Gy (range: 14 to 18 Gy) with a median isodose volume of 5 cm³. After a median follow-up of 35 months, 4 (27%) of 15 patients recurred locally or marginally. Stafford and coworkers⁹⁴ treated 13 patients with atypical meningioma and nine patients with anaplastic meningioma (see above for description of technique), with 5-year PFS rates of 68% and 0%, respectively.

Toxicity

Stafford and coworkers ⁹⁴ described a crude complications rate of 13% (24 of 190 patients) after treatment to a median TMD of 16Gy, including 15 new or worsened cranial neuropathies with a median onset of 6 months (two resolved), five cases of symptomatic edema, two internal carotid artery (ICA) occlusions, and two peritumoral cysts (Table 22–7). Pollock and colleagues¹³⁹ reported complications in 6% (6 of 62 patients) after treatment to a mean TMD of 18 Gy, including diplopia in one patient, trigeminal neuralgia and/or hypoesthesia in three patients, cyst formation requiring a shunt in one patient, and ICA occlusion in one patient, respectively.

Table 22-7 Complication Rate After Radiosurgery for Benign Mengiomas: Series of More Than 100 Patients

Kodziolka and coworkers ¹⁴¹ reported a 9% 10-year complication rate after treatment to a mean TMD of 14 Gy, including hydrocephalus in 0.4% of patients, cranial nerve deficit in 3.4% of patients, headache in 2.2% of patients, seizure in 2.4% of patients, a motor deficit in 1.4% of patients, and a sensory deficit in 0.3% of patients. A ventriculoperitoneal shunt was placed in 0.5% of patients. Symptoms completely resolved in 35% of those who sustained morbidity. On multivariate analysis, tumor volume correlated with risk of complications (P < .001, RR = 1.1 per cm³), but not TMD (P = .95).

Malik and colleagues ¹⁴⁰ described a crude complication rate of 3% (nine of 277 patients) after treatment to a median TMD of 20 Gy but with part of the tumor receiving less than the prescribed dose in 52% of cases to safeguard neurologic function. One patient experienced trigeminal hypoesthesia exacerbation, and three patients developed new transient trigeminal symptoms. Three patients developed new or altered diplopia, and two patients experienced motor weakness.

Kreil and coworkers ¹³⁸ reported a crude complication rate of 3% (five of 200 patients) after treatment to a median TMD of 12 Gy. Two patients experienced transient increased seizure activity and headache associated with peritumoral edema; two developed trigeminal neuralgia at 12 and 16 months, which resolved months later; and one had permanent optic neuropathy. Of note in the small series reported by Kim and colleagues¹⁴⁴ on the results of radiosurgery for superficially located meningiomas, 43% of patients experienced the development of new or worsening edema. The volume of increased signal on T2-weighted images was measured in three dimensions and used to define the “edema index” as the ratio of the volume of T2 signal to the volume of tumor. Edema after radiosurgery occurred at a mean interval of 6 months after treatment (range: 2 to 11 months). In nine of 11 patients, the edema resolved after a mean period of 11 months (range: 5 to 23 months). The edema index was 16.6 for parasagittal meningiomas, 2.5 for falx meningiomas, and 1.5 for convexity meningiomas; however, there was no significant relationship between location and the development of edema. In univariate analysis, high integral tumor dose and larger tumor volume were associated with the development of edema. In tumors larger than 4.2 cm³, edema occurred more frequently. Interestingly, tumor shrinkage occurred more frequently in those patients who had developed edema after treatment.

The incidence of complications after meningioma radiosurgery is low, and these are most frequently cranial nerve injury and symptomatic edema. Generally, over the years, there has been a trend toward using lower TMDs ^132,^133,¹³⁸ or compromising conformality to safeguard neurologic function¹³⁰^,¹⁴⁰ for benign meningioma, with a decrease in complications. Flickinger and colleagues¹³³ reported a significantly lower (RR = 4.5) complication rate in patients treated after 1991, which was associated with the use of lower doses and MRI for treatment planning. Selection of smaller treatment volumes¹³³ and restricting maximum dose to the optic nerve and chiasm¹³¹ are also expected to result in a decline in the incidence of radiosurgery complications.

Spinal Meningioma

The optimal treatment of spinal meningioma is total excision. A large series from the Cleveland Clinic ⁷⁸ reported only one recurrence among 80 patients managed with complete tumor removal. Subtotal resection in their experience was unusual (7% of all spinal meningioma cases), and disease recurred in only two of seven such cases, at 13 and 16 years. The authors concluded that, unlike intracranial meningiomas, subtotally resected spinal meningiomas often pursue an indolent course. This characteristic indolence agrees with observation of relatively low proliferative index in spinal meningioma.¹⁴⁵ No radiation oncology literature has addressed the role of radiation therapy in such patients, so treatment recommendations are lacking. The UCSF policy is to treat subtotally resected spinal meningiomas with a total dose of 5040 to 5400 cGy, since in general it is felt that the potential complications of recurrence or further surgery outweigh the risks of radiation therapy.

Meningioma in the Pediatric Population

Pediatric meningiomas are rare, and their treatment with irradiation is even more uncommon. Most pediatric patients are managed with surgery alone, resulting in an overall 20-year survival rate of 62%.²¹ As a consequence, there is little radiotherapy literature addressing this topic, and there are no established treatment recommendations.²⁰^,¹⁴⁶ Leibel and coworkers¹⁴⁶ reported on the treatment of three patients with intracranial meningiomas irradiated after subtotal resection. The first patient, with a convexity anaplastic meningioma, had a minimal response to 50 Gy with concurrent cytoxan chemotherapy and died 4 months later of uncontrolled disease. The second patient, also with a convexity anaplastic meningioma, received 32 Gy after a subtotal resection, followed by complete excision 6 months later, but this patient died because of postoperative complications. The third patient, with a benign meningioma of the posterior fossa, was treated to 50.4 Gy and recurred 4 years later. The recurrent tumor was then subtotally resected, and the patient was followed for an additional 9 years without progression. Irradiation for recurrence has also been reported by Leibel and colleagues¹⁴⁶ All three patients had benign meningiomas which had recurred after subtotal resection. The first patient was treated to 50.6 Gy and was free of recurrence at 6 years follow-up. The second patient was treated to 52.9 Gy, followed 6 months later by total excision, and was free of disease 9 years later. The third patient was treated to 50 Gy, but died of uncontrolled disease 3 months later. The unimpressive results and small number of patients make interpretation of this data difficult. The authors concluded that when the tumor location and potential neurologic sequelae of recurrence and salvage surgery permit, radiotherapy may be withheld. Reasonable indications for radiotherapy (to a dose of 50 to 54 Gy) would include: (1) anaplastic tumor, (2) incompletely resected or brain-invasive atypical tumor, (3) benign meningioma at a site where the potential complications of recurrence or further surgery outweigh the risks of radiotherapy, and (4) progressive unresectable disease.

Medical Treatment of Meningiomas

Medical therapy for patients with progressive meningioma following maximal resection and radiation modalities remains investigational. Chemotherapeutic as well as other drug strategies that have been evaluated in meningioma are reviewed.¹⁴⁷

Standard Chemotherapeutic Agents

The majority of reports on the use of chemotherapy for meningioma have been from single institutions. The small number of heterogeneous groups of patients evaluated in a retrospective fashion limit clear conclusions on efficacy. These agents are associated with potential significant side effects, especially myelosuppression, and since, in general, no effective chemotherapy regimens have been found, this is not considered part of standard management.

Hydroxyurea is a cell cycle–specific urea analog that inhibits the enzyme ribonucleotide diphosphate reductase, thereby interfering with DNA synthesis by reducing the available deoxyribinucleotides pool.¹⁴⁸ Controlled clinical trials of hydroxyurea are lacking. Newton and associates¹⁴⁹^,¹⁵⁰ reported on the use of hydroxyurea (20 mg/kg/day) in two studies with overlapping cohorts. The expanded cohort consisted of 21 patients in whom at least one resection had been attempted. Nine patients had had previous external-beam irradiation; none of the patients had had any previous chemotherapy. All of the tumors were WHO Grade I, except for one patient with an atypical meningioma. Eighteen of 20 evaluable patients (90%) had stable disease after treatment with hydroxyurea, with a median time to disease progression of 176 weeks (range: 20 to 328 weeks). Overall, eight of 20 evaluable patients remained stable on MR imaging for longer than 4 years.¹⁴⁹^,¹⁵⁰ Rosenthal and colleagues treated 15 consecutive patients harboring recurrent or high-risk meningiomas with hydroxyurea. Eleven patients (85%) had stable disease for a median of 11 months (range: 3 to 24 months), and two had progressive disease.¹⁵¹

Temozolomide is an alkylating agent that is effective in the treatment of patients with malignant glioma; however, it failed to show any benefit when evaluated in a prospective Phase II study in 16 patients with refractory meningioma. These patients had previous treatment with surgery and radiotherapy but no chemotherapy.¹⁵²

Combination chemotherapy regimens administered both intravenously and intra-arterially have been evaluated especially in the more aggressive malignant meningioma population. Younis reviewed 25 patients with aggressive malignant meningiomas, 10 of whom received chemotherapy but did not derive any objective benefit. Typical regimens included intra-arterial or intravenous cisplatin, intravenous dacarbazine, and intravenous doxorubicin.¹⁵³^,¹⁵⁴ Other regimens have included ifosphamide/mesna or adriamycin/DTIC.¹⁵⁵ No effective combinations have been described and the toxicities of therapy do not warrant standard use in meningioma.

Because of the poor prognosis of malignant meningioma despite maximal surgery and radiation, concurrent and adjuvant chemotherapy strategies have been described. Fourteen patients were treated in phase II clinical trial with resective surgery followed by adjuvant limited-field radiotherapy and cyclophosphamide-adriamycin-vincristine (CAV). There were three patients with a partial response to treatment and 11 with stable disease. The median time to tumor progression was 4.6 years, with a median survival of 5.3 years.¹⁵⁶ The small number of patients and lack of a concurrent control group limits the determination of the benefit of this strategy.

Immunotherapy

The most frequently recommended immunotherapy for meningiomas is interferon-alpha (IFN-α), a cytokine produced by activated lymphocytes. It is basically nontoxic in low dosages and is easily tolerated.¹⁵⁷ The major side effects include fever, flu-like symptoms, and fatigue. The mechanism of action of IFN-α includes direct cytotoxic effect, activation of natural killer cells, modulation of antibody production, antiangiogenesis, and induction of major histocompatibility complex antigens on the tumor cell surface.¹⁵⁷ There is in vitro evidence that IFN inhibits the proliferation of meningioma cells.¹⁵⁸ In a phase II clinical trial by Kaba et al¹⁵⁹ six patients with recurrent unresectable meningioma were treated with IFN-α administered subcutaneously and five exhibited positive response to treatment. Stabilization of the size of the tumor occurred in four patients and slight regression in one, with responses lasting from 6 to 14 months. Prospective studies of larger cohorts of patients need to be performed using IFN-α to confirm the benefit of this treatment.

Hormonal Treatment

Epidemiologic (female preponderance) and biochemical evidence suggest that meningioma growth may be hormone dependent. 70% of meningiomas are PR positive and 30% are ER positive with 60% positive for prolactin receptor. These findings have provided the rationale for hormonal treatment for recurrent meningioma.

Although several investigators reported encouraging preliminary results with salvage hormonal therapy for unresectable meningioma, subsequent trials have been disappointing. The Southwest Oncology Group (SWOG) studied the antiestrogen tamoxifen ¹⁶⁰ in 21 patients with unresectable meningioma. All patients received tamoxifen 40 mg per m² bid for 4 days, then 10 mg bid thereafter until progression. Of 19 evaluable patients, 1 (5%) achieved an MRI documented partial response, 2 had a minor response of short duration (4 and 20 months), 6 (32%) remained stable for a median of 31 months, and 10 (53%) progressed.

Medroxyprogesterone acetate (MPA) is a semisynthetic progestin that acts as a competitive agonist for PR. Although it has been shown to reduce the growth of menigioma cells in vitro, it failed to show any benefit in clinical studies.¹⁶¹^–¹⁶³ Another approach to hormone therapy is to use antiprogestins such as mifepristone (RU486) a derivative of the progestin norethindrone to block potential mitogenic stimulation mediated via PRs. Several in vitro and animal studies have shown growth inhibition in meningioma cells after treatment with RU486.¹⁶⁴^,¹⁶⁵ Early clinical studies demonstrated encouraging responses to mifepristone ranging from stabilization of disease to minor responses.³¹^,¹⁶⁶ On the basis of those results, the SWOG and Eastern Cooperative Oncology Group (ECOG) subsequently conducted a phase III placebo-controlled, randomized trial evaluating mifepristone (RU486) for the treatment of unresectable nonanaplastic meningioma. One hundred and ninety-three patients were enrolled, of whom 160 were evaluable. Patients received RU486 versus placebo daily over a 2-year period. The median time to progression was 10 months for RU486 and 12 months for placebo (P = .44). The study was prematurely closed and a final report has yet to be published.¹⁶⁷ Treatment was well tolerated with reported toxicities consisting mainly of fatigue, headache, and hot flushes but a significant number of female patients who received RU486 developed endometrial hyperplasia.¹⁶⁸

Targeting Surface Receptors

Studies have demonstrated the presence of IGF (insulin-like growth factor)-1 receptors in virtually all meningioma specimens. Growth factor and IGF-I have been identified as potent inducers of cell growth in many types of neoplasms. It was demonstrated that the growth hormone (GH)/IGF-I axis is also important in modulating meningioma growth.¹⁶⁹ In in vivo tumor models, downregulation of the GH/IGF-I axis significantly reduced meningioma growth and, in some instances, caused tumor regression with growth factor receptor antagonist pegvisomant treatment.¹⁷⁰ Yin et al showed that pegvisomant was well-tolerated at subcutaneous doses and was efficacious in suppressing the GH axis, resulting in substantial and sustained inhibition of circulating IGF-I, IGF-II, and IGFBP-3 concentrations.¹⁷¹ These results provide evidence in favor of further testing the hypothesis that pegvisomant, through blocking the GH receptor-mediated signal transduction pathways, could be effective in treating tumors, such as meningioma, that may be GH, IGF-I, and/or IGF-II dependent.

Somatostatin (sst) receptors are expressed in meningioma cells suggesting that there may be a therapeutic role for somatostatin inhibitors.¹⁷² An in vitro study on 16 surgically removed meningiomas showed that sst2A expression was readily detectable in 75% of the tumors, with particularly high levels in 50% of cases.¹⁷³ The addition of somatostatin inhibited meningioma growth in vitro in some preclinical studies. A pilot prospective trial of 16 patients with recurrent meningioma were treated with long-acting somatostatin (Sandostatin LAR) and four partial responses, five stable disease, and seven progressive disease patterns were seen. The overall PFS was 44% at 6 months.¹⁷⁴ Further studies need to be performed to confirm the benefit of this treatment.

Targeting Other Signal Transduction Pathways

Compared to the extensive knowledge of the molecular pathogenesis and biology of malignant gliomas or other systemic cancer, relatively little is known about the molecular pathogenesis of meningiomas and the critical molecular changes driving tumor growth. Overexpression of various growth factors—including platelet derived growth factor, epidermal growth factor, and vascular endothelial growth factor—and their receptors, as well as aberrations of signal transduction pathways—such as the Ras/MAPK, PI3K-Akt, and PLC-g1-PKC pathways—have been implicated, but their relative significance is largely unknown.¹⁷⁵ Some targeted therapeutic agents might be effective as single agents or in combination with chemotherapy in meningioma, but further studies are needed to confirm that hypothesis. Examples of targeted agents include: imatinib, erlotinib, cetuximab, sorafenib, tipifarnib, mammalian target of rapamycin inhibitors, and bevacizumab.¹⁷⁶

Novel Medical Treatment Approaches

Suppressive therapy with calcium channel antagonists (CCAs) represents an attractive adjunctive treatment for unresectable or recurrent meningiomas, because they are safe drugs with well-known side effect profiles that lend themselves to long-term chronic therapy.¹⁷⁷ In a meningioma mouse xenograft flank model, diltiazem and verapamil treatment resulted in dose-dependent decreased tumor growth over time compared with control groups. Drug treatment was not curative, however, indicating a growth-suppressive effect of CCAs.¹⁷⁸ Addition of diltiazem or verapamil to hydroxyurea or RU486 intensified in vitro meningioma growth inhibition by 20 to 60% by inducing apoptosis and G1 cell cycle arrest.¹⁷⁹ A clinical trial of this approach is ongoing.

In in vitro studies, celecoxib, a COX-2 inhibitor, showed a dose-dependent inhibition of meningioma cell growth in a malignant cell line (IOMM-Lee) and in six benign cell lines.¹⁸⁰ An in vivo mouse meningioma flank tumor model was used to show a statistically significant decrease in tumor size with high-dose celecoxib treatment in two of three cell lines, with a mean tumor volume reduction between 25% and 66%. Also tumors showed decreased microvascular density and diminished COX-2 and VEGF staining as well as increased apoptosis.¹⁸¹ It has thus been hypothesized that the use of celecoxib as a chronic therapy for meningiomas could be effective and easily tolerated.¹⁸²^,¹⁸³ Clinical confirmation of the benefit of COX-2 inhibitors remains to be shown.