Neurosurgical FOCUS - 23(4):E4

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October 2007 = Volume 23, Number = 4

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<= /TD>

Role of radiation therapy in = treating=20 intracranial meningiomas*

Leland=20 Rogers, M.D.¹ and Minesh Mehta, = M.D.²

¹GammaWest Radiation = Therapy, Salt=20 Lake City, Utah; and=20 ²Department of Human Oncology, University = of=20 Wisconsin School of Medicine and Public Health, = Madison,=20 Wisconsin

Abbreviations used in this = paper:=20 EBRT =3D external-beam radiation therapy; GTR =3D = gross-total=20 resection; MR =3D magnetic resonance; NF2 =3D = neurofibromatosis=20 Type 2; ONSM =3D optic nerve sheath meningioma; PFS = =3D=20 progression-free survival; SRS =3D stereotactic = radiosurgery;=20 STR =3D subtotal resection; WHO =3D World Health = Organization.

Address correspondence = to:=20 Leland Rogers, M.D., GammaWest Radiation Therapy, 1050 = East=20 South Temple, Salt Lake City, Utah 84102. email: leland@gammawest.com.

DOI: 10.3171/FOC-07/10/E4

Figures = and Tables=20

Abstract	IntroductionEpidemiologyOrigin of = MeningiomasHistopathologyTreatment and = OutcomeComparative Outcome:=20 EBRT...ConclusionsReferences

3D""=20 Surgery is the mainstay for many = patients with=20 meningiomas, and it remains the standard. In large=20 single-institution series, gross-total resection has = been=20 reported to achieve 5-, 10-, and 15-year = recurrence-free=20 survival rates of approximately 90, 80, and 70%, = respectively.=20 There are a growing number of series of patients with=20 prolonged follow-up in which authors have evaluated=20 fractionated external-beam radiation therapy (EBRT) = either as=20 an adjuvant to surgery for subtotally resected, = recurrent, or=20 higher-grade meningiomas, or as an alternative to = surgery. The=20 primary focus of this review is EBRT, but to lend = perspective,=20 a comparative analysis of surgery and radiosurgery is = also=20 provided.

Keywords:=20 brain neoplasm; meningioma; radiation therapy;=20 radiosurgery.

Introduction	AbstractIntroduction = <<EpidemiologyOrigin of = MeningiomasHistopathologyTreatment and = OutcomeComparative Outcome:=20 EBRT...ConclusionsReferences

Cushing = coined the=20 term =93meningioma=94²⁶ to=20 describe tumors that principally originate from the = meningeal=20 coverings of the brain and spinal cord. Considerable = progress=20 has been made characterizing histological grades, = defining=20 aggressive variants, and modernizing approaches to = treatment,=20 but many crucial questions remain. In part, this is = because=20 meningiomas tend to progress slowly and thus require = long-term=20 vigilance, which reveals that considerable morbidity, = and even=20 death can be caused by this neoplasm.^22,43

Epidemiology	AbstractIntroductionEpidemiology = <<Origin of = MeningiomasHistopathologyTreatment and = OutcomeComparative Outcome:=20 EBRT...ConclusionsReferences

Meningiomas are now the most frequently reported = primary=20 intracranial neoplasm,²²=20 constituting approximately 30% of primary central = nervous=20 system tumors.^{16,17,22,67,68} Many are=20 identified solely on the basis of imaging findings; in = recent=20 studies, 35 to 62% were diagnosed on the basis of = imaging=20 alone.^31,35=20 Furthermore, meningiomas have been identified in 2.3% = of all=20 autopsy reports.⁹¹=20 Therefore, it is likely that more intensive use of = imaging=20 will increase the detection of meningimas.

The risk of a patient developing a meningioma = increases=20 with age.^1,22,85,133=20 Meningiomas have rarely been reported during fetal = development=20 and infancy.^{7,34,97,100,157} Except=20 in the setting of NF2,¹⁰⁰=20 however, they are infrequent in the pediatric=20 population.^80,100 More=20 aggressive clinical and histological features have = been noted=20 in children and young adults.⁹⁹ In terms=20 of the absolute numbers of meningiomas, the peak = incidence=20 occurs during the sixth and seventh decades of = life.¹⁰²=20 However, the age-specific rate of development of = meningiomas=20 continues to rise thereafter. Figure 1, = created=20 based on data from a large epidemiological study = published in=20 2005, highlights that the age-specific incidence = continues to=20 rise even for individuals older than 85 years.²²

View=20 larger version = (66K)

Fig. 1. Bar = graph=20 demonstrating the age-specific incidence = of=20 meningioma, based on data from the Central = Brain=20 Tumor Registry of the United States. The = graph was=20 derived using data from the article by = Claus et=20 al.

Meningiomas occur more frequently in = females,=20 with a female/male ratio of approximately 2:1.^{41,74,80,85,133,150}=20 Progesterone and estrogen receptors have been = identified in=20 greater than 70 and 30% of meningiomas, = respectively.^102,149=20 Increased estrogenicity is associated with an increase = in=20 tumor-related symptoms during pregnancy or the luteal = phase of=20 menses.^30,149 An=20 increased risk of breast cancer has been described in = patients=20 with meningioma, as has an increased relative risk of=20 meningiomas with breast cancer.¹⁴⁹=20 However, androgen receptors have been identified in = nearly 40%=20 of meningiomas,¹⁰² and=20 therapies designed to exploit hormone receptor = overexpression=20 have, to date, met with disappointing results.^98,112

Origin of = Meningiomas	AbstractIntroductionEpidemiologyHistopathologyTreatment and = OutcomeComparative Outcome:=20 EBRT...ConclusionsReferences

The origin of the majority of = meningiomas is=20 unknown.²²=20 Associations have been made with hormones, growth = factors,=20 NF2, ionizing radiation, and trauma.^{5,10,30,36,39,48,51,80,99,100,102,118,119,139} Nearly=20 all NF2-associated meningiomas have mutations of the=20 NF2 gene on 22q12.¹¹⁵ Most=20 families identified as susceptible to meningiomas have = alterations of the NF2 locus on chromosome 22.^75,115=20 Monosomy of chromosome 22 is the most common = cytogenetic=20 alteration in meningiomas.

Histopathology	AbstractIntroductionEpidemiologyOrigin of = MeningiomasHistopathology = <<Treatment and = OutcomeComparative Outcome:=20 EBRT...ConclusionsReferences

Cell of Origin=20

Meningiomas are believed to arise from = arachnoid=20 cap cells (the epithelioid cells on the outer surface = of=20 arachnoid villi), or meningothelial progenitor = cells.^23,121=20 Meningiomas are cytologically similar to cells within=20 arachnoid caps; arachnoid villi are identified in = greater=20 numbers at sites where meningiomas frequently arise; = and cap=20 cell clusters appear to increase with age, paralleling = the=20 age-related occurrence of meningiomas.⁹⁷

Tumor Grade=20

The WHO published its grading criteria in = 2000.⁷⁶ An=20 update is expected this year (2007). The 2000 and 2007 = criteria are expected to be similar; brain invasive=20 meningiomas are now regarded as Grade II, even in the = absence=20 of atypia or anaplasia.¹⁰² As=20 depicted in Fig. 2, = using these=20 criteria, stronger associations between grade and = outcome have=20 been demonstrated in large series.^{46,65,103,104}

View=20 larger version = (27K)

Fig. 2. = Kaplan=96Meier=20 estimated recurrence-free survival (RFS) = by WHO=20 tumor grade from a compiled series of 643 = patients=20 from studies by Perry et al., 1997 and = 1999. The=20 number of patients with each grade is = given, as is=20 the percentage of patients with each = grade. The=20 grading criteria used in this study have = been=20 incorporated into the current WHO grading = scheme.=20 Courtesy of Christine Lohse, Biostatistics = Division, Mayo Clinic, and reprinted with=20 permission from Springer.

Benign meningiomas (WHO Grade I) = constitute=20 approximately 70 to 85% of intracranial meningiomas. = With=20 appropriate treatment, more than 80% of WHO Grade I=20 meningiomas remain progression-free at 10 or more=20 years.^{24,94,103,104}=20 Atypical meningiomas (WHO Grade II) likely account for = 15 to=20 25% of intracranial meningiomas.^103,104,153=20 Authors of single-institution series have tended to = include a=20 smaller percentage of patients with Grade II tumors, = ranging=20 from 4.7 to 9.6%.^54,82 It is=20 important to recognize Grade II meningiomas, given = that they=20 carry a seven- to eightfold increased recurrence risk = at 3 to=20 5 years.⁹⁸ Only=20 approximately 40 to 60% of patients with Grade II = meningiomas=20 remain disease-free at 10 years.^{24,48,54,103,104} One to=20 four percent of intracranial meningiomas are = anaplastic (WHO=20 Grade III).^{54,103,104,153} They=20 have a median recurrence-free survival of fewer than 2 = years.^103,104 We=20 plan no specific review of Grade III=20 meningiomas.

Treatment and = Outcome	AbstractIntroductionEpidemiologyOrigin of = MeningiomasHistopathologyTreatment and Outcome=20 <<ConclusionsReferences

Authors of many studies have highlighted excellent = local=20 control after resection, radiosurgery, and = fractionated EBRT=20 at approximately 5 years, but this cannot be = considered=20 definitive. Adegbite and coworkers¹ = documented=20 that even with thorough resection, the likelihood of=20 recurrence is high with a sufficient observation = interval of=20 15=9620 years (Fig. 3). = A few=20 other series, also with long-term follow-up, have = shown that=20 gross totally resected meningiomas recur 20=9630% of = the time at=20 10 to 15 years.^24,85,133

View=20 larger version = (46K)

Fig. 3. = Cumulative=20 proportion of patients free of recurrence = against=20 the number of years since surgery. = Reprinted with=20 permission from Adegbite et al., J = Neurosurg=20 58:51=9656, 1983.

Surgical Resection=20

The completeness of surgical removal is an = important=20 prognostic feature.^{24,29,108,133}=20 Resection of the meningioma, its involved dura, and = any=20 involved soft tissue and bone is an accepted = procedure,³⁰ and=20 achieves high rates of local control. The extent of = resection=20 was classically defined by Simpson,¹²⁸ who=20 linked it to recurrence risk, summarized in Table 1. = Kinjo and=20 colleagues⁶¹ defined=20 a more extensive resection as =93grade zero,=94 = entailing=20 gross-total resection of the primary, any hyperostotic = bone,=20 and all involved dura with a 2 cm dural margin. They = observed=20 no local recurrences, with more than half of 37 = patients=20 followed over 5 years.⁶¹

TABLE 1 = Extent of=20 resection according to Simpson = grading*

Table=20 2 reviews the distribution of intracranial = meningiomas.=20 The likelihood of gross-total resection varies = considerably by=20 primary sites.^29,41,85,108 Table 3=20 reviews the likelihood of complete excision. Overall, = at least=20 one third of meningiomas reported in surgical series = are not=20 fully resected.^85,108

TABLE 2 = Sites of=20 meningioma in 581 patients*

Gross-Total Resection Alone=20

Gross-total resection for benign meningiomas is = considered=20 definitive.^{24,85,108,133} Three=20 large series with extended follow-up are listed in Table 4.=20 Remarkably similar local recurrence rates were = reported in=20 all: 7 to 12%, 20 to 25%, and 24 to 32% at 5, 10, and = 15=20 years, respectively. Typically, GTR connotes Simpson = Grades 1=20 and 2,¹⁰⁸ and=20 sometimes Grade 3 resection.²⁴ Authors=20 of a study conducted at the University of Florida = found no=20 significant difference in local control or = cause-specific=20 survival between Simpson Grade 1 to 3 = resections.²⁴

TABLE 3 = Relative=20 frequency of complete excision in 225=20 = patients

TABLE 4 = Three large=20 single-institution series with 10 to 15 = years'=20 follow-up, documenting rates of recurrence = following GTR=20 = alone

Subtotal Resection Alone=20

Subtotal resection alone remains common in = practice, and Table 5=20 summarizes outcomes following STR alone, from four = series of=20 patients with 10 to 20 years of follow-up; the 5-, = 10-, and=20 longer than 15-year progression rates following = subtotal=20 resection were 37 to 47%, 55 to 63%, and greater than = 70%,=20 respectively.^{24,85,133,151}

TABLE 5 = Four=20 single-institution series with 10- to = 20-year=20 follow-up, assessing rates of recurrence = following=20 STR=20 = alone

Radiation Therapy=20

Radiation therapy improves local control. Factors=20 considered in the decision to use radiotherapy include = the=20 extent of resection,^{24,85,128,133}=20 grade,^103,104 and=20 histological subtype.⁷⁶=20 Secondarily, one might also consider imaging findings = such as=20 edema and calcifications,^49,80,89=20 age,^55,99 and=20 perhaps menopausal status,⁵⁵ although=20 these remain less well defined.

Data pertaining to a total of 42 studies with 4585 = patients=20 treated with radiotherapy or radiosurgery are = summarized in Tables 6=20 and 7.=20 These data substantiate that irradiation is beneficial = as an=20 adjunct to surgery following subtotal resection, as = treatment=20 for recurrent meningiomas, or as primary therapy. For=20 comparative purposes, a brief consideration of = radiosurgery=20 for meningiomas follows.

TABLE 6 = Compiled=20 stereotactic radiosurgery with reported = 5-year PFS=20 rates*

TABLE 7 = Compiled=20 series allowing for comparison in the = rates of PFS=20 for patients treated with GTR, STR, or = with STR=20 plus EBRT*

Stereotactic Radiosurgery=20

Local control rates following SRS are 75 to 100% at = 5 to 10=20 years.^{45,62,64,71,91,108,117,123,134,147}=20 Outcomes from several radiosurgery series are = summarized in Table 6.=20 Stereotactic radiosurgery is generally considered most = appropriate for meningiomas less than 3 to 4 cm in = diameter,=20 with distinct margins, and with sufficient distance = from=20 critical healthy tissues to allow for appropriate = normal=20 tissue dose restrictions as well as adequate target = dose.=20 DiBiase and coauthors³¹ reported=20 5-year disease-free survival rates of 91.9% for = patients with=20 meningiomas 10 cm³ or smaller (equivalent = diameter=20 2.7 cm) versus 68% for larger tumors. Authors of many = series=20 have used margin doses in the 10- to 18-Gy range. Ganz = and=20 associates³⁷ noted=20 that a minimum peripheral tumor dose of 10 Gy or less = was=20 associated with a higher risk of failure, whereas at = least 12=20 Gy resulted in improved local control. Morita and=20 colleagues⁸⁶=20 subsequently recommended tumor margin doses of at = least 15 to=20 16 Gy. Stafford and coauthors¹³⁴=20 reported no improvement in 5-year local control with = doses of=20 at least 16 Gy. Kondziolka and associates⁶² reported=20 no improvement with marginal doses of at least 15 Gy. = Margin=20 doses ranging from 12 to 16 Gy are now widely = used.^{35,64,70,93,116,132}

Early reports of SRS were associated with a high=20 complication rate. For example, in 41 patients with a = median=20 follow-up of 3.5 years, Kondziolka and = colleagues⁶² noted=20 worse outcomes in cases of larger tumors, prior = surgery, or=20 with pre-SRS neurological deficits. The adverse events = most=20 frequently attributed to SRS are cranial nerve = deficits and=20 peritumoral edema. Serious, but uncommon side effects = include=20 radiation necrosis,^33,47,62=20 peritumoral cyst formation,¹³⁴=20 carotid artery stenosis,¹³⁵ and=20 hypothalamic dysfunction.⁴⁵ With=20 margin doses of 14 to 16 Gy, authors of some studies = have=20 identified new or worsened cranial nerve deficits in=20 approximately 8% of patients.^{31,64,134,136,140,142}=20 Neuropathies are encountered more frequently with the = optic,=20 cochlear, and trigeminal nerves. Motor nerves tend to = tolerate=20 radiosurgery comparatively well. Roche and = colleagues¹¹⁷=20 observed no new oculomotor deficits in 80 patients = with=20 cavernous sinus meningiomas with a mean maximum = prescription=20 dose of 28 Gy and a median follow-up of 30.5 months.=20 Conversely, sensory nerves of the anterior visual = pathway have=20 been particularly susceptible. Doses of only 10 Gy or=20 less^86,136 carry=20 a roughly 1 or 2% rate of optic neuropathy. With = higher doses,=20 the rate and severity of complications rise = steeply.^69,136

Posttreatment edema has been widely reported = subsequent to=20 SRS (Table=20 8).^{38,59,62,90,113,147}=20 Meningiomas produce vasoactive mediators.^56,80,95,111 Edema=20 is more commonly encountered with nonbasal primary = tumors,=20 which are apt to have a broader pial interface^6,49=20 permitting vasogenic substrates greater access to = adjacent=20 brain. Basal primaries have more limited pial=20 involvement.^6,49,50 Edema=20 developed in 25 to 78% of the patients with nonbasal=20 meningioma, compared with 0 to 22% of patients with = basal=20 primary tumors. With parasagittal meningiomas, for = which edema=20 has been frequently reported,⁶² bridging=20 vein and/or sagittal sinus occlusion may also = contribute.=20 Other factors potentially associated with an increased = risk of=20 edema are the following: margin dose greater than 15 = Gy, tumor=20 size (diameter ≥ 3 cm or volume ≥ 4 = cm³), and the=20 presence of pretreatment edema.

TABLE 8 Six = series=20 (with 226 total patients) with new or = worsening=20 edema following SRS*

External-Beam Radiation Therapy=20

Meningiomas were historically considered resistant = to=20 irradiation,^60,85 and=20 authors of several older retrospective studies = described=20 infrequent radiographic regression.^1,60,148,155 In=20 addition, there has been apprehension regarding the = malignant=20 degeneration of irradiated tumors as well as about the = relationship between irradiation and the ultimate = development=20 of meningiomas.^{40,118,119,139}=20 Therefore, many patients with inoperable or subtotally = resected meningiomas have been observed.^3,55,133=20 Malignant degeneration now is widely believed to be = related to=20 the natural history of a subgroup of meningiomas, and = has=20 never been explicitly linked with radiation therapy. = The risk=20 of developing a meningioma after cranial irradiation = has been=20 reviewed by Strojan et al.,¹³⁹ who=20 reported the actuarial risk after radiation therapy to = be=20 0.53% at 5 years, and 8.18% at 25 years.

In the 1970s and early 1980s, several authors = reached the=20 conclusion that EBRT improved local control after = incomplete=20 resection or recurrence,^11,15,18,151=20 despite the fact that meningiomas often remained = stable or=20 regressed slowly.

Primary EBRT=20

Radiation therapy may be used as = primary=20 treatment following biopsy, or even on the basis of = imaging=20 findings.^{15,24,77,106,122} An=20 early report described 47% disease-free survival at 15 = years=20 in 32 patients who underwent EBRT without resection. = This was=20 lower than the 61% rate following partial resection = plus=20 radiotherapy.⁴⁰ In a=20 more recent series, Debus et al.²⁸ noted no=20 difference in outcomes between patients who underwent = primary=20 EBRT (59 patients) and those who underwent surgery = plus EBRT=20 (130 patients). In fact, there were no recurrences in = patients=20 treated with radiotherapy alone; the 10-year = recurrence-free=20 probabilities were 100%.²⁸ Several=20 other authors have also reported excellent results = with=20 primary EBRT.^{15,24,77,92,106,122}

Primary EBRT for ONSM=20

Optic nerve sheath meningiomas arise from the dura=20 encompassing the optic nerve, and account for only 1 = to 2% of=20 meningiomas.^{13,72,73,81,129}=20 Surgery plays a very limited role in the management of = ONSMs.=20 Observation results in gradual loss of vision, and = surgery is=20 often associated with immediate blindness of the = affected eye.=20 Resection of ONSMs while keeping the optic nerve in = situ has=20 been tried, but carries a high risk of visual = complications=20 and local recurrence.^{8,25,52,58,143}=20 Resection commonly impairs the blood supply and = results in=20 blindness, even though the nerve is left grossly = intact.

External-beam radiation has become = integral in=20 the management of ONSMs.^92,130,143 Turbin=20 et al.¹⁴³=20 reported on 64 patients with ONSM and found that = radiation=20 therapy alone provided more favorable outcomes than=20 observation, surgery alone, or even surgery plus EBRT. = They=20 used total doses ranging from 40 to 55 Gy, and had = median=20 follow-up periods of 8.3 years. In another study, and = after a=20 median follow-up of 51.3 months, Narayan et al.⁹² found no=20 radiographic progression in any of their 14 patients = with=20 ONSMs treated with conformal EBRT, and 86% had either = improved=20 or stable visual acuity. This study, along with six = additional=20 studies in which highly conformal or fractionated = stereotactic=20 therapy was used,in composite analyzing of 75 eyes, = has=20 reached similar conclusions.^{9,12,72,92,107,114,120}=20 Overall disease control is excellent (95%); early = visual=20 improvement (within 3 months of radiotherapy) is often = attained (54.7%); and complications are relatively = uncommon.=20 With these findings, it has been suggested that = earlier=20 treatment of symptomatic patients may provide better = visual=20 outcome;¹³ however,=20 there is no uniform agreement as to whether patients = with both=20 stable ONSMs and stable vision should be approached = with=20 observation or early EBRT.

Postoperative EBRT=20

Many retrospective studies now support = a role=20 for postoperative EBRT after STR. These have shown = improvement=20 in local control (Table 7), = and=20 possibly even survival.^24,79

Technical Factors and Dose=96Volume=20 Considerations=20

With image-based techniques, treatment can be = delivered=20 with more precision and conformality (Fig. 4), = and=20 improved results are to be expected.^88,122,126=20 Improvements in local control have, in fact, been = documented=20 with computed tomography=96 or MR imaging=96based = planning.=20 Goldsmith et al.⁴³ and=20 Milosevic and colleagues⁸³ each=20 substantiated improvements in local control consequent = to=20 improved targeting with modern imaging.⁴¹ Patients=20 whose treatments were planned and delivered in this = fashion=20 had a remarkable 10-year PFS rate of 98% compared with = 77%=20 without.⁴³

View=20 larger version = (119K)

Fig. 4. = Magnetic=20 resonance image and isodoses for radiation = therapy=20 of a paracavernous meningioma, treated to = 54 Gy in=20 30 fractions. The dose was prescribed at = the=20 isocenter. The percentage values for each = of the=20 pictured isodoses are given in the legend = at the=20 lower right-hand corner of the = image.=20 Courtesy of Dennis Shrieve, M.D., Chair of = Radiation Oncology, Huntsman Cancer = Institute,=20 University of Utah.

Recommended doses generally range from 50 to 55 Gy = in=20 fractions of 1.8 to 2.0 Gy.^{15,24,41,42,66,92,125,144,150}=20 Goldsmith et al.⁴³ reported=20 that doses greater than 52 Gy resulted in an improved = 10-year=20 local control of 93% compared with 65% with lower = doses, but=20 this finding lost significance on multivariate = analysis. Among=20 67 patients, Winkler et al.¹⁵⁴ found=20 no clear dose response from 36 to 79.5 Gy.

The recommended planning target volume has ranged = from=20 gross tumor volume (that is, the tumor visible on MR = imaging)=20 or the gross tumor volume plus a margin, ranging from = a few=20 millimeters to up to 4 cm.^{8,24,28,40,82,127}=20 Marginal failures are uncommon.^28,93 The=20 targeting of the =93dural tail=94 remains contentious. = Figure 5=20 depicts a dural tail, not included within the defined=20 target.³¹=20 Pathology studies have revealed the dural tail to be = composed=20 entirely or almost entirely of hypervascular dura in = most=20 cases,^{2,14,57,87,101} and=20 including it in the radiotherapy field is of = questionable=20 value.

View=20 larger version = (146K)

Fig. 5. = Magnetic=20 resonance image and isodoses for intensity = modulated radiation therapy of a = cerebellopontine=20 angle meningioma, treated to 54 Gy in 30 = fractions=20 (fx) prescribed to the 90% isodose. In = this case,=20 the dural tail was not specifically = targeted,=20 although it was largely encompassed by the = 70%=20 isodose volume. The yellow line is = the 70%=20 isodose, green 50%, and = sky-blue=20 30%.

Planning target volumes with radiosurgery have = tended to=20 include only the contrast-enhancing tumor without a=20 margin.^{63,64,123,134}=20 Nevertheless, as illustrated in Fig. 6, = by 1 year=20 the tumor had already modestly responded and the dural = tail=20 largely resolved. Nicolato and colleagues⁹³ found no=20 advantage to larger radiosurgery margins. With median=20 follow-up of 4 years, they had 100% tumor growth = control with=20 a conformity index (ratio of prescription isodose = volume to=20 target volume) of 1.5 or less. Using fractionated = radiotherapy=20 with 2-mm margins, Debus et al.²⁸ noted no=20 marginal failures in 189 patients with a 3-year median = follow-up period.

View=20 larger version = (93K)

Fig. 6. = Magnetic=20 resonance images before and after = radiosurgery of=20 a large petroclival and cavernous sinus = meningioma=20 treated with single fraction radiosurgery, = 14 Gy=20 to the 50% isodose. The dural tail was not = targeted. A: The long enhancing tails of = dura=20 bilaterally around the tentorium are seen. = B: The=20 largest pretreatment dimensions of the = meningioma=20 are shown. C: Follow-up image obtained 1 = year=20 after radiosurgery, demonstrating modest = tumor=20 shrinkage and resolution of the majority = of the=20 untreated dural tail.

Another confounding variable in the = definition=20 of the planning target volume is hyperostosis.^27,105 Pieper=20 et al.¹⁰⁵=20 correlated imaging to histopathology in 26 patients; = tumor=20 invasion of the hyperostotic bone was conclusively = present in=20 all but one. In addition, nine of 25 patients without = imaging=20 evidence of hyperostosis were found to have = histological=20 invasion of bone. It remains unresolved whether = resection of=20 bone, or for that matter its inclusion within the = radiation=20 therapy target, is necessary for every patient. = Recurrence=20 rates for patients who have undergone GTRs not = inclusive of=20 hyperostotic bone have traditionally been low, as have = recurrences after radiosurgery and EBRT regardless = whether=20 neighboring bone was targeted.

Toxicity of EBRT=20

The side effects of EBRT, especially with current = methods=20 of treatment planning and delivery, are relatively = uncommon,=20 but by no means are they negligible. In the largest = recent=20 series of fractionated irradiation in the literature, = Debus et=20 al.²⁸ reported=20 on 189 patients treated with a highly conformal = stereotactic=20 approach, using median daily fractions of 1.8 Gy to a = mean=20 dose of 56.8 Gy. With a median follow-up of nearly 3 = years,=20 they identified clinically significant (Grade 3) = toxicity in=20 four patients (2.2%), three (1.7%) in the absence of a = preexisting deficit. These were reduced vision, a new=20 visual-field deficit, and trigeminal neuropathy. This = is,=20 however, a substantial improvement over the 38% = reported by=20 Al-Mefty et al.⁴ = with older=20 methods of radiation delivery.

Goldsmith et al.⁴³=20 recognized complications in five (3.6%) of 140 = patients, which=20 they believed may have been attributable to EBRT. = These were=20 retinopathy in two, optic neuropathy in one, and = cerebral=20 necrosis in two patients.⁴³ They=20 also constructed a model to predict optic nerve = tolerance, and=20 recommended a maximum dose of 890 optic ret (for = example, 54=20 Gy in 30 fractions).⁴² Optic=20 complications are quite rare with doses lower than 54 = Gy,=20 particularly with fractional doses of 2.0 Gy or = less.^40,84,106 Uy et=20 al.¹⁴⁵ noted=20 no optic pathway toxicity with a median dose of 50.4 = Gy and=20 fractions of 1.7 to 2 Gy. The beneficial impact of = lower doses=20 per fraction on optic tolerance has been recently = confirmed by=20 Shrieve and colleagues,¹²⁵ who=20 concurred that 54 Gy (in 30 fractions) was both safe = and=20 effective. Nonocular cranial nerve deficits may = occur²⁸ but are=20 uncommon. Selch and colleagues¹²² found=20 no treatment-related cranial neuropathy in 45 patients = with=20 cavernous sinus meningiomas that were treated with = fractions=20 of 1.7 to 1.8 Gy to a median dose of 50.4 Gy. Urie and = coauthors¹⁴⁴ also=20 remarked that doses in this range rarely cause cranial = neuropathy.

Brain or brainstem necrosis is also uncommon but = has been=20 observed by Goldsmith et al.⁴² and=20 others.^4,84 Al-Mefty=20 et al.⁴ = reviewed=20 post-EBRT toxicity in 58 adult patients with a variety = of=20 skull base, parasellar, or pineal region tumors. = Seventeen=20 (29%) developed late brain parenchymal changes, with = latencies=20 of 4 months to 23 years. These included = encephalomalacia,=20 cerebral atrophy, gliosis, and/ or necrosis, = generalized or=20 involving the temporal lobes in 14 (82%) of the 17=20 cases.⁴ = Such=20 occurrences are almost certainly related to antiquated = treatment techniques, for example, low-energy opposed = lateral=20 fields. Integral doses to the temporal lobes and to = large=20 volumes of untargeted brain are much lower with = current=20 multifield conformal and intensity modulation.

Pituitary dysfunction,^4,84,94,106=20 cerebrovascular events,^40,94,122 second=20 malignancy,^4,94 orbital=20 fibrosis,⁷⁷ and=20 other sporadic toxicities have been noted. In an older = series=20 in which an array of techniques and doses was used, = Glaholm et=20 al.⁴⁰ found=20 that all complications occurred with the convention of = treating only a portion of the fields daily, and with=20 fractional doses greater than 1.8 Gy (to final doses = of 50=9655=20 Gy).

Edema is uncommon following EBRT. Table 7 = summarizes=20 data from 23 EBRT studies with a total of 2971 = patients. Only=20 six patients (0.2%) reportedly developed edema, and = two of=20 these six were asymptomatic. Selch and = colleagues,⁸⁴ who=20 specifically evaluated edema, noted none in 45 = patients with 3=20 years of median follow-up.

Authors of some retrospective studies, = typically=20 with less conformal techniques, have identified = personality=20 changes,¹⁴⁵ and=20 memory loss^24,77,84.⁹⁴ as=20 complications of EBRT. Cognitive outcome was = prospectively=20 evaluated by Steinvorth et al.,¹³⁷ with=20 the aid of a comprehensive battery administered = before, after=20 the first fraction, at completion, and 12 months = subsequent to=20 EBRT. They observed no significant cognitive=20 deterioration.¹³⁷

Treatment of Atypical = Meningiomas=20

Atypical (WHO Grade II) meningiomas comprise = roughly 20% of=20 all meningiomas (Fig. 2). = Most=20 investigators have recommended irradiation, = irrespective of=20 resection extent.^24,48,154=20 However, in one study, in which eight of 22 patients = with=20 atypical meningiomas received postoperative EBRT, = local=20 control was 87% at 5 and 10 years following GTR, and = EBRT had=20 no significant impact on local control or overall=20 survival.⁴⁴ That=20 series highlighted some of the difficulties in = deciphering the=20 literature respective to atypical tumors. The sample = size is=20 small, the percentage of patients with Grade II tumors = (6.7%)=20 is too low to be representative of current WHO = grading, and=20 the doses used (50=9654 Gy) may be too low for Grade = II=20 tumors.⁴⁸ Hug and=20 associates⁴⁸ found=20 that the local control of atypical meningiomas was=20 significantly enhanced by cumulative doses of at least = 60=20 cobalt Gy equivalents.⁴⁸ Perry=20 and colleagues¹⁰⁴=20 reported 108 atypical meningiomas treated with modern = surgical=20 techniques, grading, and postoperative imaging and = found a=20 5-year recurrence rate of 40% even after GTR. In = another=20 study, recurrences of atypical meningiomas after = either=20 subtotal or =93radical subtotal resection=94 were 39 = and 61% at 5=20 and 10 years, respectively.¹³³

Radiosurgery has been used in the = treatment of=20 atypical meningiomas. Stafford and colleagues¹³⁴=20 described 5-year actuarial local control of 93% for = Grade I=20 meningiomas, compared with 68% for Grade II = meningiomas. This=20 is very similar to the 64% (seven of 11 patients) = reported by=20 Condra et al.²⁴ with=20 lower EBRT doses, but inferior to the 5-year local = control of=20 90% with at least 60 cobalt Gy equivalents observed by = Hug and=20 coauthors.⁴⁸ There is=20 relative consensus for irradiation following subtotal=20 resection; however, it is difficult at present to = predict=20 which patients with Grade II tumors that were = gross-totally=20 resected will benefit from adjuvant therapy.

Treatment of Recurrent = Meningiomas=20

Recurrent meningiomas exhibit a = several-fold=20 increased rate of progression over newly diagnosed=20 tumors.^24,84,85,141=20 Miralbell and coauthors⁸⁴ found a=20 78% 8-year PFS in patients treated with surgery and = EBRT for=20 recurrent tumors, versus 11% with surgery = alone.⁸⁴=20 Similarly, Taylor et al.¹⁴¹ found=20 the respective 5-year PFS rates to be 88% compared = with=20 30%.¹⁴¹ They=20 noted that the 5-year overall survival was 90% with = surgery=20 plus EBRT compared with 45% after surgery alone. These = data=20 support aggressive treatment for recurrent=20 meningiomas.

Comparative Outcome: EBRT and=20 SRS	AbstractIntroductionEpidemiologyOrigin of = MeningiomasHistopathologyTreatment and = OutcomeComparative Outcome: EBRT...=20 <<ConclusionsReferences

Tables=20 6 and 7 display = data from=20 numerous studies suggesting relative equivalence of = EBRT and=20 SRS with regard to PFS, with the caveat that patient = selection=20 differs significantly between these two approaches. Table 9=20 encapsulates these data further and reveals that 5- to = 10-year=20 PFS rates have ranged from 80 to 100% with EBRT and = from 75 to=20 100% with SRS. For example, Sibtain and Plowman¹²⁷=20 published a study comparing EBRT and SRS for cavernous = sinus=20 meningiomas. They retrospectively evaluated 13 = patients with=20 tumors smaller than 3 cm in diameter, most of whom = received=20 radiosurgery, and 15 patients with tumors larger than = 3 cm,=20 most of whom had EBRT. Tumors in all patients were = locally=20 controlled (follow-up 12=9683 months).

TABLE 9 = Compiled=20 series allowing comparison of fractionated = EBRT=20 with SRS, with 5- to 10-year PFS as the = end=20 point*

Conclusions	AbstractIntroductionEpidemiologyOrigin of = MeningiomasHistopathologyTreatment and = OutcomeComparative Outcome:=20 EBRT...References

As a consequence of a frequently observed pattern = of slow=20 growth as well as a lack of large cooperative group or = randomized trials, standardized recommendations are = difficult=20 to formulate. With these limitations, we make the = following=20 suggestions.

Small, asymptomatic, stable, or slowly progressive=20 meningiomas can be carefully observed with clinical=20 evaluations and serial imaging. For other patients, = GTR=20 remains the benchmark against which other therapeutic=20 strategies should be measured. However, complete = removal=20 within the constraints of acceptable morbidity is = often not=20 possible. Indeed, meningiomas of the cavernous sinus = or=20 petroclival region often involve critical neural or = vascular=20 structures, and are generally unresectable.¹³⁸

Following subtotal resection, radiation therapy = improves=20 local control, and in some series, survival.²⁴ However,=20 there are no randomized data to support this = observation, and=20 it is still debatable whether these patients should be = carefully observed or treated preemptively. This = decision is=20 complex, given that some patients will do well for = many years=20 after subtotal resection alone.

There is growing experience with = radiotherapy=20 (EBRT or SRS) as a primary treatment modality, either = after a=20 limited biopsy or based purely on imaging findings.=20 Fractionated EBRT and radiosurgery result in = comparable local=20 control rates, and either can be recommended for many=20 patients, but not for all. External-beam radiation = therapy is=20 suitable for a broader range of patients, whereas = excellent=20 outcome with SRS is realized among a more selected = cohort.=20 Radiosurgery is most judiciously applied to smaller=20 meningiomas located at an adequate distance from the = optic=20 apparatus, and perhaps those associated with a low = risk for=20 developing edema. Fractionated EBRT does not have = these=20 limitations. With currently accepted techniques and = dose and=20 fractionation guidelines, EBRT appears to carry only a = small=20 risk of side effects such as optic neuropathy or=20 edema.

References	AbstractIntroductionEpidemiologyOrigin of = MeningiomasHistopathologyTreatment and = OutcomeComparative Outcome:=20 EBRT...ConclusionsReferences = <<

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