Update on Meningioma: Neurosurgeon and Medical Neuro-oncologist Perspective


Introduction

No other intracranial tumor better typifies
the broad range of therapeutic challenges that confront the
neuro-oncologist than the meningioma, the most common primary brain
tumor in adult patients. Meningiomas range in spectrum from small,
incidentally slow-growing lesions, requiring only observation, to large
inexorably progressive masses, engulfing vital areas in the brainstem
and cranial nerves, with few if any therapeutic options.
Despite recent studies in advanced molecular
genetics and attempts at targeted biological therapies, neurosurgical
operative resection remains the mainstay of therapy and, in many cases,
results in a cure if complete resection can be achieved. Advances in
radiation delivery techniques have greatly increased the options for
incompletely excised or recurrent tumors, but systemic chemotherapy
approaches have been uniformly dismal. This update focuses on the most
recent analytic and therapeutic advances in the care of patients with
these historically challenging intracranial lesions.

Epidemiology

The Central Brain Tumor Registry of the
United States collects data from 18 state cancer registries belonging to
the Centers for Disease Control and Prevention National Program of
Cancer Registries and the Surveillance, Epidemiology and End Results
Program (SEER) of the National Cancer Institute.^[1]

According to the most recent update,
meningiomas account for 33.8% of all intracranial tumors, with 53,455
reported in 2004-2006. The age-adjusted yearly incidence rate was 6.29
per 100,000 person-years, with 39,336 diagnosed in women and 14,119 in
men. This results in a yearly incidence rate of 8.44 per 100,000
person-years for women and 3.76 per 100,000 person-years for men.
The data also indicate that meningiomas are
the most common primary brain tumor based on histologic criteria after
age 35 years and remain the most common in the 85-years-plus age group.
The vast majority were classified as benign (52,247/53,455; 97.7%) and
only 1208 classified as malignant (2.3%).^[1]

Pathology

Three classes of meningioma have been recognized by the World Health Organization (WHO) based on histologic criteria.^[2]
More than 90% of meningiomas are classified as grade 1 (benign); 5%-7%
are grade 2 (atypical), and fewer than 3% are grade 3 (malignant).
The classification is based primarily on the
degree of nuclear atypia and occurrence of mitotic figures. Four mitoses
per high power field is the lower limit for an atypical diagnosis, and
20 mitoses per high power field is the lower limit for a malignant
diagnosis. Additional features taken into account when fewer than 4
mitoses are identified include hypercellularity, increased
nucleus-to-cytoplasm ratio, prominent nucleoli, sheet-like growth, and
necrosis. By definition, the histologic subtypes of atypical, clear
cell, and chordoid and those with brain invasion are classified as grade
2, and the histologic subtypes papillary, rhabdoid, and anaplastic
(malignant) are classified as grade 3.
The WHO 2000 grading scheme for meningioma
provided criteria for atypia (including necrosis) and anaplasia and
noted the effect of brain invasion on prognosis for recurrence. The 2007
update includes brain invasion as a criterion for atypia and is the
most significant modification of this most recent version.^[2]

Despite these landmark works on the characterization of meningioma, Commins and colleagues^[3]
note unresolved issues in the grading of meningioma. First, the effect
of invasive behavior is not clear in all cases. Grade 1 tumors can
invade local structures but it is not clear whether this affects
prognosis unless brain invasion is observed. Also, the relationship
between histologic subtype and propensity for metastatic spread is
unclear. More than subtype alone may contribute to the risk for
metastatic recurrence or progression and may be related to proximity of
vascular or lymphatic structures. The reproducibility of establishing
the number of mitotic figures remains a challenge, and finally, the
issue of mixed histologic subtypes and their impact on prognosis remains
undefined.

Prognosis

Pathologic diagnosis is useful in predicting
the likelihood of recurrence. Grade 1 meningiomas recur in 7%-20% of
patients after surgical resection and grade 2 tumors recur in 40% of
cases; grade 3 recur in 50%-80% of cases and are associated with overall
poor long-term survival.^[4-6]

Yang and colleagues^[6]
reported on 74 patients diagnosed with grade 2 or 3 meningiomas and
found a mean overall survival of 142.5 months and a mean
progression-free survival of 138.5 months for atypical meningiomas
compared with a median overall survival of 39.8 months and a median
progression-free survival of 32.2 months for malignant meningiomas.
These authors also estimate that up to 2% of lower-grade meningiomas
progress to a higher grade over time and that this is generally
associated with a worse prognosis.
Based on data from 119 patients diagnosed with grade 2 and 3 meningiomas, Pasquier and colleagues^[5]
reported a 5-year survival rate of 67.5% and 60%, respectively, and a
5-year progression-free survival rate of 62% and 48%, respectively.
A multi-institutional retrospective analysis^[7]
of 199 patients diagnosed with grade 2 (n = 166) or grade 3 (n = 33)
meningiomas showed 5- and 10-year overall survival rates of 78.4% and
53.3%, respectively, for patients with grade 2 meningiomas and 44.0% and
14.2%, respectively, for patients with grade 3 meningiomas. The 5- and
10-year progression-free survival rates were 48.4% and 22.6%,
respectively, for patients with grade 2 meningioma and 8.4% and 0%,
respectively, for patients with grade 3 meningiomas. Multivariate
analysis determined that age < 60 years, complete surgical resection,
and histologic grade 2 were all independent prognostic factors for
survival.
Finally, even though grade 1 tumors may have a
low recurrence rate after complete surgical excision, the location and
size of many of these tumors make surgical resection impossible without
significant neurologic morbidity and therefore result in a poor overall
prognosis despite the benign histologic growth pattern.

Cellular and Molecular Biology

Recent research in murine and human models
suggests the identification of the cell of origin as a prostaglandin D
synthase-positive meningeal precursor cell. These studies also
demonstrate a relationship and temporal sequence between
neurofibromatosis type 2 inactivation, which is commonly associated with
meningioma, and prostaglandin D2 synthase expression in primordial
meningeal cells that may account for the pathologic subtypes of
meningioma.^[8]

The initiation of the neoplastic process in
meningiomas appears to be linked to inactivation of genes in the NF2 and
DAL-1 family.^[9]
Other implicated genes located on chromosome 22q include BAM22, BCR,
and TIMP-1, which has been specifically implicated in higher-grade
meningiomas. Grade 2 meningiomas often contain chromosomal losses of 1p,
6q, 10, 14q, and 18q, including 2 candidate genes on chromosome 14q
(MEG3 and NDRG2). Other potential factors implicated in the transition
to anaplastic meningioma include alterations of CDKN2A, p14 (ARF),
CDKN2B tumor-suppressor genes on 9p21, modification of proteins
E-cadherin and beta-catenin, and changes in the hedgehog signaling
pathway.^[9]
A recent review^[10]
of 13 microarray gene-expression profiling studies found that
meningioma-specific genes and genes associated with the 3 WHO grades
have been identified and that automated microarray technology can
potentially be used to successfully classify tumors. A similar review of
7 proteomic studies on meningioma identified 15 proteins that define
the difference between grade 1 and grade 2 meningiomas and 9 proteins
that define the difference between grade 2 and grade 3 meningiomas, but
their biological significance remains unclear.^[11]

Although this type of advanced analysis is
promising, authors of both papers note that, for the present, the
complexity and lack of consensus on the use of microarray and proteomic
data remain a significant challenge that must be resolved before the
important genes and pathways universally involved in meningioma biology
can be elucidated. However, the expansion of tumor classification,
building on the current histopathologic foundation while adding
information gained from developmental biological studies and complex
genomic and proteomic data, should eventually allow not only improved
prognostic ability but also identify key points for targeted molecular
therapies.

Treatment Modalities

Surgery Achieving complete surgical
resection has long been the goal in initial management of meningioma.
Success seems to depend on the size, location, tumor characteristics,
and involvement with adjacent structures. In 1957, Simpson^[12]
proposed a 4-tiered grading scheme for estimating risk for recurrence
after resection: Grade 1, or compete excision, yields a 10-year
recurrence rate of 9%; grade 2, consisting of excision with coagulation
of the dural remnant, yields a 10-year recurrence rate of 19%; grade 3
excision without coagulation of the dural remnant yields a 10-year
recurrence rate of 29%; and grade 2, or incomplete excision, yields a
10-year recurrence rate of 40%.
In support of these principles, a large surgical series with long-term follow-up was published in 1986.^[13]
The series included 657 patients in whom complete removal was reported,
including at least 59 (9%) in whom tumors recurred. Despite incomplete
follow-up, the estimated recurrence rate at 20 years was calculated at
19%. Multivariate analysis found that coagulation of the dural
insertion, invasion of bone, and softer tumor consistency were
significantly associated with recurrence. If none of these 3 risk
factors was present, the estimated recurrence risk was 11% at 20 years,
compared with 15%-24% if 1 factor were present and 34% to 56% if 2
factors were present.
In contrast to these findings, Sughrue and colleagues^[14]
retrospectively revisited the classic Simpson grading scheme,
evaluating their series of patients with WHO grade 1 meningiomas who had
craniotomy for resection by using Kaplan-Meier methodology for
determination of recurrence or progression-free survival. The authors
found that the 5-year recurrence or progression-free survival did not
differ significantly for Simpson grade 1, 2, 3, or 4 resections, and was
95%, 85%, 88%, and 81%, respectively. The authors also looked
specifically at meningiomas arising from the skull base (excluding the
cavernous sinus) and, somewhat surprisingly, found no significant
benefit to Simpson grade 1 or 2 resections over other grades. The
authors concluded that the benefit of aggressive attempts to resect the
tumor with dura and underlying bone was minimal compared with removing
the tumor alone, or even leaving residual tumor attached to critical
structures, rather than risk injury and add to the morbidity of the
procedure. Other surgical series of meningioma management have supported
this type of "maximal safe resection" concept for WHO grade 1
meningiomas.^[15,16]

Data are somewhat more limited on the higher-grade lesions, but Sughrue and colleagues^[17]
published an analysis of 63 patients undergoing resection for grade 3
malignant meningioma, with a median follow-up of 5 years (range 1-22
years). The 2-, 5-, and 10-year survival rates after initial surgery
were 82%, 61%, and 40%, respectively. Patients who were candidates for
repeated surgery at recurrence had significantly improved survival (53
months vs 25 months; P = .02), but gross-total resection at
initial operation was not necessarily associated with improved overall
survival. In fact, patients undergoing near-total resection had
increased overall survival compared with patients having initial
gross-total resection. There was significant morbidity associated with
surgery in this population, with 12 of 63 (19%) showing significant
neurologic deficits directly attributable to the surgical procedure.
The authors concluded that, although surgical excision can be an
effective treatment for WHO grade 3 malignant meningiomas, attempts to
achieve gross-total resection may result in significant neurologic
morbidity. Of note, regardless of grade, relatively recent data support
the observation that reduction of morbidity and mortality may be
associated with surgery done at higher-volume centers.^[18]

Areas of interest for advancing surgical management of meningiomas
include development of novel approaches, such as endonasal and
supraorbital "eyebrow" craniotomies.^[19]
Another exciting technology under study for meningioma and other
intracranial tumors is the use of intraoperative indocyanine green
videoangiography. In the course of surgical resection, a fluorescent dye
is injected intravenously and assists with localization and resection
of tumors by using a fluorescent microscope. The safety of the technique
appears to be established, but although promising, its long-term
effects on tumor resection and reduction of recurrence remain under
study.^[20]

Embolization The role of preoperative embolization for meningioma has evolved over the past decade. In a review, Engelhard^[21]
concluded that, when done by an experienced team, preoperative
embolization seems reasonably safe and of benefit in select cases and
particularly in situations in which the blood supply will be difficult
to access during a direct surgical approach. Carefully planned surgical
approaches also seem to enable excellent control of intraoperative
vascular supply and improve the ability to maintain a controlled
surgical environment.^[22]

A comparative 2-center study by Bendszus and colleagues^[23]
concluded that the benefit of embolization seemed to be limited to
those cases in which complete preoperative embolization could be
accomplished. Of note, they raised the question of whether this
increased benefit was overshadowed by the potential for permanent
neurologic deficits related to attempted embolization, even though this
occurred in only 1 of the 30 (3%) patients having embolization. Gruber
and colleagues^[24] reported no embolization-related complications in 128 procedures done in 66 patients.
A rather unanticipated complication of preoperative embolization is
the effect that embolic material has on the ability to perform an
accurate histopathologic analysis following resection. The ischemic and
associated cytologic changes seen following embolization seem to be
similar to some changes noted in the higher-grade meningiomas. Thus, it
is recommended that this information be shared with the pathologist to
avoid an erroneously inflated grade.^[25]

Radiation, Radiosurgery, Brachytherapy
Traditionally, radiation has been a second-line therapy for managing
intracranial meningiomas, and was often reserved for use in the setting
of recurrence or otherwise inoperable lesions. However, with the
increasing use of such focused therapies as radiosurgery, tumor control
has dramatically increased even for tumors in challenging anatomical
areas.^[26]

Rosenberg and colleagues^[27]
reported on combination therapies for grade 3 and 2 meningiomas and
addressed the role of adjuvant radiotherapy following surgical resection
for these challenging tumors. The radiotherapeutic modalities included
both fractionated radiotherapy and radiosurgery. Median survival was 3.4
years, with a median time to recurrence of 9.6 months; 5- and 8- year
survival rates were 47.2% and 12.2%, respectively. Of note, there was a
trend toward increased survival for patients treated with adjuvant
radiotherapy after initial surgery compared with those treated with
surgery alone. The authors pointed out the suboptimal outcomes usually
seen in patients with atypical and malignant meningiomas, and indicated
that surgery plus adjuvant radiotherapy could improve overall survival
in this challenging patient population.
Stereotactic radiosurgery has had increasing impact on neuro-oncology
decision-making. For example, in selected cases, aggressive attempts at
resection could be deferred in favor of near-total excision followed
either by upfront radiosurgery or fractionated radiotherapy in an
attempt to alleviate immediate symptoms but minimize risk for immediate
postoperativeneurologic deficits. A meta-analysis^[28]
analyzed 15 studies comprising 2734 patients treated with stereotactic
radiosurgery for intracranial meningioma, 77% of which were skull-base
lesions. The overall disease stabilization rate was, remarkably, nearly
90%.
Location is often a critical factor in treatment decisions for
meningiomas. For example, petroclival tumors are a significant challenge
because of their critical location adjacent to brainstem, cranial
nerve, and vascular structures. In these cases, stereotactic
radiosurgery has become an attractive alternative to open surgical
resection. A recent report^[29]
describes experience with radiosurgery in 168 patients, some of whom
were followed for more than 10 years. Remarkably, the 5- and 10-year
progression-free survival rates were 91% and 86%, respectively, and
minimal complications were seen.
Recurrent malignant meningioma is also particularly challenging. In
selected cases that are not suitable for radiosurgery, brachytherapy
with implantable radioactive implants has been reported with modest
success, although the high rate of radionecrosis (nearly 30%) must be
taken into consideration.^[30]

Chemotherapy and Medical Management
Due to the low mitotic activity in most meningiomas, success with
traditional chemotherapeutic approaches has been limited. Hydroxyurea
seems to have modest activity against meningiomas and may be considered
for poor surgical candidates, for patients with large residual or
unresectable tumors, or if progression occurs after maximum treatment.^[31,32] The combination of hydroxyurea with concurrent radiotherapy has been shown to be safe, but efficacy awaits additional study.^[33]
Of note, despite success against primary brain tumors, temozolomide
does not seem to have activity against refractory meningioma.^[34]
The presence and significance of hormone receptors has been an area
of active investigation. In some cases, hormonal activity has been
proposed to elicit symptomatic progression of otherwise inactive
lesions.^[35]
Pravdenkova and colleagues^[36]
reported that progesterone receptors alone is a favorable prognostic
sign, whereas the lack of progesterone receptors or the presence of
estrogen receptors correlates with more aggressive clinical behavior. Of
note, receptor status may change at progression or recurrence, and
hormonal replacement therapy does not seem to increase the incidence of
meningiomas.^[36,37] However, dopamine has been hypothesized to play a role in meningioma progression based on limited clinical data.^[38]

Exciting translational studies exploring novel biological agents and targets include the photosensitizer 5-aminolevulinic acid,^[39] fatty acid synthase,^[40] and HIV-1 protease inhibitors.^[41]
Cost and Outcomes

A critical area of future investigation in
meningioma management will involve obtaining the best clinical outcome
for the lowest cost, both in terms of medical resources and patient
safety and satisfaction.
At present, there are no evidence-based
recommendations for meningioma management approved by the relevant
professional organizations, such as the American Association of
Neurological Surgeons, the Congress of Neurological Surgeons, or the
Society for Neuro-Oncology. The Response Assessment in Neuro-Oncology
Working Group has published recommendations for assessing response in
high-grade gliomas and is developing response criteria for meningiomas
and other nervous system tumors.^[42]

In the meantime, Tan and colleagues^[43]
reported an economic assessment of both initial and follow-up costs
associated with management of 59 patients with meningioma treated with
various commonly used surgery and radiotherapy approaches.^[43]
As might be expected, the initial costs associated with surgery were
higher than with radiotherapy alone; however, the follow-up costs tended
to balance the overall expense over time.
Future studies are needed to incorporate not
only costs but also clinical outcome and patient satisfaction to
formalize recommendations for optimal management of the spectrum of
meningioma patients, creating a cost-effective, clinically successful
treatment paradigm.

Update on Meningioma: Neurosurgeon and Medical Neuro-oncologist Perspective: Neuro-oncologist Perspective: Marc Chamberlain, MD

Introduction

Medical neuro-oncologists have an admittedly
limited role in treating patients with meningiomas. Based on several
studies of natural history, newly discovered asymptomatic meningiomas
may be followed with serial MRI and this task is often performed by the
neuro-oncologist.^[44-49]
Additionally, management of meningioma-related symptoms (eg, headaches
or seizures) and long-term follow-up after definitive treatment (surgery
or radiation therapy) is often delegated to the neuro-oncologist.
The special purview of medical neuro-oncology
-- chemotherapy -- is evolving with respect to management of patients
with meningiomas that are refractory to surgery and radiation therapy.
Nonetheless, the utility of chemotherapy in the treatment of recurrent
meningioma remains ill-defined, notwithstanding limited evidence for the
use of hydroxyurea (HU), alpha interferon, and somatostatin analogues
in this setting.^[50-66]
Limited Role of Chemotherapy

HU has constituted the primary therapy based
on several studies and on the initial report of both in vitro and in
vivo activity by Schrell and colleagues.^[53,54]
Several subsequent clinical trials suggested in vivo efficacy with
modest and acceptable toxicity. However, a confounding issue with the
various HU trials is that radiation therapy had not failed or was
administered concurrently in many patients.
At present, data on outcome measures that
best define response to an investigational agent for recurrent
meningiomas are limited. As has become customary in brain tumor trials
and most trials of recurrent gliomas, 6-month progression free survival
(PFS-6) serves as the endpoint for recurrent meningiomas; however, the
definition of a clinically relevant PFS-6 varies.
In the imatinib trial, a PFS-6 of 45% was
seen in patients with recurrent grade 1 meningiomas and was believed to
indicate lack of efficacy.^[64]
By contrast, in the alpha interferon and octreotide trials for
recurrent meningioma, a PFS-6 of 40% was felt to indicate efficacy.^[55,56]
These differences reflect prior treatments (surgery and radiation
therapy) as well as various interpretations of the meager literature
regarding disease progression in previously treated patients with
recurrent meningiomas.
In the only randomized, placebo-controlled
trial of patients with recurrent grade 1 meningiomas previously treated
with radiation therapy (SWOG-9005) and evaluating an investigational
progesterone antagonist called mifepristone (RU-486), there were 45
patients for analysis (22 from the treatment group and 23 from the
placebo group).^[52]
Of the 45 patients, 30 died at the time of reporting and median
survival was 31 months. Forty-two of the 45 patients had disease
progression, with a median time to progression of 6 months. Time to
tumor progression was similar in both patient groups (placebo and
mifepristone), implying that mifepristone was not efficacious. The study
suggests a 50% PFS-6 as a baseline outcome measure from which to
compare other medical therapies in similarly treated patients (WHO grade
1 meningiomas). By contrast, recurrent atypical and anaplastic
meningiomas (WHO grades 2 and 3) represent distinct entities with a
different response to treatment at recurrence. Consequently, separate
trials -- or at least separate strata -- should be inherent in future
clinical trials for these meningioma subtypes. Several studies suggest
that a PFS-6 of 30% may indicate an active treatment in this patient
group.^[64-66]

What has changed in the contemporary
management of recurrent meningiomas is the frequent use of both
fractionated external beam radiotherapy as well as stereotactic
radiotherapy. Whether the PFS-6 in this patient group is reflective of
that seen in the SWOG-9005 trial is unknown but at present serves as the
statistical benchmark for new clinical trials with such targeted agents
as bevacizumab, sunitinib, vatalanib (PTK787), and the somatostatin
analogue pasireotide (SOM230).
There are several challenges in treating
recurrent meningiomas with targeted and chemotherapeutic agents,
including a lack of interest by the pharmaceutical industry (the most
common funding source for cancer clinical trials). Additionally, there
is minimal interest by neuro-oncology cooperative groups that are
predominantly glioma-focused as well as a perception that patients who
are eligible for study are uncommon -- even though meningiomas are the
most common primary brain tumor. As a consequence, there are very few
open trials for patients with surgery- and radiation therapy-refractory
recurrent meningioma (all are comparatively small, single-group phase 2
studies), attesting to an unmet need in neuro-oncology.

Summary

Most meningiomas are benign extra-axial
tumors of the central nervous system that, when symptomatic, are
typically treated with definitive surgical resection or radiation
therapy. Several trials of chemotherapeutic and hormonal agents for
progressive or recurrent meningiomas have been reported and are ongoing.
However, these studies should be interpreted with caution because no
large cohorts have been studied, nor has the therapy been shown to cause
regression of disease. In addition, given the natural biology and
inherently slow rate of growth of these tumors, "stability" must be
scrutinized carefully. The studies also have not consistently treated
patients in whom both surgery and radiation therapy have failed. There
is a clear need for neuro-oncology to develop new biological, genetic,
and chemotherapeutic strategies for patients with recurrent meningiomas
who have exhausted surgical and radiation therapy options. Future
treatments will be based on an improved understanding of the molecular
biology of meningiomas.
Supported by independent educational grants from EMD Serono, Merck & Co., Inc., and Genentech, Inc.

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