Benign and aggressive intracranial meningiomas, as the authors
state, are seemingly simple tumors (even with benign histology)
that can behave in a clinically malignant fashion solely by location.
Clinicians with experience in the management of patients with
aggressive, recurrent, or malignant meningiomas are all too well
aware of the difficulties of recommending effective therapy beyond
surgery and radiation therapy. Clearly, there is much room for
improvement in the treatment of recurrent or malignant meningiomas
with local or systemic chemotherapy and/or biologic therapies.
A key to the uniform reporting and analysis of the results of
the treatment of meningiomas is a standard classification system
based on histopathologic features. Although many different schemes
have been proposed since the time of Cushing and Eisenhardt ,
the scheme by Russell and Rubenstein , and the World Health
Organization Classification of Tumors, Second Edition (WHO-2)
, seem to be the most widely used. As the authors point out,
these descriptors of pathologic type may be supplemented by the
Helsinki grading system, which attributes either 0 or 3 points
for the absence or presence of six features of anaplasia .
These features include loss of cell architecture, increased cellularity,
nuclear pleomorphism, mitotic figures, focal necrosis, and brain
infiltration. The sum of these points is then used to assign a
grade from I to IV corresponding to descriptions of benign, atypical,
anaplastic, and sarcomatous forms of meningiomas.
Although bromodeoxyuridine labeling indices (developed by Dr.
Takao Hoshino at the Brain Tumor Research Center at the University
of California, San Francisco) were used in the past, we have now
turned to ex vivo labeling studies, including the use of Ki-67
and MIB-1 . MIB-1 is commercially available and can be used
on paraffin-embedded tumor sections; these sections can be recovered
in such a fashion as to reactivate an epitope of Ki-67, which
stains for the expression of several proliferation-associated
nuclear proteins, and a proliferating cell index can be derived.
Typically, with this technique, the labeling index is 2.4 to 1.8
times higher than it is with the bromodeoxyuridine labeling index.
There is, however, a strong correlation among the bromodeoxyuridine,
MIB-1, and Ki-67 proliferating cell indices . These indices
correlate with the proliferative potential of a tumor more accurately
than do other tissue descriptive assessments. The results of the
combination of histopathologic information, tumor grade, labeling
index information, and the Simpson surgical grade, as discussed
by the authors, should be available from future clinical series
reporting on the treatment of meningiomas .
Surgical Treatment Options
Although surgical resection remains an important part of the treatment
of both benign and malignant meningiomas, not all patients with
intracranial meningiomas require surgery, especially elderly patients
. Now, for a variety of reasons, small dura-based tumors with
imaging characteristics compatible with meningiomas are more often
detected via imaging of the central nervous system. Beyond the
determination of whether or not a meningioma is responsible for
any signs or symptoms, patient and tumor factors must be weighed
to determine the appropriateness, and benefit, of any recommended
surgical procedure. It is not uncommon to see a patient with a
heavily calcified meningioma that does grow appreciably for a
considerable period. Clearly, if a decision is made not to intervene,
the patient should agree with this approach and be available for
regular clinical and radiologic follow-up, so if new symptoms
or signs develop, or there is objective evidence of tumor growth,
the situation can be reevaluated.
Preoperative medical therapy for patients with meningiomas does
not necessarily have to include embolization, as the authors indicated.
With a convexity meningioma, the dural blood supply can be exposed
easily and interrupted during the exposure necessary for resection
of the tumor. Furthermore, in certain locations, such as the olfactory
groove, embolization may present too high a risk. In the case
of a small falx meningioma, for which preoperative angiography
is not necessary, we have found magnetic resonance venography
to be an important adjunct in surgical decision-making regarding
the side from which to approach the tumor, given the pattern of
veins draining into the superior sagittal sinus. Any additional
information that may reduce the potentially devastating consequences
of interrupting a "safe" parasagittal draining vein
should be considered.
There is no question that during the mid-to-late 1980s, the development
of skull-base approaches allowed surgeons to remove tumors previously
thought to be unapproachable. However, by their very nature, these
procedures are complex and lengthy and may be associated with
significant morbidity. In a recent seminal article, Larson et
al pointed out the pathologic findings of infiltration of cranial
nerves within the cavernous sinus by benign meningiomas, excluding
any realistic possibility of "surgical cure" while maintaining
extraocular muscle function and an acceptable rate of operative
morbidity.8 Some impressive surgical results have been reported
by surgeons accomplished in skull-base approaches; however, 5-year
and 10-year rates of recurrence-free survival will be necessary
to evaluate the efficacy of this complex surgical procedure.
Radiotherapy and Chemotherapy
It seems somewhat paradoxical that radiation therapy would be
recommended as an adjuvant therapy for incompletely resected,
recurrent, or malignant meningiomas when both low- and high-dose
irradiation to large volumes of the scalp have been implicated
in the development of meningiomas. Beyond the experience of Israeli
children treated for tinea capitis with meningiomas, a recent
review of the literature has revealed that the higher the dose
and the younger the patient undergoing irradiation, the shorter
the latency period for tumor development . It must be understood
that with conventional external-beam irradiation techniques and
three-dimensional treatment planning, the volume of normal tissue
irradiated to a significant dose has been greatly limited.
The authors have rightly assessed the utility of modern-day radiotherapy
for subtotally resected and recurrent meningiomas. Series published
since 1990 document 5-year progression-free survival rates for
benign meningiomas of 84% to 89% . In the University of California
at San Francisco series published by Goldsmith et al, treatment
complications, occurred in 5 patients (3.6%), 3 of whom had a
sudden onset of blindness 20 to 22 months after treatment .
Others have reported such complications as hearing loss, memory
impairment, pituitary dysfunction, and chronic otitis media. For
surgeons and radiotherapists, information about microscopic rests
of meningothelial cells at up to 3 cm from the margin of the original
tumor in 57% of specimens is essential for treatment planning
Although radiosurgery is a relatively new treatment for meningiomas,
at least 2 series reported a median follow-up of at least 40 months.
In the two series, tumor control rates were 76% and 80%, respectively
[12,13]. As mentioned by the authors, reduction in tumor size
is not the only end point in evaluating therapy, and no increase
in tumor size is also an acceptable result. In our experience,
only about 30% of meningiomas will become smaller after radiosurgery.
Radiosurgery can be used for small, focal occurrences of benign
meningiomas or as a boost for residual disease in malignant meningiomas.
In their discussion of interstitial brachytherapy, the authors
refer to two series by the same author, who reported remarkable
radiologic response rates without complications. Our experience
is encouraging but not nearly as dramatic! In an evaluation of
21 patients with recurrent or malignant meningiomas treated with
iodine-125, low-activity permanent implants at the time of reoperation,
the median time to tumor progression was 96 weeks and the median
survival was 124 weeks from the time of implantation . Complications
occurred in a significant number of patients (38%). These implants
are usually reserved for patients with a significant mass of recurrent
tumor and for patients in whom other treatment modalities have
failed. Obviously, these patients still must be strong enough
for an open surgical procedure.
Conventional chemotherapy for recurrent or malignant meningiomas
has certainly been disappointing. We have not found a regimen
of cyclophosphamide (Cytoxan, Neosar), doxorubicin, and vincristine
to be of any significant benefit, given the side effects; in 11
patients, our failure rate was 73% at 1 year and 100% at 2 years
after the start of treatment . Clearly, some other approach
is warranted, given these poor results.
Experimental studies have demonstrated a number of receptors present
in meningioma cells, including progestins, androgens, glucocorticoids,
dopamine (DA1), interferon alpha, epidermal growth factor, and
platelet-derived growth factor, to mention a few . Experimental
evidence in animal models does exist for the use of some receptor
antagonists against these different receptors in controlling tumor
growth. In one study, trapidil, a drug with antiplatelet-derived
growth factor activity, was combined with bromocriptine (Parlodel),
a DA1-dopamine receptor blocker; this combination of drugs inhibited
tumor growth more than either agent alone . Obviously, the
clinical applications of such experiments require further study.
Although the antiprogestational agent mifepristone has generated
much excitement, the small amount of objective data documenting
tumor control requires further investigation. In addition, high
doses of tamoxifen may, in fact, act against meningioma cells
by inhibiting protein kinase C activity, rather than by any effect
on estrogen receptors, few as they are.
A potentially exciting area of current laboratory investigation
is the use of novel biologic therapies for the treatment of meningiomas.
In this regard, options include using modified attenuated live
virus and infecting the proliferating tumor; the enzyme activity
of these proliferating cells is directed toward replication of
the virus, and cell death occurs through the normal mechanisms
of virus-induced cell lysis . As well, the introduction of
a specific gene, such as herpes simplex virus I thymidine kinase,
with a retroviral vector may permit the incorporation of a small
amount of this gene in actively proliferating cells . The
administration of a prodrug such as ganciclovir (Cytovene) permits
the phosphorylation of the drug through the activity of thymidine
kinase; the triphosphate form of ganciclovir is toxic to the tumor
cells. According to Fick et al current research now indicates
that the bystander effect is likely related to the passage of
phosphorylated forms of ganciclovir between tumor cells, and it
appears that the efficiency of this bystander effect relates to
the density of gap junctions that exist on the tumor cell surface
. Conveniently, meningioma cells happen to have abundant gap
junctions. Therefore, these tumors may be well suited to this
form of therapy. Obviously, if laboratory studies continue to
indicate the effectiveness of this treatment, it will be some
time before this therapy is brought to the clinical sphere.
Although it is true that the mainstay of therapy for meningiomas
is surgery, clearly there are a significant number of patients
for whom this option does not provide a cure, and other adjuvant
therapies are necessary. Neurosurgeons, radiation oncologists,
and medical oncologists with a special interest in these tumors
have long been frustrated by their tenacity to resist conventional
treatment. Advanced surgical techniques, improved radiotherapy
using three-dimensional conformal treatment planning, and radiosurgery
units have nearly reached their technical limits. Clearly, it
is necessary to identify the most effective form of adjuvant chemotherapy,
immunotherapy, or viral/genetic therapy for recurrent, aggressive,
or malignant meningiomas.
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