Die derzeitige Behandlung von Meningeomen

[Ulrich]

Current Management of Meningiomas
Die derzeitige Behandlung von Meningeomen
Franco De Monte, MD, FRCS(C)
Quelle: ONCOLOGY Vol 9, No 1(January1996)

Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston

Reviewer's Comments:
Edward R. Laws, Jr., MD, University of Virginia Health Sciences Center, Charlottesville
James Fick, MD, and Philip H. Gutin, MD, Brain Tumor Research Center, University of California, San Francisco

Übersetzung der Zusammenfassung:
Obwohl es sich um Tumoren handelt, die in der Regel gutartig sind, können Meningeome zu schweren neurologischen Schäden führen und ärgerliche Probleme bei der Behandlung verursachen. Derzeit besteht Übereinstimmung darüber, daß zur Behandlung dieser Tumoren eine komplette chirurgische Entfernung angestrebt werden sollte, wenn dies technisch möglich und mit annehmbarem Risiko verbunden ist. Dieses Ziel der totalen Entfernung (Resektion) kann jedoch auch dann nicht erreicht werden, wenn mit neuester technischer Ausrüstung und ausgefeilten operativen Techniken gearbeitet wird. Für diese Patienten und für solche mit Rezidiven ist die Behandlungoption eine erneute Operation, Strahlentherapie und Chemotherapie. Neue Entwicklungen in der chirurgischen Technik und Instrumentierung, Strahlentherapie bzw. Strahlentherapie in der Operationshöhle ["brachytherapie"] haben die Behandlungschancen verbesert, klinische Versuche mit Tamoxifen und Mifepristone (RU486) [besser bekannt als "die-Pille-danach"] geben Hinweise auf die Nützlichkeit dieser Substanzen als Chemotherapeutika. Die Suche nach einer einheitlichen erfolgreichen Behandlungsstrategie geht weiter, die Ärzte müssen sich über die vorhandenen Möglichkeiten im klaren sein und, gestützt auf das derzeitige medizinische Wissen, dem Patienten bei der Entscheidung helfen, zu entscheiden, welche Behandlung für ihn angemessen ist.

Ab hier Zitat!
Although generally benign tumors, meningiomas can cause serious neurological injury and, at times, vexatious management difficulties. Currently, the accepted management of these tumors is attempted total surgical excision when technically possible and associated with an acceptable risk. However, even with innovations in instrumentation and refinements in surgical technique, the goal of total resection may not be achievable. For these patients, and for those with recurrent tumors, options for treatment include reoperation, radiation therapy, and chemotherapy. Recent developments in surgical technique and instrumentation, radiosurgery, and brachytherapy have increased the treatment options, while clinical trials with tamoxifen and mifepristone (RU486) are adding information on the effectiveness of these drugs as chemotherapeutic agents. While the search continues for a uniformly successful management plan, physicians must be aware of the available options and try to help the patient decide which treatment is appropriate, based on current medical knowledge. [ONCOLOGY 9(1):83-100]

Introduction
Histologically, meningioma is a typically benign neoplasm that would not present a therapeutic challenge if located in any less vital or less anatomically complex region of the body than the intracranial or intraspinal spaces. When located inside the cranium, and especially along the skull base, this usually benign tumor must be viewed as a locally aggressive soft-tissue tumor that will recur if incompletely treated. The following case presentation highlights just such a problem.

Case Report
In 1965, a 31-year-old woman had a left frontotemporal craniotomy and a subtotal resection of a sphenoid ridge meningioma. Postoperatively, a wound infection led to the removal of the craniotomy bone flap. In 1968, progressive left-sided proptosis due to tumor regrowth developed, and the patient underwent a left orbital exenteration with subtotal removal of the meningioma. Progressive enlargement of the residual meningioma led to two subsequent cranial operations in 1974. Following these surgeries, external beam radiation to a dose of 50 Gy was delivered. The patient remained stable for 17 years.

In 1991, an increased frequency of seizures, somnolence, and memory loss led to reinvestigation. Massive tumor recurrence was found. The initially left-sided sphenoid ridge meningioma had now spread to the right middle fossa and into the posterior fossa. The large right middle fossa component of the tumor was resected. In early 1994, the patient, now 59 years old, developed an ataxic gait and right-sided hearing loss. Enlargement of the tumor was noted. The patient was enrolled in an experimental trial using the antiprogesterone agent mifepristone (RU486). Progressive tumor enlargement with the onset of obstructive hydrocephalus led to the discontinuation of the medication and the insertion of a ventriculoperitoneal shunt. The patient's current magnetic resonance (MR) images are shown in Figure 1. Surgical removal of the large petroclival component of the meningioma has been recommended.

Incidence
Reported incidence rates of meningioma vary from less than 1 to more than 6 per 100,000 population [1,2]. If the results of three large recent studies of intracranial neoplasms are combined, the overall incidence of meningioma is 2.6 per 100,000 population [1,3,4]. The ratio of male to female cases ranges from 1:1.4 to 1:2.8. The incidence of intracranial meningioma increases with age [1,3,4]. The rates peak in the sixth decade for males and in the seventh for females. These peak rates are 6.0 and 9.5 per 100,000, respectively [5]. Autopsy data suggest that the declining incidence rates beyond the seventh decade may be the result of a less aggressive investigative posture in the elderly [1].

Pathology
The World Health Organization (WHO) classification of meningiomas is shown in Table 1. Numerous histologic variants of meningioma exist, none of which has any prognostic significance; all are considered histopathologically benign tumors. The most common of these variants are the meningothelial and fibrous meningiomas (Figure 2).

Certain histopathologic features, which can be detected by light microscopy, portend an increased tumor aggressiveness and increased likelihood for recurrence (Table 2) [6,7]. It is these features that define the atypical meningioma. The diagnosis of malignant meningioma generally requires histologic evidence of brain invasion or distant metastasis, which, in most cases, is accompanied by further evidence of aggressivity such as is seen with the atypical meningiomas. An exception to this requirement is the finding of a papillary pattern [8]. This pattern is associated with a predictable aggressive behavior, with late distant metastases occurring with significant frequency [9]. When dissemination occurs, the more common sites of implantation and growth are the lungs and/or pleura, bones, abdominal viscera (especially the liver), and lymph nodes [10].

Because the identification of histologic features of aggressiveness is occasionally imprecise, and their presence does not necessarily correlate with future regrowth or recurrence of the tumor, researchers have attempted quantitative measurements of various parameters. Using flow cytometry, May et al [11] have shown that recurring meningiomas have a significantly higher proliferative index (% S-phase + % G(2)/M-phase) than do nonrecurrent meningiomas. They indicated that a proliferative index of more than 20%, irrespective of the histopathologic appearance, strongly suggested that the tumor would recur.

The determination of the bromodeoxyuridine (BUdR) labeling index or of the number of argyrophilic nucleolar organizer regions (AgNOR) has been used to identify intracranial meningiomas with a higher propensity to recur. Hoshino et al [12] found that a BUdR labeling index of 1% or higher was indicative of meningiomas with a faster than typical growth rate (higher proliferative potential) and that meningiomas with a BUdR labeling index of 5% or higher had a 100% recurrence rate. The recurrence rate dropped to 55.6% for meningiomas with a BUdR labeling index between 3% and 5% and to 30.6% for those with a BUdR labeling index between 1% and 3% [12,13]. Chin and Hinton [14] reported that the mean AgNOR counts were statistically different among benign (245 ± 156), atypical (497 ± 135), and malignant meningiomas (921 ± 59). They also noted a statistically different AgNOR count for recurrent meningiomas (544 ± 76) when compared with nonrecurrent meningiomas (329 ± 183).

Finally, positron emission tomography (PET) studies have shown glucose utilization to be lower (1.9 mg/dL/min ± 1.0) in nonrecurring tumors than in recurrent tumors (4.5 mg/dL/min ± 1.9) [15].

Diagnosis
Contrast-enhanced MR imaging provides the best means of detecting meningiomas [16]. Most meningiomas enhance intensely and homogeneously with intravenous paramagnetic contrast material, and in approximately 10% of cases, small additional meningiomas are encountered that are missed on unenhanced MR images. Likewise, contrast enhancement of the dura extending away from the margins of the mass is typical of meningioma, although it can be seen with other dural-based lesions. This "dural tail" can indicate tumor extension, and its resection is important to reduce the risk of recurrence. Postoperative enhanced MR imaging has also been found to be more sensitive and specific in the detection of residual or recurrent meningioma. Thick and nodular enhancement has a high correlation with recurrent or residual neoplasm [17].

The MR characteristics of meningiomas are relatively consistent. On noncontrasted T(1)-weighted images, 60% to 90% of meningiomas are isointense, whereas 10% to 30% are mildly hypointense when compared with gray matter. T(2)-weighted imaging reveals that 30% to 45% of meningiomas have increased signal intensity, whereas approximately 50% are isointense to gray matter [16,18-20].

Vascular distortion or encasement and tumor vascularity are better assessed by MR imaging than by computed tomography (CT) scanning. Flow-voids produced by flowing blood identify the vasculature local to the tumor (Figure 1).

There is increasing interest in using MR characteristics to tissue-subtype meningiomas preoperatively. The results of these studies have been varied, with some reporting 75% to 96% accuracy, and others finding no correlation [18-21]. The MR characteristics that allowed accurate preoperative identification of meningioma subtypes were confined to findings on T2-weighted studies. Specifically, meningothelial meningiomas were found to have a consistently higher signal intensity on T2-weighted sequences than did fibroblastic or transitional meningiomas, which demonstrated a higher relative signal intensity on intermediate images. High signal intensity on T2-weighted images has also been correlated with microscopic hypervascularity and soft tumor consistency [22].

Treatment
The primary treatment modality for meningiomas remains surgical resection, with the extent of resection being the primary factor influencing the recurrence rate. Simpson's 1957 classification of the extent of meningioma removal, which correlates well with rates of recurrence, continues to be a useful means of grading the extent of tumor removal (Table 3) [23]. Mirimanoff et al [24] reported recurrence-free survival rates for total resection of 93% at 5 years, 80% at 10 years, and 68% at 15 years, whereas with partial resection, recurrence-free survival rates dropped to 63%, 45%, and 9%, respectively. Similarly, Chan and Thompson [25] reported a longer survival time and a higher quality of life when complete tumor excision was accomplished.

The most comprehensive studies to date come from Finland, where the structure of the health-care system allows for identification of essentially all cases of meningioma in the population. Jääskeläinen [26], in his study of patients with benign intracranial meningiomas, found an overall recurrence rate at 20 years of 19% (life table analysis). Multivariate analysis showed that strong risk factors for recurrence included coagulation (rather than removal) of the dural insertion, invasion of bone, and soft consistency of the tumor. For patients with none of these risk factors, the recurrence rate at 20 years was 11%, whereas the presence of one or two risk factors increased the recurrence rate to 15% to 24% and 34% to 56%, respectively. In a second study from the same group, the diagnosis of atypical or malignant meningioma carried an increased risk of recurrence of 38% and 78% at 5 years, respectively [27]. Finally, a recently published survival study reported that the cumulative relative survival rates (ratio of observed rate to expected rate) at 1, 5, 10, and 15 years were 83%, 79%, 74%, and 71%, respectively, indicating a persisting incidence of increased mortality in patients with meningiomas [28].

Critical parameters that affect the ease of surgical removal include tumor location, size, consistency, vascular and neural involvement, and, in the case of recurrence, prior surgery and/or radiotherapy. New and innovative approaches have been devised to reach and widely expose meningiomas in any location. Furthermore, a greater appreciation of risk factors for, and patterns of, tumor recurrence has changed surgical planning and goals. To decrease the incidence of recurrence, resection of all of the neoplasm and all of the involved dura, soft tissue, and bone is now the accepted procedure.

Radiation therapy is currently the only validated form of adjuvant therapy for meningiomas, but investigators continue to search for an effective chemotherapeutic agent.

Surgery
For all patients with supratentorial meningiomas, anticonvulsant therapy is initiated if it is not already being used, dexamethasone is administered beginning one to several days prior to the operation, and an H(2) antagonist is co-prescribed. Pneumatic compression devices are placed on the legs when the patient is admitted to the hospital, and they remain in use for the entire period of hospitalization, because of the clearly increased risk of venous thrombosis in a patient harboring a meningioma [29]. Perioperative antibiotics are used prophylactically for staphylococcal organisms in all patients; a third-generation cephalosporin with activity against pseudomonal organisms and, at times, metronidazole (for anaerobic organisms) are added when surgery in the mouth, paranasal sinuses, ear, or mastoid is planned.

In the vast majority of first operations for meningiomas, a layer of arachnoid separates the tumor from the brain parenchyma, cranial nerves, and blood vessels. When it does, the chances of neural and/or vascular injury can be greatly reduced by defining and staying within this surgical plane. In the case of a reoperation, or occasionally at the primary operation, the arachnoidal plane of dissection will not be present. This increases the risk of both neural and vascular injury, and requires meticulous sharp dissection with the aid of the operating microscope. Identification of vascular and neural structures in normal areas allows the surgeon to follow these structures through areas of scar and tumor encasement. One maneuver that facilitates the definition of the arachnoidal borders is extensive debulking of the tumor, thus allowing the tumor capsule to collapse inward. The methods used to debulk the tumor, which may be suction, coagulation, sharp excision, or use of the ultrasonic aspirator or the surgical laser, depend on the tumor consistency, vascularity, and location.

Once the mass of the meningioma is resected, careful attention must be given to removing the involved dura and bone. The extent of bone that must be removed can be determined by inspection of the preoperative CT scan's "bone windows" (Figure 3). All of the hyperostotic bone should be considered contaminated by neoplastic cells [30]: The fear of entering the mastoid air cells or the paranasal sinuses is not cause for failing to remove this diseased bone. A wide margin of dura should be resected, and the defect should be repaired with pericranium, temporalis fascia, or fascia lata.

Skull-Base Approaches--The development of skull-base approaches is a more recent surgical innovation that has facilitated the removal of meningiomas, especially those along the base of the cranium. With these approaches, the facial skeleton is temporarily mobilized and portions of the temporal bone are removed, to give the surgeon a wider, shallower, and more basal approach to the undersurface of the brain. The most commonly used of these approaches are the cranio-orbital zygomatic [31], the petrosal [32], and the transcondylar [33]. All three allow improved visualization with less need for retraction of the brain. Lessening brain retraction is vital, especially during long procedures, to minimize the risk of brain injury (Figure 4).

The cranio-orbital zygomatic approach, or one of its variations, is an excellent choice for most basally located meningiomas of the anterior and middle fossae (Figure 5) [34]. Osteotomies of the orbital rims and/or the zygomatic arch allow for a low basal approach that can be 1.5 to 2 cm lower than conventional approaches [35]. Meningiomas of the anterior and middle fossae usually derive their blood supply from branches of the external carotid artery, ethmoidal branches of the ophthalmic artery, and meningeal branches of the internal carotid artery. Interruption of this transbasal blood supply is the initial step when removing these tumors, and is greatly facilitated by using the cranio-orbital zygomatic approach.

Meningiomas of the posterior part of the middle fossa may extend into the posterior fossa. These meningiomas, as well as petroclival and some cerebellopontine angle meningiomas, are best accessed for removal by the petrosal (subtemporal-presigmoid) approach (Figure 6). Many variations of this approach exist, all of which are based on the extent of temporal bone removal [36]. In patients with intact hearing, only enough bone is removed to expose the presigmoid dura, leaving intact the semicircular canals and the fallopian canal (with the enclosed facial nerve). If the meningioma has produced deafness by interference with the auditory pathways, then the exposure can be extended to incorporate a translabyrinthine and, if needed, a transcochlear approach [37]. These more anterior exposures may require transposition of the facial nerve. This removal of a portion of the temporal bone provides a greater anterior and anterolateral view of the brainstem, thereby allowing easier identification and protection of the critical neurovascular structures in this area.

A similar quest for a more anterior approach to the lower brainstem led to the development of the transcondylar approach [33], which achieves this goal by the removal of the occipital condyle and the lateral mass of C(1). This approach also affords greater access to, and control of, the vertebral artery (Figure 7). Meningiomas of the foramen magnum and upper cervical spine are ideally approached and removed by this route.

New Technologies--Developments in electrophysiologic monitoring, frameless stereotaxy, and medical lasers have been quite beneficial to the neurosurgeon. Continuous electrophysiologic monitoring of the third through the 12th cranial nerves is routinely used when surgical dissection in the region is required [38]. This allows for easier identification of the cranial nerves, the position and appearance of which may have been drastically altered by the meningioma. Also, cranial nerve monitoring provides the surgeon with continuous feedback as to the status of the nerve being monitored. Early warning of nerve dysfunction allows the surgeon to take appropriate steps to remedy the situation.

Frameless stereotactic systems (eg, ISG Viewing Wand, ISG Technologies Inc., Toronto, Canada) allow the integration of the preoperative imaging data with the position of anatomic structures at the time of surgery, thereby aiding in the planning and the trajectory of the surgical approach. Such a system also provides the surgeon with feedback on current location, at times in an anatomically distorted surgical field. The Viewing Wand is especially useful during skull-base surgery, because the surrounding structures (bony skull base) are rigid. This rigidity greatly improves the accuracy of the system. The Viewing Wand is also quite useful for identifying the margins of bone pathology (eg, hyperostosis), which may not be appreciable by visual inspection only and are not amenable to frozen section study.

The development of contact fibers for the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser allowed a greater degree of tactile feedback to the surgeon than was possible with earlier methods. Because the fibers interact with tissue only upon actual contact, the safety factor is considerably improved. Conical fibers allow for sharp dissection, while "hemispherical" fibers allow greater dispersion of light for ablation of a larger area of tumor (Nd:YAG Sculpted Contact Fibers--Sharplan Lasers Inc., Allendale, NJ). These fibers are especially useful in the cauterization of the dural site of origin of meningiomas when the dura cannot be resected (eg, lateral wall of the posterior third of a patent superior sagittal sinus).

Radiation Therapy
The use of external beam irradiation as part of the management of meningiomas has become commonplace. External beam irradiation has been reported effective both following subtotal resection at the primary operation and at the time of recurrence, whether or not preceded by reoperation [39-41]. Goldsmith et al [39], reporting on 140 patients treated from 1967 to 1990, found a 5-year progression-free survival rate of 89% for benign meningiomas, and 48% for malignant meningiomas treated by subtotal surgical resection and postoperative radiation therapy (median dose, 54 Gy). If only those patients with benign meningiomas treated after 1980 (n = 77) are evaluated, the 5-year progression-free survival rate increases to 98%. This improvement has been attributed to improved treatment planning using CT and MR imaging [39]. Less conclusive effectiveness has been reported for meningiomas considered inoperable because of location, poor patient health, or patient refusal of surgery [42-44].

External beam irradiation would seem to be beneficial for aggressive meningiomas (atypical, malignant), but to date very little information exists to support this thesis. Salazar [45] combined several studies and found a 58% recurrence rate following gross total resection, and a 90% recurrence rate following subtotal resection of malignant meningiomas; the rates decreased to 36% and 41%, respectively, when surgery was followed by external beam irradiation. In our own series of aggressive meningeal tumors, no statistically significant difference could be found in either time to recurrence or patient survival between those patients who did or did not receive postoperative radiation therapy [10]. The recommended radiation dose and target volume for malignant meningiomas are greater than for benign meningiomas, averaging at least 60 Gy with a 3 to 4 cm margin [46].

The effectiveness of higher radiation doses must be weighed against possible complications, especially when dealing with benign meningiomas [47]. The optic nerves are particularly sensitive to doses greater than 55 Gy, but lower doses have also been implicated in the production of radiation-induced optic neuropathy [47,48]. In the group of 140 patients reported above by Goldsmith et al, five patients (3.6%) experienced a complication related to the radiation therapy (blindness in three, cerebral necrosis in two) [39]. Other potential complications include the production of pituitary insufficiency and, because of the long survival of patients with benign meningiomas, secondary (radiation-induced) neoplasms.

Radiosurgery
The use of stereotactic radiosurgery to treat intracranial meningiomas began in the 1960s with the Harvard proton beam [49]. Since then, stereotactic irradiation has been used increasingly to treat meningiomas. The first use of the gamma knife to treat a patient with a meningioma was in 1970 [50]. Use of the linear accelerator (LINAC) as an energy source for stereotactic radiosurgery was delayed until the 1980s due to a lack of technology. Today, the technique is used with various energy sources, the most common of which are photons from cobalt-60 gamma-ray sources (Gamma Knife) or linear accelerators (LINAC) and heavy particles (protons, helium ions) from cyclotrons. Irradiation with heavy particles has a distinct radiobiologic advantage, especially for larger lesions, but all forms of radiation beams in use have shown a low incidence of complications, especially for lesions less than 2.5 cm in size [51].

Luchin et al (Burdenko Neurosurgical Institute), using the proton beam, and Kjellberg and Candia (Harvard Cyclotron) showed 84% and 40% local control rates, respectively [49]. The mean length of follow-up for both groups was less than 5 years. Steiner et al [50], in their review of patients treated with the Gamma Knife, found an 88% control rate. This series also had a mean length of follow-up of less than 5 years. Lunsford [52] recently reported a 4-year actuarial tumor control rate of 92% for 94 patients who underwent gamma knife radiosurgery for benign meningiomas.

Experience with the linear accelerators is the most limited. In 1990, Engenhart et al [53] reported on 17 patients treated with linear accelerator-generated stereotactic irradiation with a mean dose of 29 Gy. Of 13 patients available for follow-up, none had had recurrence over a median follow-up time of 40 months.

Despite the promising results of stereotactic irradiation, limitations and uncertainties remain. Tumor size should be limited to 30 to 35 mm. Treating larger volumes results in an increased risk of radiation injury and complications [53]. Even for smaller target sizes, a 3% risk of radiation necrosis persists [50]. The advent of fractionated delivery of stereotactic irradiation may overcome this size limitation [54].

The nature of recurrence and spread of meningiomas along dural margins (dural tails on MR images) pose a significant hindrance to focal therapies, due to the difficulty in targeting extensions of the tumor. Since the basic feature of stereotactic irradiation is the quick drop-off of radiation dose, this may result in these more diffuse margins receiving inadequate doses. Furthermore, little is known about the acute and especially the long-term effects on encased or immediately adjacent neurovascular structures. At present, some authors recommend a minimum distance of 5 mm from the optic chiasm as a selection criterion, whereas others limit the dose to the optic apparatus to 10 Gy or less [50,55]. The optimal treatment dose required for meningiomas is also unknown, but some guidelines have been extrapolated from experience with acoustic neuromas. Doses of 15 to 20 Gy to the tumor margin are the most commonly employed, since higher dosages have been associated with higher rates of morbidity [53].

Stereotactic irradiation will likely become increasingly pertinent to the management of meningiomas, either as a primary therapy or following planned subtotal microsurgical resection (as part of a multimodality treatment plan), but the full extent of its benefits can be determined only with the passage of time.

Brachytherapy
The stereotactic and direct microsurgical implantation of radioactive seeds into meningiomas has been reported by several groups who have found these procedures to be beneficial, but so far the number of patients treated is low and the length of follow-up is short [56,57]. The concern with tumor size is not as great as it is with stereotactic irradiation, since the radiation dose is slowly delivered by the decay of the radioisotope (usually iodine-125). Accurate and precise planning of dosimetry is crucial. Marked changes in tumor size that can be seen with treatment indicate a concern that seed migration and the delivery of unwanted radiation to nearby neurovascular structures might occur [58]. If this concern can be successfully overcome, then brachytherapy may become a very valuable adjunct for treating meningiomas.

[Ulrich]

Current Management of Meningiomas
Die derzeitige Behandlung von Meningeomen Teil 2
Franco De Monte, MD, FRCS(C)
ONCOLOGY Vol 9, No 1(January1996)

Chemotherapy
Little information is available on the efficacy of the traditional antineoplastic agents against either benign or malignant meningiomas. Adjuvant chemotherapy for malignant meningiomas and for recurrences of benign or atypical meningiomas has been administered to a small number of patients at The University of Texas M.D. Anderson Cancer Center. Chemotherapeutic regimens using intravenous and/or intra-arterial cisplatin (Platinol), dacarbazine, doxorubicin (Adriamycin), cyclophosphamide (Cytoxan, Neosar), ifosfamide (Ifex), mesna (Mesnex), and vinblastine have generally been unsuccessful (Groves, DeMonte, Yung, unpublished data), despite their effectiveness against other soft-tissue tumors. Recently, several patients with malignant meningioma have been treated with interferon-alfa with apparent stabilization of their disease (Yung A: personal communication, 1994).

Antagonism of possible mitogenic hormones or factors has also been attempted. Early human trials were conducted with tamoxifen (Nolvadex) (antiestrogen) and mifepristone (antiprogesterone). The Southwest Oncology Group (SWOG) used tamoxifen (40 mg/m2 twice daily for 4 days and 10 mg twice daily thereafter) to treat 19 patients with unresectable or refractory meningiomas [59]. There was progression of tumor in 10 patients, temporary stabilization of the disease process in six patients, and a partial or minor response in three. Mifepristone was given for 2 to 31 months in two separate studies of a 200-mg daily dose. In one study, five of 14 patients demonstrated objective improvement, namely a minor decrease in the size of the tumor in four patients and an improved visual field examination without change in tumor size in the fifth; regrowth subsequently occurred in one of these patients [60]. A later study from the Netherlands that included 10 patients showed that disease progressed in four patients, remained stable in three, and minimally decreased in size in three [61]. These agents are currently under investigation in larger trials, but as yet no known role has been determined regarding their use in the treatment of meningiomas.

In vitro studies with bromocriptine (Parlodel) and trapidil (a platelet-derived growth factor antagonist) have yielded promising results, and human trials are likely to follow [62,63].

References
1. Kurland LT, Schoenberg BS, Annegers JF, et al: The incidence of primary intracranial neoplasms in Rochester, Minnesota. Ann NY Acad Sci 381:6-16, 1982.
2. Schoenberg GS, Christine BW, Whisnant JP: The descriptive epidemiology of primary intracranial neoplasms: The Connecticut experience. Am J Epidemiol 104:499-510, 1976.
3. Preston-Martin S, Henderson BE, Peters JM: Descriptive epidemiology of central nervous system neoplasms in Los Angeles County. Ann NY Acad Sci 381:202-208, 1982.
4. Sutherland GR, Florell, R, Louw D, et al: Epidemiology of primary intracranial neoplasms in Manitoba, Canada. Can J Neurol Sci 14:586-592, 1987.
5. Rohinger M, Sutherland GR, Louw DF, et al: Incidence and clinicopathological features of meningioma. J Neurosurg 71:665-672, 1989.
6. Burger PC, Scheithauer BW, Vogel FS: Surgical Pathology of the Nervous System and its Coverings, 3rd Ed, p 83. New York, Churchill Livingstone, 1991.
7. De la Monte SM, Flickinger J, Linggood RM: Histopathologic features predicting recurrence of meningiomas following subtotal resection. Am J Surg Pathol 10:836-843, 1986.
8. Ludwin SK, Rubenstein U, Russell DS: Papillary meningiomas: A malignant variant of meningioma. Cancer 36:1363-1373, 1975.
9. Pasquier B, Gasnier F, Pasquier D, et al: Papillary meningioma: Clinicopathologic study of seven cases and review of the literature. Cancer 58:299-305, 1986.
10. Younis GA, Sawaya R, DeMonte F, et al: Aggressive meningeal tumors: Review of a series. J Neurosurg (in press).
11. May PL, Broome JC, Lawry J, et al: The prediction of recurrence in meningiomas: A flow cytometric study of paraffin-embedded archival material. J Neurosurg 71:347-351, 1989.
12. Hoshino T, Nagashima T, Murovic JA, et al: Proliferative potential of human meningiomas of the brain: A cell kinetics study with bromodeoxyuridine. Cancer 58:1466-1472, 1986.
13. Shibuya M, Hoshino T, Ito S, et al: Meningiomas: Clinical implications of a high proliferative potential determined by bromodeoxyuridine labeling. Neurosurgery 30:494-498, 1992.
14. Chin LS, Hinton DR: The standardized assessment of argyrophilic nucleolar organizer regions in meningeal tumors. J Neurosurg 74:590-596, 1991.
15. DiChiro G, Hatazawa J, Katz DA, et al: Glucose utilization by intracranial meningiomas as an index of tumor aggressiveness and probability of recurrence. Radiology 164:521-526, 1987.
16. Zimmerman RD: MRI of intracranial meningiomas, in Al-Mefty O (ed): Meningiomas, pp 209-223. New York, Raven Press, 199

The De Monte Article Reviewed
Edward R. Laws, Jr., MD, University of Virginia Health Sciences Center, Charlottesville

Dr. DeMonte has used an interesting case report to provide an excellent summary of the state of the art in the management of meningiomas of the brain.

These lesions are the most common benign tumors affecting the central nervous system. For many years, they have represented a major challenge for neurosurgeons, both technically and conceptually [1]. The fact that most of these tumors can be cured surgically has stimulated a variety of innovative approaches. It has led to the recent developments of successful surgery within the cavernous sinus and successful approaches to the skull base--both areas that were previously considered surgically inaccessible.

There are many fascinating aspects to the problem of meningioma. The benign nature of most meningiomas makes them generally favorable lesions, ones which, at least theoretically, can be cured by surgical therapy alone. Sex and age predilection for the occurrence of meningiomas have been the foundation for investigation regarding the hormonal basis of tumor pathogenesis for this lesion. The presence of estrogen and progesterone receptors on meningiomas has been well documented. As is pointed out in this review, this fact has served as the basis for attempts at hormonal therapy. These attempts are still under analysis.

Histologically, meningiomas can be differentiated into a number of different groups, but it is curious that the histology of the tumor rarely provides pertinent information with regard to the behavior of the lesion or its likelihood of recurrence. It appears that any histologic subtype of meningioma can have either a focal or a diffuse origin from the meninges, and there is no consistent correlation of specific type with intracranial location. What does appear to be correct, however, is that those tumors with a focal origin are the ones most likely to be cured surgically, and those with a more diffuse dural origin are those that tend to defy complete surgical resection and are most likely to recur following any form of treatment.

A Major Problem

The aggressive "cellular" or "atypical" meningioma represents a major problem in neurosurgical management. These tumors usually have suspicious histologic features, such as increased numbers of mitoses, but otherwise they look like fairly typical meningiomas. Unfortunately, they can follow a very aggressive course, with rapid and multiple recurrences unresponsive to standard forms of treatment. The nature of this aggressive change is not understood, and it represents a challenge for the future.

Equally difficult to explain has been the problem of cerebral edema surrounding many meningiomas [2]. A number of biochemical abnormalities have been identified, and a number of theories have been proposed in explanation of this phenomenon. It appears that the tumor "poisons" the surrounding brain, producing the edematous reaction, but the nature of this process is still speculative. Fortunately, this edema usually responds well to treatment with steroids, which sometimes need to be maintained for relatively long periods following successful surgery.

The peculiar features of meningioma biology surely are clues to the basic nature of this tumor and its etiology. Current studies emphasizing the molecular biology of these lesions offer great promise in helping us deal more effectively with meningiomas in the future. With the accurate characterization of tumor cell receptors, particularly with hormone receptors, new avenues for diagnosis and therapy are developing. With information regarding alterations in the genome of meningiomas [3], the opportunity for novel forms of diagnosis and therapy exist, and should hold significant promise as our basic understanding of this difficult tumor evolves.

References
1. Newman SA: Meningiomas: A quest for the optimum therapy. J Neurosurg 80:191-194, 1994.
2. Philippon J, Foncin JF, Grob R, et al: Cerebral edema associated with meningiomas: Possible role of a secretory-excretory phenomenon. Neurosurgery 14:295-301, 1989.
3. Detta A, Kenny BG, Smith C, et al: Correlation of proto-oncogene expression and proliferation in meningiomas. Neurosurgery 33:1065- 1074, 1993.

The De Monte Article Reviewed
James Fick, MD, and Philip H. Gutin, MD, Brain Tumor Research Center, University of California, San Francisco

Surgical resection has been the preferred treatment for meningiomas since the era of the pioneering neurosurgeon, Harvey Cushing. The great majority of these tumors are histologically benign, circumscribed lesions that grow slowly and tend to compress and displace, rather than invade, the surrounding intracranial structures. In contrast to the intrinsic brain tumors of glial origin, most meningiomas have well-defined borders, enabling the surgeon to dissect the tumor capsule from the arachnoid lining of the adjacent brain, blood vessels, and cranial nerves. Consequently, complete removal can be accomplished without needing to sacrifice functional tissue. In these cases, surgery is often curative, and associated with the preservation of, if not improvements in, the neurological condition.

The size and location of some meningiomas at the time of original discovery sometimes precludes the possibility of complete removal. Four decades ago, Simpson recognized that the extent of surgical resection was an important determinant of the recurrence rate for meningiomas [1]. Since then, numerous groups have retrospectively analyzed the outcome of meningioma patients treated with surgery, to confirm Simpson's observation that the rate of recurrence following surgery was increased in cases where a limited resection was performed [2-4]. Others have subsequently demonstrated that the regrowth of incompletely resected tumors is associated with decreased life expectancy [5].

Unfortunately, meningiomas can recur after a seemingly complete removal [6]. The lifelong threat of recurrence was a topic that Cushing discussed in his classic monograph on meningiomas published in 1938 [7], and this problem continues to plague afflicted patients and their treating physicians. A cause for concern in these cases is that, at the time of recurrence, a previously benign meningioma is sometimes found to be malignant, although this is not a common occurrence [8,9].

While most meningiomas are believed to have a clonal origin from a single cell [10], there is increasing evidence from neuroradiographic [11,12] and pathological [13] studies that patients with these tumors have abnormalities throughout the dura that may actually represent early meningioma foci. It is apparent that surgery, while sometimes curative, is not always successful in ridding the patient of tumor, and even when it does, cannot always ensure freedom from recurrence and protection from future malignancy.

The Rationale for Prompt Treatment

When the diagnosis of a meningioma is made, surgery is the therapy favored by most physicians. The reasons given to support a recommendation for prompt treatment include the desire to confirm the clinical suspicions; to establish a tissue diagnosis on which the need for future therapy will be based; to offer a better chance of maintaining neurological function with early treatment rather than delaying therapy until the tumor has grown in size; and the likelihood that if the tumor proves to be a benign meningioma, the procedure will often prove curative.

The goal of surgery is straightforward: The removal of as much of the tumor as possible while minimizing the chance of neurological injury. The technical demands for a given operation are determined by the size, location, and vascularity of the tumor, a history of previous surgery or radiotherapy, and involvement of critical structures such as dural venous sinuses, major arteries, and cranial nerves. In complex cases, the preoperative neurological condition is an important consideration in deciding upon the extent of resection to be undertaken, as existing deficits may become worse after surgery, delaying postoperative recovery, or be made a permanent cause of long-term morbidity.

The Surgical Approach

For the most part, the general principles of meningioma surgery remain unchanged from the early days of the specialty: An approach is chosen to ensure an adequate exposure of the margins of the tumor; an attempt is made to interrupt the blood supply to the tumor early in the procedure to minimize blood loss; and, when possible, an internal decompression of the tumor is performed to reduce the need to retract the brain and to ease the dissection of the tumor capsule away from critical structures.

Recently, multidisciplinary surgical teams have utilized new approaches to remove meningiomas from the base of the skull. Reports describing the use of techniques that include the preoperative balloon occlusion of major intracranial arteries encased by tumor [14], arterial bypass procedures [15,16], grafting of transected cranial nerves [17], and the use of autologous tissue flaps to prevent cerebrospinal fluid (CSF) leaks through cranial defects [18] have been published. Ojemann has cautioned against aggressive surgical approaches for skull-base tumors in cases where the risks associated with their use were great and the chance of altering the natural course of the disease uncertain [19].

Undoubtedly, modern neuroimaging technology such as CT and MR scanning has made it easier to detect recurrent meningiomas, and has resulted in the discovery of an increased number of asymptomatic, coincidentally discovered meningiomas.

Advances in molecular genetics may soon make available screening tests for neurofibromatosis. The identification of these patients who are predisposed to developing meningiomas at an early age, combined with vigilant monitoring, makes it likely that an ever-increasing number of these tumors will be discovered among those afflicted with neurofibromatosis.

Presently, meningiomas are most commonly diagnosed after 5 decades of life, suggesting that the incidence of these tumors will increase as our population increases and continues to age. To confront the therapeutic challenge posed by these scenarios, the treating physician will become increasingly dependent on adjuvant therapy following surgery to prevent tumor progression. In cases where the removal of tumor is incomplete, radiation therapy is the most effective way to prevent or delay recurrence after surgery.

The Case for Fractionated Radiotherapy

At the University of California, San Francisco, fractionated radiotherapy is the recommended treatment for most patients following incomplete resections of intracranial meningiomas. This approach represents an alternative to radical surgery. The management of cavernous sinus meningiomas is a case in point. The resection of tumors from this location is often a formidable challenge; the technical demands are great and the associated risks to the patient considerable. In those cases where surgery is unlikely to be curative, subtotal resection of tumor followed by radiotherapy can minimize operative morbidity and effectively control the growth of these tumors. A recent report from our institution has shown that, in those patients with benign meningiomas treated after 1980, the 5-year progression-free survival rate was 98%--a result comparable to that achieved with complete surgical removal [20].

Lundsford has addressed the topic of adjuvant radiation therapy in the management of meningiomas [21], and together with his colleagues has reported on a series of meningioma patients treated with stereotactic radiosurgery [22]. Their results suggest that this technique may also one day prove to be an effective way to prevent the growth of selected meningiomas. The microsurgical implantation of I-125 sources into recurrent, previously radiated malignant meningiomas, when performed in conjunction with surgical debulking, can lead to long-term remission [23].

Although there is little data to support a role for chemotherapy or hormone therapy in the contemporary management of meningiomas, knowledge of the molecular mechanisms involved in the progression of a microscopic meningioma focus to a frankly malignant tumor may lead to new therapeutic insights. Identification of genetic mutations common to meningiomas provides reason for optimism that corrective gene therapy may one day play a role in the management of these tumors.

Words of Caution

The allure of surgery as a cure for intracranial meningiomas must be tempered by the realization that these tumors recur even after they have been completely removed, that incompletely removed tumors tend to regrow, and that the threat of malignant transformation surfaces at the time of recurrence. Always keen to cure, the surgeon must remain aware of the insidious behavior of so many of these meningiomas, and be prepared to resort to adjuvant therapies to prevent the progression of this disease. Future breakthroughs will undoubtedly depend upon a combination of continued improvements in surgical technique, new methods to increase the therapeutic ratio of irradiation, and insights into the molecular alterations that underlie tumorigenesis in the meninges.

References
1. Simpson D: Recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 20:22-39, 1957.
2. Mirimanoff RO, Dosoretz DE, Linggood RM, et al: Meningioma: Analysis of recurrence and progression following neurosurgical resection. J Neurosurg 62:18-24, 1985.
3. Adegbite AB, Khan MI, Paine KWE, et al: The recurrence of intracranial meningiomas after surgical treatment. J Neurosurg 58:51-56, 1983.
4. Chan RC, Tompson GB: Morbidity, mortality, and quality of life following surgery for intracranial meningiomas: A retrospective study in 257 cases. J Neurosurg 60:52-60, 1984.
5. Kallio M, Sankilla R, Hakulinen T, et al: Factors affecting operative and excess long-term mortality in 935 patients with intracranial meningiomas. Neurosurg 31:2-12, 1992.
6. Jaaskelainen J: Seemingly complete removal of histologically benign intracranial meningioma: Late recurrence rate and factors predicting recurrence in 657 patients. A multivariate analysis. Surg Neurol 25:233-242, 1986.
7. Cushing H, Eisenhardt L: The Meningiomas: Their Classification, Regional Behavior, Life History, and Surgical End Results. Springfield, Illinois, Charles C. Thomas, 1938.
8. Jaaskelainen J, Haltia M, Servo A: Atypical and anaplastic meningiomas: Radiology, surgery, radiotherapy, and outcome. Surg Neurol 25:233-242, 1986.
9. Wilson CB: Meningiomas: Genetics, malignancy, and the role of irradiation in their induction and treatment. Schneider Lecture, presented at the American Association of Neurological Surgeons Meeting, San Francisco, 1992.
10. Jacoby LB, Pulaski K, Rouleau GA, et al: Clonal analysis of human meningiomas and schwannomas. Cancer Res 50:6783-6786, 1990.
11. Goldsher D, Litt AW, Pinto RS, et al: Dural "tail" associated with meningiomas on Gd-DTPA-enhanced MR images: Characteristics, differential diagnostic value, and possible implications for treatment. Radiology 176:447-450.
12. Larson JJ, Tew JM, Wiot JG, et al: Association of meningiomas with dural "tails": Surgical significance. Acta Neurochir 114:59-63, 1992.
13. Borovich B, Doron Y: Recurrence of intracranial meningiomas: The role played by regional multicentricity. J Neurosurg 64:58-63, 1986.
14. Sekhar LN, Patel SJ: Permanent occlusion of the internal carotid artery during skull-base and vascular surgery: Is it really safe? (editorial). Am J Otol 14:421-422, 1993.
15. Sen C, Sekhar LN: Direct vein graft reconstruction of the cavernous, petrous, and upper cervical internal carotid artery: Lessons learned from 30 cases. Neurosurg 30:732-742, 1992.
16. Iwai Y, Sekhar LN, Goel A, et al: Vein graft replacement of the distal vertebral artery. Acta Neurochir 120:81-87, 1993.
17. Sekhar LN, Lanzino G, Sen CN, et al: Reconstruction of the third through sixth cranial nerves during cavernous sinus surgery. J Neurosurg 76:935-943, 1992.
18. Izquierdo R, Leonetti JP, Origitano TC, et al: Refinements using free-tissue transfer for complex cranial base reconstruction. Plast Reconstr Surg 92:567-574, 1993.
19. Ojemann RG: Skull-base surgery: A perspective. J Neurosurg 76:569-570, 1992.
20. Goldsmith BJ, Wara WM, Wilson CB, et al: Postoperative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 80:195-201, 1994.
21. Lunsford LD: Contemporary management of meningiomas: Radiation therapy as an adjuvant and radiosurgery as an alternative to surgical removal? J Neurosurg 80:187-190, 1994.
22. Duma CM, Lunsford DL, Kondziolka D, et al: Stereotactic radiosurgery of cavernous sinus meningiomas as an addition or alternative to microsurgery. Neurosurg 32:699-705, 1993.
23.Gutin PH, Leibel SA, Hosobuchi Y, et al: Brachytherapy of recurrent tumors of the skull base and spine with iodine-125 sources. Neurosurg 20:938-945, 1987.