Behandlung von gutartigen und aggressiven Meningeomen

[ulrich]

Zitat:

Management of Benign and Aggressive Intracranial Meningiomas
Die Behandlung von gutartigen und aggressiven intrakraniellen Meningeomen Teil 1

Edward W. Akeyson, MD, PhD and Ian E. Mccutcheon, MD, FRCS(C)
Quelle: ONCOLOGY Vol 10, No 5 (May 1996)
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston

Reviewer's Comments:
Steven M. Grunberg, MD, University of Vermont Burlington
Michael McDermott, MD, University of California San Francisco

Usually considered benign tumors, meningiomas can display aggressive behavior characterized by multiple recurrences and invasion of the brain, dura, and adjacent bone. The aggressive or malignant phenotype is difficult to characterize due to the broad spectrum of behaviors exhibited by meningiomas. Recent classification schemes based on features of anaplasia rather than histopathology have been used successfully to identify meningiomas that exhibit features of the aggressive phenotype. Some such tumors can be identified preoperatively by radiographic characteristics. Surgery is the cornerstone of treatment for all types of meningiomas. Conventional radiation therapy is beneficial for patients with recurrent (or incompletely resected) benign meningiomas and is recommended for those with aggressive and malignant meningiomas. Stereotactic radiation and interstitial brachytherapy are useful in some refractory or recurrent meningiomas. Traditional chemotherapeutic agents are not very effective against meningiomas, but hormonal manipulation is under study for patients with inoperable tumors or those who are medically unsuitable for surgery. [ONCOLOGY 10(5):747-759, 1996]Introduction
Meningiomas are histologically benign tumors of the intracranial and intraspinal compartments arising from meningothelial cells of the arachnoid layer ("arachnoidal cap cells") surrounding the central nervous system. Their behavior is sometimes far from benign, however, as they can be the source of significant morbidity and even mortality. Although slow-growing, meningiomas cannot be completely resected in many instances, and are characterized by a high rate of recurrence, propensity for disturbing vital and anatomically complex structures within the nervous system, and poor response to traditional medical treatment regimens. Recurrence is often accompanied by a more aggressive profile of histopathology and biologic activity. The more aggressive varieties, the so-called atypical and malignant meningiomas, present their own specific problems for treatment. Meningiomas, therefore, pose definite therapeutic challenges to practicing neurosurgeons and oncologists.

Pathology
Recent advances in the neuropathology of meningiomas have produced more specific histopathologic and cytologic criteria for classifying these tumors, more sophisticated markers of aggressive behavior, and further clarification and characterization of the malignant phenotype. This information is essential for the practitioner treating patients harboring these tumors, as it helps identify those requiring more aggressive medical and surgical treatment regimens.

Classification
Traditionally, meningiomas have been classified based on their histologic appearance, and predictions of aggressive behavior are derived from such classifications. Cushing and Eisenhardt proposed a scheme containing nine types of meningioma with 22 subtypes [1]. The most widely used classification system, that of Russell and Rubenstein, described three classic types of meningiomas (syncytial, fibroblastic, and transitional), with a number of histologic variants or subtypes [2].

With the exception of the papillary, hemangiopericytic, and angioblastic varieties of meningiomas, classification by histologic appearance alone has no bearing on prognosis or behavior [2]. However, such features as hypervascularity, hemosiderin deposition, indistinct architectural pattern, increased numbers of mitotic figures, necrosis, prominent nucleoli, and moderate nuclear pleomorphism have been associated with recurrence in meningiomas [3]. It remains controversial as to whether the hemangiopericytoma truly belongs among the meningiomas by virtue of a common precursor cell, or whether it represents a separate tumor type with a distinct oncogenesis [2].

The system of classification proposed by the World Health Organization (WHO) in 1979 [4] and revised in 1993 [5] is based on cytologic features of anaplasia rather than purely histopathologic descriptions. This system classifies meningiomas as benign, atypical, or malignant based on six individual features of anaplasia: loss of architecture, hypercellularity, nuclear pleomorphism, mitotic figures, focal necrosis, and brain invasion.

Jääskeläinen et al [6] and Rohringer et al [7] have refined the WHO system by applying scores from 0 to 3 to each of the parameters based on the degree of severity of that feature, with the exception of brain invasion, which is scored as absent (0) or present (3). Based on the sum of the scores, meningiomas are designated as benign (grade I; 0 to 2 points), atypical (grade II; 3 to 6 points), anaplastic (grade III; 7 to 11 points), or sarcomatous (grade IV; 12 or more points). Mahmood et al [8] have further revised this scheme by providing defined, objective criteria for the scores of 1, 2, or 3 for each of the classification parameters.

Cell Kinetics
In an attempt to determine more precisely the correlates of aggressiveness and future growth of these tumors, researchers have developed quantitative methods of measuring the proliferative activity of meningioma cells. Analyses of the DNA content of meningioma cells using flow cytometry have been performed [9-11]. Tumor aneuploidy has been associated with poor clinical outcome [9]. The proliferation index, ie, the percentage of cells in the S + G2/M phases of the cell cycle, correlates with clinically aggressive behavior in meningiomas [10] and with meningioma recurrence [11].

The mitotic, or labeling, index of many meningiomas has been determined using bromodeoxyuridine labeling. The labeling index is obtained by briefly exposing the tumor to a thymidine analog and calculating the percentage of total tumor cells incorporating the analog into DNA. By combining the in vivo exposure of the tumor to bromodeoxyuridine with in vitro exposure to iododeoxyuridine, the time required for DNA synthesis can be calculated [12,13].

Bromodeoxyuridine labeling correlates well with recurrence rates of meningiomas. Shibuya et al [12] demonstrated that tumors with a bromodeoxyuridine labeling index > 5% have a 100% recurrence rate, as compared with a 56% recurrence rate for tumors with a labeling index of 3% to 5%, and a 31% rate for those with a labeling index of 1% to 3%. Labeling indexes of 9% and 13.6% were reported by Fukui et al for two recurrent meningiomas with highly malignant behavior, as compared to labeling indexes of 0.1% to 0.9% for benign meningiomas [13].

Malignant Meningioma Phenotype
A concise definition of the malignant meningioma remains elusive and controversial. The situation is complicated by the fact that a histologic and biologic continuum probably exists between atypical or aggressive meningiomas and malignant meningiomas. Nevertheless, the modified WHO system of classification has proved useful in identifying meningiomas with potential for either aggressive future behavior or for recurrence. Using these criteria, recurrence at 5 years after complete removal is 3% for grade I tumors, 38% for grade II, and 78% for grade III, with median times to recurrence of 7.5, 2.4, and 3.5 years, respectively [14]. Mahmood et al found 5-year recurrence rates after total surgical excision of 50% for atypical tumors (grade II) and 33% for malignant meningiomas (grades III and IV), but these differences were not statistically significant [8].

In many recent studies of meningiomas, the term "malignant" is usually applied to both grade III and IV tumors, ie, those expected to display evidence of more aggressive biologic behavior. However, in practical use, the diagnosis of malignant meningioma is reserved for those tumors displaying histologic evidence of brain invasion or evidence of distant metastasis, features that are not always easily assessed. Traditionally, pathologists have been reluctant to classify a meningiomas as "malignant" unless definite brain invasion is present. Those few meningiomas that metastasize (1% or less of all histologic types, and one-third of those designated as malignant) would by definition need vascular invasion, occult or overt, to accomplish distant spread. Evaluating brain invasion remains subjective, in that postsurgical changes seen in patients with recurrent meningiomas can make delineation of the boundaries between tumor and brain difficult. Sampling bias may cause underdiagnosis of brain invasion, and some atypical tumors may actually be malignant by that criterion.

Comprehensive Classification Scheme--The most comprehensive classification of meningiomas would combine histopathologic, cytologic, and kinetic information to reveal the precise position of a given tumor within the broad and complex spectrum of these tumors. One such scheme is that proposed by Wilson [15], who suggested meningioma designations such as grade I, which consists of meningotheliomatous tumors and those with a labeling index of 1% ("classic" or "benign"); and grade III, which includes tumors with a papillary pattern or a labeling index of 3.5% (anaplastic). Thus, the malignant designation would be applied to tumors with one or more indices of aggressive behavior, such as a high grade (III or IV), a histologic appearance associated with aggressive behavior, a labeling index > 3%, and/or evidence of brain invasion. The presence of distant metastasis provides additional evidence of highly aggressive behavior, and thus, a poorer expected outcome.

The clinical predictive value of such an ecumenical scheme remains to be shown in systematic studies. For now, it provides useful criteria with which to stratify those meningiomas expected to display more aggressive biologic behavior, and thus, to require more aggressive surgical and medical treatment.

Clinicopathologic Correlation
Certain features have been identified that distinguish the aggressive meningiomas from the more common benign types. The reported incidence of meningiomas with histologic anaplasia varies based on the specific criteria used, and is obviously dependent on referral patterns, but it ranges from 0.9% to 11% [16-19]. Salcman combined the incidence of malignant meningiomas in several large recent studies that use a variety of classification criteria and found that an average of 2.8% of meningiomas qualify for the malignant designation [20]. Using the WHO classification and its modifications mentioned above, benign meningiomas represent 93% (grade I) and atypical tumors, 5% (grade II); about 2% are anaplastic or sarcomatous (grades III and IV) [5,6,8,14].

Although the most common presenting symptoms, seizures and headaches, are equally frequent in benign and malignant meningiomas [7], the incidence of hemiparesis or focal neurologic deficits is higher in patients with malignant meningiomas [8,14,20]. While benign meningiomas are known to show nearly a 2:1 female-male predilection, malignant meningiomas demonstrate either a male predominance [14] or are evenly split between the genders [8]. In two series combined, 10 of 12 malignant meningiomas occurred in males [21,22]. Most malignant meningiomas are located over the convexity or in parasagittal locations [7,8].

Distinguishing Radiographic Features--Certain radiographic features may be used to distinguish malignant meningiomas from benign tumors. Malignant meningiomas are approximately half as likely as benign tumors to show homogeneous enhancement on CT scans and are more frequently associated with moderate to severe peritumoral edema [7,14]. Unlike their benign counterparts, few, if any, malignant meningiomas are calcified [7,14].

Other features seen on CT that correlate with an aggressive histology or behavior are "mushrooming," or irregular projections of the tumor along or into the brain surface; indistinct tumor margins; fringes of tumor extending into the brain substance; marked bone destruction; and large areas of low-density, central necrosis [7,8,14]. Some malignant meningiomas display a CT appearance consistent with dural-based glioma or metastasis [14]. In one retrospective series, 12 of 17 atypical mengiomas and 13 of 16 anaplastic tumors could have been distinguished from benign meningiomas preoperatively based on radiographic characteristics alone [14].

Malignant meningiomas commonly display increased signal on both T1- and T2-weighted MRI studies (see Figure 1) [20]. As with other intracranial tumors, however, correlation of radiologic with histologic features is imperfect. Although tumors that appear aggressive on radiologic images are generally confirmed to be atypical or malignant, those with a benign appearance may grow and recur quickly and show anaplastic features, despite the absence of radiologic predictors.

Surgical Treatment

Preoperative Embolization
Because of the rich blood supply of meningiomas from the dura and adjacent bone, preoperative embolization has become an important adjunct to surgical removal for some of these tumors. Embolization of major dural feeders to these tumors has several theoretical benefits, such as reducing blood loss during surgery, shortening operative time, and allowing more intraoperative manipulation of the tumor owing to softening of the neoplasm; thus, it affords theoretical protection to the surrounding brain from surgical trauma [23]. Preoperative embolization may also reduce the incidence of recurrence [24]. However, we do not embolize tumors with dural or osseous vascular supply that is easily transected during the approach to the tumor. In this sense, patients with convexity meningiomas are much less likely to benefit from embolization than are those with basal tumors approached through cisterns of the subarachnoid space.

Embolization alone, without subsequent surgical removal, is usually reserved for cases in which surgical treatment is contraindicated. However, transient improvement and resolution of clinical symptoms have been observed following endovascular treatment of meningiomas [25].

The goals of the endovascular approach are to reach the tumor's capillary bed and then obliterate its arterial/arteriolar feeders while preserving normal arterial vessels and allowing adequate healing of the scalp during the recovery period [25]. Endovascular treatment of meningiomas usually requires a specially trained interventional neuroradiologist. Superselective catheterization of the feeding arterial vessels is performed using specially designed guidewires and catheters, and various materials (the nature of which depends on the size of the vessels to be embolized) are then mixed with a contrast agent and injected into the arterial feeder during systole.

Endovascular approaches are limited to tumors with vessels that can be selectively catheterized; atherosclerotic narrowing or vessel tortuousity may preclude this form of treatment. Branches of the internal carotid artery, including the ophthalmic artery, and pial vessel supply to the tumor are not typically embolized because of the attendant risk of stroke. However, in the case of aggressive or malignant meningiomas, more aggressive devascularization can be employed and may be necessary. For certain meningiomas located at the skull base, a large functional artery (typically, the intracavernous carotid artery) may need to be sacrificed in order to control the tumor. This should only be done after a trial occlusion of the appropriate vessel with concomitant functional testing and measurement of cerebral blood flow before and during arterial occlusion. (New surgical techniques for skull-base meningiomas are discussed below.)

Embolization is optimally done 3 to 5 days prior to the planned surgical resection [25]. It is best viewed as a way of reducing the blood supply of a meningioma, rather than eliminating it.

Benign Meningiomas
Surgical resection remains the mainstay of treatment for benign meningiomas. Many factors affect the ease of complete surgical resection, including the tumor's location, size, or consistency; the extent of vascular and neural involvement; and, in the case of recurrence, prior surgery and radiotherapy. The goal of surgery depends on the location of the tumor and the age and overall medical condition of the patient [26]. Complete resection should be attempted for most convexity, olfactory groove, and parafalcine tumors along the anterior third of the sagittal sinus and for some tentorial and posterior fossa tumors. The challenge of operating on a convexity meningioma is to achieve complete removal while leaving the patient neurologically intact, which usually requires meticulous surgical technique.

Complete resection may not be possible for some medial sphenoid wing meningiomas or for those along the posterior sagittal sinus and clivus. Biopsy alone or simple observation is indicated for some tumors in critical and delicate locations, such as meningiomas of the optic nerve sheath or those at the cranial base.

Basic Surgical Principles--A complete discussion of specific surgical approaches for the various types of meningiomas is beyond the scope of this article. However, a few basic surgical principles regarding resection of all types of meningiomas deserve attention. It has been known since the report of Simpson almost 40 years ago that extent of resection is the primary factor influencing the rate of recurrence of meningiomas [27]. His classification was based on the degree of resection of the tumor and the adjacent bone and dura; grade I resection implies complete removal of the tumor as well as involved dura and bone, while grade V resection involves partial debulking producing only decompression. In Simpson's series, resection of grades I, II, III, and grade IV had recurrence rates of 9%, 19%, 29%, and 40%, respectively, at 10 years. It is therefore common practice to remove all affected dura and bone during tumor resection with a 1- to 2-cm margin around the tumor where possible.

Mortality After Resection--In an attempt to determine outcome for patients after surgical resection of meningiomas, the mortality associated with intracranial meningiomas has been studied. Reported mortality following surgical resection of meningiomas ranges from 7% to 17% at 5 years [28-32]. Observed survival rates from 43% to 77% have been reported at 10 years after resection of meningiomas in large series of patients [27,29,30,32]. An average postoperative survival of 9 years was reported in one series of benign meningiomas, whereas the median survival of patients with malignant meningiomas has been reported to be as low as 7 months [33].

As many patients with meningiomas are elderly, it is difficult to determine precisely the mortality associated with meningiomas exclusive of all other causes. Using cumulative relative survival rates (age-corrected ratios of observed rate to expected rate), Sankila et al [32] and Kallio et al [29] reported that patients undergoing resection of meningiomas exhibited average excess mortality relative to the general population of 14%, 16.5%, 22%, and 25.5%, at 1, 5, 10, and 15 years, respectively. Factors contributing to perioperative mortality (within 30 days) were poor preoperative clinical condition, absence of epilepsy, old age, incomplete tumor removal, postoperative pulmonary embolism, and reoperation for removal of an intracranial hematoma [29]. The extent of tumor removal was the most significant factor responsible for excess mortality 2 to 15 years following surgery, with the presence of hyperostosis achieving significance after the seventh year following surgery [29].

Skull-Base Meningiomas: A Special Case
Many meningiomas in or near the cranial base, including those in the cavernous sinus and at the petro-clival junction, have historically been regarded as unresectable due to their proximity to the brainstem, cranial nerves, and vessels of the circle of Willis. More recently, surgical techniques utilizing advanced microsurgery and specialized approaches beyond the scope of this article have been applied to patients with skull-base meningiomas and have made meaningful resection feasible [34-37]. The more recent reports show complete removal in about 75% of patients overall, with minimal perioperative mortality, and good functional outcome in 50% to 60% of patients. However, many of these patients develop new cranial nerve deficits, and some are not symptomatically improved following surgery. Recurrence of the tumors in these reports is low; however, they often omit the long-term follow-up needed to show whether these innovative approaches have significantly arrested tumor progression. Only then will it be known whether acquisition of new cranial nerve or other neurologic deficits is an acceptable outcome.

In addition, many new therapies are becoming available for the treatment of skull-base tumors that further expand treatment options. Especially important in this respect are advances in imaging, interventional neuroradiology, and radiation oncology, especially stereotactic radiosurgery (discussed below). Outcome following surgical resection must be assessed in light of the progressive deterioration associated with the natural history of these tumors, and relative to the efficacy of these newer treatment options.

Atypical and Malignant Meningiomas
The surgical principles involved in resection of malignant meningiomas are similar to those for removal of benign meningiomas. However, the atypical and malignant lesions pose some unique problems. Complete removal of atypical and anaplastic meningiomas can be problematic due to unrecognized spread along the dura [38] or infiltration of the adjacent cortex by small "finger" projections from the tumor surface [6,39].

Because of these considerations, a more radical operation has been suggested by some authors [14] and is practiced by many surgeons. In such an operation, excision or coagulation of the dura should be broader than is performed for benign meningiomas. Also, additional steps should be taken to ensure removal of small nodules of tumor within the cortical substance, often achieved with the use of a laser and/or an operating microscope.

Truly invasive meningiomas should be treated like gliomas. Infiltrated brain adjacent to the tumor should be resected to the maximum extent allowed by adjacent, clinically significant cortex or cortical projections; or until frozen sections confirm the absence of tumor. In patients in whom the tumor has recurred, a more aggressive removal of dura and, if necessary, of brain should be performed to decrease the chances of another regrowth of the tumor.

Radiotherapy
Conventional wisdom suggests that ordinary meningiomas, as slow-growing tumors, should be relatively resistant to radiotherapy. As radiotherapy techniques have become more sophisticated and knowledge of the radiobiology of meningiomas has increased, however, the therapeutic role of radiation therapy has expanded. Currently available information generally supports the use of conventional, external-beam irradiation, stereotactically delivered single high-dose irradiation, and continuous interstitial brachytherapy in the treatment of meningiomas. Specific applications of these radiotherapy techniques will be addressed in the following sections.

Fractionated Radiation
Numerous authors support the use of fractionated radiotherapy following incomplete surgical resection of benign meningiomas [17,30,33,40-51]. When given in adequate doses, postoperative radiation therapy of residual meningiomas slows tumor growth and delays recurrence.

In a recent review, Salazar provided a partial summary of currently available results with this form of treatment [52]. These studies indicate that the average rate of recurrence of benign meningiomas 5 years after subtotal surgical excision drops from 40% without adjuvant radiotherapy (range, 26% to 69%) to 18% with its use (range, 0% to 33%). This improvement in recurrence rate applies not only to subtotal resection, but also to biopsy alone (Simpson grade V), and applies as well as after the first recurrence [47,51,52].

Recurrence rates when postoperative adjunctive radiotherapy follows subtotal surgical resection are similar to those reported for patients in whom "total" surgical excision was accomplished [41,47,50,51]. Taylor et al reported a local control rate at 10 years of 82% for subtotal excision and radiation, as compared with 18% for subtotal resection alone, with 10-year survival rates of 81% and 49%, respectively [47]. Similar local control rates have been reported in other recent series [50,51].

Use in Benign Meningiomas--Published experience regarding effective doses of radiation in the treatment of benign meningiomas suggests that doses ranging from 4,500 to 6,000 cGy (average, 5,000 to 5,500 cGy) at 180 to 200 cGy per fraction (amounting to five fractions per week over 5 to 6 weeks) are adequate [41,43,46,47,50-53]. Taylor et al found no correlation between radiation dose and tumor control in their series of benign meningiomas [47]. However, Goldsmith et al reported a 10-year progression-free survival of 93% for patients who received a tumor dose > 52 cGy, as compared with 65% for those treated with a lower dose, although the difference was not statistically significant [50], and may have been due to uncontrolled variations in tumor size between the two groups.

Most centers now irradiate the presurgical tumor volumes plus a 1- to 2-cm margin. Currently available data suggest that these radiation doses can be given in the treatment of meningiomas with few to no complications [47,50,51].

There may also be a role for high-energy photon irradiation in the treatment of meningiomas, but it has been used in only a few patients [51].

Use in Malignant Meningiomas--Due to the relative rarity of malignant meningiomas, few data exist on the efficacy of radiation in treating them. Adjuvant radiotherapy following both total and subtotal excision decreases the rate of recurrence of malignant meningiomas (Table 1). Taken as a whole, the data indicate that the incidence of local recurrence is reduced for patients with malignant meningiomas who have undergone either total or subtotal excision followed by postoperative radiation therapy. Goldsmith et al reported an overall 5-year survival rate of 58% and a progression-free survival rate of 48% in 23 patients with malignant meningiomas who were treated with postoperative irradiation [50]. Although the numbers of patients are small, the aggressive clinical course of atypical and malignant meningiomas should prompt serious consideration of postoperative radiation regardless of the presence or absence of residual tumor.

Despite the fact that malignant meningiomas certainly require different dose-volume relationships than their benign counterparts, rigorous analyses of this topic are scarce. Many radiotherapists believe that because invasion of the brain and its attachments is common with malignant meningiomas, treatment fields should be more generous than those used to treat benign tumors. Most centers utilize a radiation field that encompasses the preoperative tumor volume plus a 1- to 3-cm margin.

Conventional doses used in benign meningiomas may be insufficient to control residual disease in patients with more aggressive tumors [44], and many centers use at least 6,000 cGy over 6 to 7 weeks to treat them [52]. At the University of California in San Francisco, for example, patients with benign meningiomas are routinely given 54 Gy and those with malignant meningiomas are given 60 Gy [50]. This practice is supported by a 5-year progression-free survival rate of 63% in patients with malignant meningiomas receiving > 53 Gy, as compared with a rate of 17% for those treated with 53 Gy or less [50].

Stereotactic Radiosurgery
Stereotactic radiosurgery involves the delivery of single-fraction, high-dose radiation to a small volume with anatomic precision. Radiosurgery relies on a different radiobiologic principle than fractionated external-beam radiotherapy. Rather than depending on the differential sensitivity of normal and neoplastic cells to fractionated radiation, radiosurgery relies on a steep radiation fall-off at the margins of the radiation field to provide only the tumor with doses that cause cellular and vascular damage that lead to tumor necrosis. Whereas conventional radiation relies on the sensitivity of cells in the G2 phase of the cell cycle, radiosurgery causes the death of cells that are not actively dividing, and thus, may have a theoretical advantage in slow-growing tumors such as meningiomas. Radiation beams for radiosurgery have been generated by a multisource cobalt-60 gamma unit (the so-called gamma knife), a modified linear accelerator, and a cyclotron producing heavy, charged particles.

Because radiosurgery is a relatively new technique, and the lesions in question grow slowly, adequate follow-up for patients with meningiomas treated with radiosurgery has been lacking. The most comprehensive series is that reported by Kondziolka et al [54]. They described the results of gamma knife irradiation of 50 patients with meningiomas who were followed from 6 to 36 months after stereotactic radiosurgery, 24 of whom were followed for at least 12 months. Over half (54%) of the latter group showed a decrease in tumor size and 38% showed no progression. In two patients (8%), tumors progressed outside the radiation field. Most patients treated in this manner remained neurologically stable 12 to 36 months following radiosurgery, and the complication rate was low.

Follow-up over a longer term, 10 to 20 years, will be necessary to confirm these initially promising results of radiosurgical treatment of meningiomas. It is important to remember that tumor shrinkage is not necessarily the end point in evaluating results. Good tumor control may be expressed by lack of tumor progression and resolution of neurologic deficits.

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Management of Benign and Aggressive Intracranial Meningiomas
Die Behandlung von gutartigen und aggressiven intrakraniellen Meningeomen Teil 2

Edward W. Akeyson, MD, PhD and Ian E. Mccutcheon, MD, FRCS(C)
Quelle: ONCOLOGY Vol 10, No 5 (May 1996)
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston

Brachytherapy

Direct and stereotactic placement of high-activity iodine-125 seeds into both recurrent and primary meningiomas has been reported [55-58]. This method has at least three theoretical advantages over conventional fractionated or single high-dose irradiation in the management of meningiomas [56,57]. First, continuous radiation may be more likely than discontinuous forms of radiation to damage slow-growing cells as they pass through the vulnerable period of the cell cycle, yet normal tissues are more resistant to this form of radiation. Second, a very tight dosimetry is possible using this isotope; this may have several benefits when treating tumors at the skull base in proximity to the brainstem, cranial nerves, and vessels. Third, the dose distribution can be tailored to fit an irregular tumor contour, and placement of each seed can be verified radiologically. As with radiosurgery, the number of patients treated with this modality is small, and follow-up is relatively short.

The largest single series of patients undergoing this form of radiation therapy is that of Kumar et al, who reported the results of interstitial brachytherapy in 15 patients with recurrent or primary meningiomas in whom other treatment options had been exhausted or who were medically unsuitable for more conventional treatment modalities [56,57]. The number of seeds implanted depended on the geometry of the tumors, with spherical tumors receiving a single seed; oval tumors, two seeds; and irregular tumors, three seeds. The dose administered to these patients was 100 to 500 Gy at a rate of 0.05 to 0.25 Gy/h over the life of the radionuclide, which averages 87 days.

In 11 (73%) of these patients, the meningiomas showed near-complete resolution at a median follow-up of 29 months; a limited response in 2 patients was attributed to significant calcification in the tumors, as only the noncalcified portion of the tumors responded to the treatment [56,57]. There were no complications in this series.

Some authors have expressed concern over the effects of seed migration and the delivery of unwanted radiation to nearby neurovascular structures [59]. However, these initially promising results indicate that, if technical problems such as seed migration can be adequately addressed, brachytherapy may become a useful adjunct for certain patients with meningiomas.

Medical Treatment

Medical treatment for meningiomas ranges from pharmacologic interventions for relief of symptoms referable to meningiomas to chemotherapeutic regimens that attempt to reduce tumor growth or cause tumor necrosis.

Symptomatic Medical Treatment

Many of the neurologic symptoms associated with meningiomas can be palliated with medical therapy alone, but all surgical patients should also have maximal medical therapy prior to surgery to minimize potential peri-operative complications. All patients with supratentorial meningiomas should be placed on anticonvulsant prophylaxis. Corticosteroids, such as dexamethasone, are routinely used to minimize brain edema associated with these tumors, either to palliate neurologic symptoms when surgery cannot be done or in the perioperative period to minimize brain swelling. When corticosteroids are administered, H2-antagonists are also routinely prescribed. Patients who are immobilized by neurologic deficits produced by their meningiomas should have antiembolism or pneumatic compression stockings placed to prevent pulmonary embolism.

Chemotherapy

Few data exist concerning the efficacy of traditional antineoplastic agents against either benign or malignant meningiomas. Traditional thinking would dictate that due to the slow growth pattern of benign meningiomas, agents that rely on cell replication for effectiveness would not be expected to be of significant benefit. In a recent retrospective review of 15 patients with aggressive meningeal neoplasms, Groves et al reported minimal success with a variety of chemotherapeutic agents, including cisplatin (Platinol), dacarbazine, doxorubicin, and interferon-alfa (Intron A, Roferon-A), given alone or in combination [60]. One patient who was given interferon-alfa had a positive response, and this is the basis for a phase II trial of interferon-alfa that is currently underway. The use of intra-arterial cisplatin and intravenous doxorubicin controlled tumor growth in two patients with inoperable recurrent meningiomas [61], and necrosis of an incidental meningioma was seen in a patient receiving multidrug chemotherapy for rectal carcinoma [62].

Sporadic evidence such as this indicates that there may be a role for multidrug chemotherapy. However, multicenter trials will be necessary to confirm these results on a larger scale.

Hormonal Therapy

Although surgery and radiation constitute the usual treatment modalities for meningiomas, adjuvant endocrinologic manipulation of these tumors could be beneficial both at initial presentation and at the time of recurrence when surgical resection is not possible, either due to advanced age of the patient or location of the tumor. Furthermore, hormonal therapy might represent another way to lower the rate of tumor recurrence following conventional surgery and radiotherapy.

Clinical epidemiologic studies suggest hormonal influences on meningioma growth and a potential role for hormonal modulation in the treatment of meningiomas. These clinical studies and in vitro investigations of meningioma cell biology are the basis for several clinical trials of hormonal agents in the treatment of meningiomas.

Epidemiologic and Physiologic Evidence

Three lines of evidence point to the sex hormones as growth factors in meningiomas. First, intracranial meningiomas are twice as common in women as men, and this female predominance is even greater for spinal meningiomas [39,63]. This 2:1 ratio is most evident in the fourth through seventh decades of life, presumably due to the unique hormonal milieu present in women in this age range [64].

Second, the exacerbation of neurologic symptoms during pregnancy in women known to have meningiomas, with resolution of these symptoms after delivery in some, is common. As of 1991, there were 223 cases of meningioma growth during pregnancy reported in the literature [65]. This phenomenon is most commonly seen during the third trimester, when circulating progesterone levels are highest, and in cases where the tumor is associated with vessels or cranial nerves at the skull base [64].

Third, meningiomas are associated with breast cancer, a tumor known for its dependence on steroid hormones. Women with breast cancer have a greater than twofold increased risk of developing meningiomas over the population as a whole [66], and the association between sphenoid wing meningiomas and either breast or reproductive tract carcinoma is particularly high [67].

Based on the results of the epidemiologic studies, investigations of steroid hormone responsiveness of meningiomas were undertaken with breast cancer as a model. The initial report of Donnell et al supported the contention that steroids may play a role in meningioma physiology by demonstrating significant amounts of estrogen-binding activity in four of six meningiomas tested [68]. Since this original report, many investigators have addressed the presence of steroid receptors in meningiomas, and have generally found a predominance of progesterone-binding proteins over those activated by estrogens (average, 70% vs 17.5%, respectively) [68-73]. In addition, the progesterone-binding site has characteristics that qualify it as a specific receptor in the classic sense, while the estrogen-binding site is much less specific and may be biologically inactive. Androgen receptors have also been found in a large fraction of meningiomas, and in one study the amount of androgen receptor was linearly related to the amount of progesterone receptor [74,75].

Controversy continues over whether these steroid-binding proteins truly represent receptors with a functional role in the physiology of meningiomas. However, a full discussion of these biologic issues is beyond the scope of this article. Moreover, the special case of aggressive meningiomas has not been addressed in these experimental studies.

Clinical Trials of Hormonal Manipulation

Clinical trials employing estrogen antagonists, progesterone supplementation or depletion, and progesterone antagonists have been performed. Using breast carcinoma as a model, a few investigators have explored the use of tamoxifen (an antiestrogen) in patients with unresectable meningiomas [76,77]. The results of these studies were disappointing; only a small number of patients demonstrated a positive response. Similarly disappointing results have been obtained in trials of progesterone supplementation with medroxyprogesterone acetate [78] or megestrol acetate [79]. A single case of symptomatic relief with progesterone depletion has been reported [80].

Mifepristone--Results from studies employing progesterone receptor blockade with the progesterone antagonist mifepristone (RU 486) are now available. In a trial of mifepristone (200 mg/d) at the University of Southern California Comprehensive Cancer Center, 8 of 28 patients experienced objective improvement, as judged by either reduction in tumor size on imaging studies or improvement in visual field deficits [81,82]. This was accompanied by subjective improvement in five patients.

Using a similar regimen of mifepristone, Lamberts et al reported reduction in tumor size in 3 of 10 patients with unresectable meningiomas [83]. Headache was reduced in five patients in that study. One of two postmenopausal women with unresectable meningiomas experienced a reduction in tumor growth in the mifepristone study of Haak et al [84]. Interestingly, vision deteriorated in both patients after cessation of therapy, but improved when the drug was reinstated.

Treatment regimens using mifepristone such as those cited above are generally well-tolerated by patients. Side effects of severe fatigue, nausea, vomiting, and anorexia are common but are easily managed with exogenous corticosteroid administration [82,83]. A large randomized, double-blind, placebo-controlled phase III trial of mifepristone in the treatment of unresectable meningiomas is now underway [81].

Conclusions

Because of the broad spectrum of behaviors exhibited by meningiomas and their poor response to traditional medical treatment regimens, the treatment algorithms for patients harboring meningiomas remain complex. An attempt should be made to completely characterize a particular meningioma, using all available grading schemes and cell kinetic data, so as to identify those tumors with a propensity for recurrent or aggressive behavior. Benign meningiomas should be completely resected when possible, and surgery should be followed by adjuvant radiotherapy when complete resection cannot be performed or the tumor recurs. Radical surgery followed by radiation therapy should be used in all aggressive or malignant meningiomas. Hormonal manipulation, although relatively new and incompletely tested, may provide additional benefit inoperable recurrent meningiomas or those exhibiting aggressive behavior.

Neurosurgeons and oncologists must continue to seek better methods of classifying and treating aggressive meningiomas, which remain a significant risk to life and function in patients that harbor them.

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The Akeyson/McCutcheon Article Reviewed

Steven M. Grunberg, MD, University of Vermont Burlington

Meningioma is a prime example of a tumor requiring a multimodality approach. This tumor is usually benign and often grows slowly. Under many circumstances, such a benign tumor would never attract the attention of the oncologist or even require treatment at all. However, a meningioma is a benign tumor in a malignant location. In the closed space of the skull, there is no room for expansion of even a benign lesion; thus, effective treatment of this potentially neurologically devastating lesion is necessary. Neurosurgeons, neuroradiologists, radiotherapists, and medical oncologists are all directly involved in treatment decisions. Rapidly expanding knowledge concerning the etiology and natural history of meningiomas may now also involve epidemiologists, molecular geneticists, and endocrinologists. Despite this concentration of expertise, numerous questions remain unanswered or incompletely answered.

The epidemiology of meningiomas has always been of great interest [1]. Observations that meningiomas are twice as common in women as in men, that they may wax and wane with pregnancy, and that they are positively associated with breast cancer opened the door to investigation of the role of sex hormone receptors in the growth of meningiomas and to a greater understanding of the pathways that control the expression and function of these receptors. However, other risk factors have also been identified. Trauma may be a factor in the induction of meningiomas; they may be the only tumors associated with participation in a competitive sport (head trauma from boxing) [2]. Radiation may also play a role in the induction of meningiomas, including either therapeutic radiation to the brain or scalp [3] or possible risk from excessive dental x-rays [2]. Description of deletions of chromosome 22 as a possible marker for meningiomas may help identify a common pathway of chromosomal damage for these various risk factors [3].

Treatment Options

Surgery remains the acknowledged mainstay for potentially curative treatment of meningiomas. Surgical results have improved both through technical advances and through the development of effective multispecialty surgical teams, particularly in the area of skull-base procedures. However, planning the extent of appropriate surgery depends upon appreciation of the malignant potential of the tumor in question, and this has been a special area of difficulty for meningioma.

Some meningiomas may be obviously histologically malignant or may present as malignant tumors by metastasizing to distant sites. However, the description of an aggressive meningioma is often based more on the clinical picture than on particular histologic or cytologic features. In addition, there is a propensity for meningiomas that intermittently recur over many years to demonstrate increasingly aggressive behavior. More extensive surgery is therefore finally needed at the time when previous interventions make such an approach more difficult. Improvement of techniques for early identification of malignant or aggressive potential through the definition of appropriate markers of proliferation or through metabolic imaging (such as the use of positron emission tomography) is thus a major requirement for improvement in long-term results.

A significant literature now supports the use of radiotherapy for the treatment of advanced meningiomas or for adjuvant treatment after tumor resection [4]. In much of neuro-oncology, the use of aggressive cranial radiotherapy with potential delayed toxicity can be justified, in part, by the poor expectations for long-term outcome. In the case of meningiomas, where survival for a decade or more can be expected in many cases, the question of persistent or late toxicity becomes more important. Further work to identify the subset of patients who may be at increased risk for deterioration in cognitive function after cranial radiotherapy is required. In addition, a greater appreciation of the possible delayed effects of cranial radiotherapy, such as hypothalamic-pituitary dysfunction resulting in hypothyroidism [5], is necessary for physicians involved in the long-term care of patients with meningiomas.

Although isolated reports of success with cytotoxic chemotherapy or embolization of meningiomas can be found, neither treatment has become a significant part of general care. In contrast, the role of various growth factors has been a fascinating area. The epidemiologic association of meningiomas with female gender led to the original description of female sex hormone receptors with potential proliferative function on meningioma cells. Since then, the realization that progesterone receptors on meningiomas may be expressed independently of estrogen receptor stimulation has led to potentially important insights into the regulation of these receptors (including the possibilities of either totally independent expression of progesterone receptors or expression induced by a constitutively activated modified estrogen receptor) [6].

The suggestive results of early trials of antiprogesterone manipulation of meningiomas (now being tested in larger phase III trials) have introduced a new form of hormonal manipulation to the antineoplastic armamentarium [7]. This line of research has advanced the idea that sex hormones and sex hormone receptors may function as growth factors and growth factor receptors, even in the absence of an obvious gender relationship of the organ in question. This concept may have far-reaching implications for the management of numerous medical conditions. Furthermore, the identification of additional hormone receptors that could potentially serve as growth factor receptors on meningiomas (including androgen and somatostatin receptors) may suggest an increasingly important role for biologics (rather than cytotoxics) in the medical management of meningiomas [1].

Although treatment of benign tumors should be simple (ie, resection), meningiomas, by virtue of their location and natural history, have turned this simple question into a multifaceted research and treatment challenge. In view of the expected long survival of patients with meningiomas, superb surgical and radiotherapeutic techniques for the avoidance of chronic and late toxicities are needed. Meningiomas also have provided the opportunity to gain greater insights into the role of hormonal and other growth factors, which may have widespread implications for the understanding and management of both malignant and nonmalignant conditions. Increased knowledge of these signalling pathways may be the most important contribution to emerge from the many ongoing avenues of meningioma research.

References
1. Grunberg SM: The role of progesterone receptors in meningioma. In: Muggia FM (ed), New Drugs, Concepts, and Results in Cancer Chemotherapy, pp 127-137. Boston, Kluwer Academic Publishers, 1991.
2. Preston-Martin S, Yu MC, Henderson BE, et al: Risk factors for meningiomas in men in Los Angeles county. J Natl Cancer Inst 70:863-866, 1983.
3. Black PM: Meningiomas. Neurosurgery 32:643-657, 1993.
4. Wilson CB: Meningiomas: Genetics, malignancy, and the role of radiation in induction and treatment: The Richard C. Schneider Lecture. J Neurosurg 81:666-675, 1994.
5. Constine LS, Woolf PD, Cann D, et al: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328:87-94, 1993.
6. Blankenstein MA, Koehorst SGA, van der Kallen CJH, et al: Oestrogen receptor independent expression of progestin receptors in human meningioma--A review. J Steroid Biochem Mol Biol 53:361-365, 1995.
7. Grunberg SM, Weiss MH, Spitz IM, et al: Treatment of unresectable meningiomas with the antiprogestational agent mifepristone. J Neurosurg 74:861-866, 1991.
The Akeyson/McCutcheon Article Reviewed

Michael Mcdermott, MD, University of California San Francisco

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 [1], the scheme by Russell and Rubenstein [2], and the World Health Organization Classification of Tumors, Second Edition (WHO-2) [3], 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 [4]. 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 [5]. 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 [5]. 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 [6].

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 [7]. 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 [9]. 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% [6]. 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 [10]. 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 [11].

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 [14]. 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 [15]. Clearly, some other approach is warranted, given these poor results.

Experimental Therapies

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 [6]. 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 [16]. 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 [17]. 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 [18]. 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 [19]. 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.

References
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15. Wilson CB: Meningiomas: Genetics, malignancy, and the role of radiation in induction and treatment. J Neurosurg 81:666-675, 1994.
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17. Yazaki T, Manz HJ, Rabkin SD, et al: Treatment of human malignant meningiomas by G207, a replication-competent multimutated herpes simplex virus 1. Cancer Res 55:4752-4756, 1995.
18. Culver KW, Ram Z, Wallbridge S, et al: In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256:1550-1552, 1992.
19. Fick J, Barker FG II, Dazin P, et al: The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro. Proc Natl Acad Sci USA 92: 11071-11075, 1995.

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