Management of Benign and Aggressive Intracranial Meningiomas

Benign and aggressive intracranial meningiomas, as the authorsstate, 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 withaggressive, recurrent, or malignant meningiomas are all too wellaware of the difficulties of recommending effective therapy beyondsurgery and radiation therapy. Clearly, there is much room forimprovement in the treatment of recurrent or malignant meningiomaswith local or systemic chemotherapy and/or biologic therapies.

A key to the uniform reporting and analysis of the results ofthe treatment of meningiomas is a standard classification systembased on histopathologic features. Although many different schemeshave been proposed since the time of Cushing and Eisenhardt [1],the scheme by Russell and Rubenstein [2], and the World HealthOrganization 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 theHelsinki grading system, which attributes either 0 or 3 pointsfor 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 braininfiltration. The sum of these points is then used to assign agrade 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 Universityof California, San Francisco) were used in the past, we have nowturned to ex vivo labeling studies, including the use of Ki-67and MIB-1 [5]. MIB-1 is commercially available and can be usedon paraffin-embedded tumor sections; these sections can be recoveredin such a fashion as to reactivate an epitope of Ki-67, whichstains for the expression of several proliferation-associatednuclear proteins, and a proliferating cell index can be derived.Typically, with this technique, the labeling index is 2.4 to 1.8times 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 indicescorrelate with the proliferative potential of a tumor more accuratelythan do other tissue descriptive assessments. The results of thecombination of histopathologic information, tumor grade, labelingindex information, and the Simpson surgical grade, as discussedby the authors, should be available from future clinical seriesreporting on the treatment of meningiomas [6].

Surgical Treatment Options

Although surgical resection remains an important part of the treatmentof both benign and malignant meningiomas, not all patients withintracranial meningiomas require surgery, especially elderly patients[7]. Now, for a variety of reasons, small dura-based tumors withimaging characteristics compatible with meningiomas are more oftendetected via imaging of the central nervous system. Beyond thedetermination of whether or not a meningioma is responsible forany signs or symptoms, patient and tumor factors must be weighedto determine the appropriateness, and benefit, of any recommendedsurgical procedure. It is not uncommon to see a patient with aheavily calcified meningioma that does grow appreciably for aconsiderable period. Clearly, if a decision is made not to intervene,the patient should agree with this approach and be available forregular clinical and radiologic follow-up, so if new symptomsor signs develop, or there is objective evidence of tumor growth,the situation can be reevaluated.

Preoperative medical therapy for patients with meningiomas doesnot necessarily have to include embolization, as the authors indicated.With a convexity meningioma, the dural blood supply can be exposedeasily and interrupted during the exposure necessary for resectionof the tumor. Furthermore, in certain locations, such as the olfactorygroove, embolization may present too high a risk. In the caseof a small falx meningioma, for which preoperative angiographyis not necessary, we have found magnetic resonance venographyto be an important adjunct in surgical decision-making regardingthe side from which to approach the tumor, given the pattern ofveins draining into the superior sagittal sinus. Any additionalinformation that may reduce the potentially devastating consequencesof interrupting a "safe" parasagittal draining veinshould be considered.

There is no question that during the mid-to-late 1980s, the developmentof skull-base approaches allowed surgeons to remove tumors previouslythought to be unapproachable. However, by their very nature, theseprocedures are complex and lengthy and may be associated withsignificant morbidity. In a recent seminal article, Larson etal pointed out the pathologic findings of infiltration of cranialnerves within the cavernous sinus by benign meningiomas, excludingany realistic possibility of "surgical cure" while maintainingextraocular muscle function and an acceptable rate of operativemorbidity.8 Some impressive surgical results have been reportedby surgeons accomplished in skull-base approaches; however, 5-yearand 10-year rates of recurrence-free survival will be necessaryto evaluate the efficacy of this complex surgical procedure.

Radiotherapy and Chemotherapy

It seems somewhat paradoxical that radiation therapy would berecommended as an adjuvant therapy for incompletely resected,recurrent, or malignant meningiomas when both low- and high-doseirradiation to large volumes of the scalp have been implicatedin the development of meningiomas. Beyond the experience of Israelichildren treated for tinea capitis with meningiomas, a recentreview of the literature has revealed that the higher the doseand the younger the patient undergoing irradiation, the shorterthe latency period for tumor development [9]. It must be understoodthat with conventional external-beam irradiation techniques andthree-dimensional treatment planning, the volume of normal tissueirradiated to a significant dose has been greatly limited.

The authors have rightly assessed the utility of modern-day radiotherapyfor subtotally resected and recurrent meningiomas. Series publishedsince 1990 document 5-year progression-free survival rates forbenign meningiomas of 84% to 89% [6]. In the University of Californiaat San Francisco series published by Goldsmith et al, treatmentcomplications, occurred in 5 patients (3.6%), 3 of whom had asudden onset of blindness 20 to 22 months after treatment [10].Others have reported such complications as hearing loss, memoryimpairment, pituitary dysfunction, and chronic otitis media. Forsurgeons and radiotherapists, information about microscopic restsof meningothelial cells at up to 3 cm from the margin of the originaltumor 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 sizeis not the only end point in evaluating therapy, and no increasein 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 benignmeningiomas or as a boost for residual disease in malignant meningiomas.

In their discussion of interstitial brachytherapy, the authorsrefer to two series by the same author, who reported remarkableradiologic response rates without complications. Our experienceis encouraging but not nearly as dramatic! In an evaluation of21 patients with recurrent or malignant meningiomas treated withiodine-125, low-activity permanent implants at the time of reoperation,the median time to tumor progression was 96 weeks and the mediansurvival was 124 weeks from the time of implantation [14]. Complicationsoccurred in a significant number of patients (38%). These implantsare usually reserved for patients with a significant mass of recurrenttumor and for patients in whom other treatment modalities havefailed. Obviously, these patients still must be strong enoughfor an open surgical procedure.

Conventional chemotherapy for recurrent or malignant meningiomashas certainly been disappointing. We have not found a regimenof cyclophosphamide (Cytoxan, Neosar), doxorubicin, and vincristineto be of any significant benefit, given the side effects; in 11patients, our failure rate was 73% at 1 year and 100% at 2 yearsafter the start of treatment [15]. Clearly, some other approachis warranted, given these poor results.

Experimental Therapies

Experimental studies have demonstrated a number of receptors presentin meningioma cells, including progestins, androgens, glucocorticoids,dopamine (DA1), interferon alpha, epidermal growth factor, andplatelet-derived growth factor, to mention a few [6]. Experimentalevidence in animal models does exist for the use of some receptorantagonists against these different receptors in controlling tumorgrowth. In one study, trapidil, a drug with antiplatelet-derivedgrowth factor activity, was combined with bromocriptine (Parlodel),a DA1-dopamine receptor blocker; this combination of drugs inhibitedtumor growth more than either agent alone [16]. Obviously, theclinical applications of such experiments require further study.Although the antiprogestational agent mifepristone has generatedmuch excitement, the small amount of objective data documentingtumor control requires further investigation. In addition, highdoses of tamoxifen may, in fact, act against meningioma cellsby inhibiting protein kinase C activity, rather than by any effecton estrogen receptors, few as they are.

A potentially exciting area of current laboratory investigationis the use of novel biologic therapies for the treatment of meningiomas.In this regard, options include using modified attenuated livevirus and infecting the proliferating tumor; the enzyme activityof these proliferating cells is directed toward replication ofthe virus, and cell death occurs through the normal mechanismsof virus-induced cell lysis [17]. As well, the introduction ofa specific gene, such as herpes simplex virus I thymidine kinase,with a retroviral vector may permit the incorporation of a smallamount of this gene in actively proliferating cells [18]. Theadministration of a prodrug such as ganciclovir (Cytovene) permitsthe phosphorylation of the drug through the activity of thymidinekinase; the triphosphate form of ganciclovir is toxic to the tumorcells. According to Fick et al current research now indicatesthat the bystander effect is likely related to the passage ofphosphorylated forms of ganciclovir between tumor cells, and itappears that the efficiency of this bystander effect relates tothe density of gap junctions that exist on the tumor cell surface[19]. Conveniently, meningioma cells happen to have abundant gapjunctions. Therefore, these tumors may be well suited to thisform of therapy. Obviously, if laboratory studies continue toindicate the effectiveness of this treatment, it will be sometime before this therapy is brought to the clinical sphere.

Although it is true that the mainstay of therapy for meningiomasis surgery, clearly there are a significant number of patientsfor whom this option does not provide a cure, and other adjuvanttherapies are necessary. Neurosurgeons, radiation oncologists,and medical oncologists with a special interest in these tumorshave long been frustrated by their tenacity to resist conventionaltreatment. Advanced surgical techniques, improved radiotherapyusing three-dimensional conformal treatment planning, and radiosurgeryunits have nearly reached their technical limits. Clearly, itis necessary to identify the most effective form of adjuvant chemotherapy,immunotherapy, or viral/genetic therapy for recurrent, aggressive,or malignant meningiomas.

References:

1. Cushing H, Eisenhardt L: Meningiomas: Their Classification,Regional Behavior, Life History, and Surgical End Results. Springfield,OH, Charles C. Thomas, 1938.

2. Russell DS, Rubenstein LJ: Pathology of Tumors of the NervousSystem, 5th ed. Baltimore, Williams & Wilkins, 1989.

3. Kleihues P, Burger PC, Scheithauer BW (eds): Histological Typingof Tumors of the Central Nervous System, pp 33-42. New York, Springer-Verlag,1993.

4. Jaaskelainen J, Haltia M, Laasonen Erkki, et al: The growthrate of intracranial meningiomas and its relation to histology.Surg Neurol 24:165-172, 1985.

5. Onda K, Davis RL, Shibuya M, et al: Correlation between thebromodeoxyuridine labeling index and MIB-1 and Ki-67 proliferatingcell indices in cerebral gliomas. Cancer 74:1921-1926, 1994.

6. McDermott MW, Wilson CB: Meningiomas. In: Youmans JR, ed. NeurologicalSurgery, 4th ed, pp 2782-2825. Philadelphia, WB Saunders, 1996.

7. Mastronardi L, Ferrante L, Qasho R, et al: Intracranial meningiomasin the ninth decade of life: A retrospective study of 17 surgicalcases. Neurosurgery 36:270-274, 1995.

8. Larson JJ, van Loveren HR, Balko MG, et al: Evidence of meningiomainfiltration into cranial nerves: Clinical implications for cavernoussinus meningiomas. J Neurosurg 83:596-599, 1995.

9. Harrison MJ, Wolfe DE, Lau TS, et al: Radiation-induced meningiomas:Experience at the Mount Sinai Hospital and review of the literature.J Neurosurg 75:564-574, 1991.

10. Goldsmith BJ, Wara WM, Wilson CB, et al: Postoperative irradiationfor subtotally resected meningiomas: A retrospective analysisof 140 patients treated from 1967 to 1990. J Neurosurg 80:195-201,1994.

11. Borovich B, Doron Y: Recurrence of intracranial meningiomas:The role played by regional multicentricity. J Neurosurg 64:58-63,1986.

12. Engenhart R, Kimmig BN, Hover KH, et al: Stereotactic singlehigh dose radiation therapy of benign intracranial meningiomas.Int J Radiat Oncol Biol Phys 19:1021-1026, 1990.

13. Kaplan ID, Castro JR, Phillips TL: Helium charged particleradiotherapy for meningioma: Experience at UCLBL. Int J RadiatOncol Biol Phys 28:257-261, 1993.

14. Rogano LA, McDermott MW, Larson DA, et al: Permanent I-125implants for recurrent malignant tumors. Proc Congress NeurolSurg, 45th Annual Meeting, p 382, 1995.

15. Wilson CB: Meningiomas: Genetics, malignancy, and the roleof radiation in induction and treatment. J Neurosurg 81:666-675,1994.

16. Todo T, Adams EF, Fahlbusch R: Inhibitory effect of trapidilon human meningioma cell proliferation via interruption of autocrinegrowth stimulation. J Neurosurg 78:463-469, 1993.

17. Yazaki T, Manz HJ, Rabkin SD, et al: Treatment of human malignantmeningiomas by G207, a replication-competent multimutated herpessimplex virus 1. Cancer Res 55:4752-4756, 1995.

18. Culver KW, Ram Z, Wallbridge S, et al: In vivo gene transferwith retroviral vector-producer cells for treatment of experimentalbrain tumors. Science 256:1550-1552, 1992.

19. Fick J, Barker FG II, Dazin P, et al: The extent of heterocellularcommunication mediated by gap junctions is predictive of bystandertumor cytotoxicity in vitro. Proc Natl Acad Sci USA 92: 11071-11075,1995.