Complete surgical resection is the first-line therapy for meningiomas. However, tumor location and biological aggressiveness can make surgical cure impossible. Treatment options for these refractory meningiomas include further surgery, conventional external beam irradiation, stereotactic radiosurgery, and systemic therapies. In this paper, we discuss new and emerging systemic therapies when these “local” treatment options are not successful.
Methods
We reviewed predictors of refractory meningiomas and novel systemic therapies in the treatment of refractory meningiomas.
Results
Tumor location, atypical or malignant histologic subtypes, and staining for the Ki-67 protein (MIB-1 antibody) with a high labeling index are the best predictors of tumor recurrence. Novel systemic treatment options include angiogenesis inhibition, meningioma cell growth inhibition, blockade of growth factor effects, inhibition of intracellular secondary pathways, and gene therapies.
Conclusions
MIB-1 labeling index staining is a good predictor for refractory meningiomas. Currently, the best-studied systemic treatment for patients with refractory meningiomas is hydroxyurea. Blockade of the growth hormone receptor by pegvisomant is promising because in vivo and in vitro studies have shown good results and the drug has a known side effect profile.
References
1.
CarrollR.S., ZhangJ., BlackP.M.. Expression of estrogen receptors alpha and beta in human meningiomas.J Neurooncol.1999; 42: 109–116.
2.
GonzalesM.F.. Classification of brain tumors. In: KayeA.H., LawsE.R., eds. Brain Tumors: An Encyclopedic Approach.Edinburgh, New York: Churchill Livingstone;1995: 675.
3.
SimpsonD.. The recurrence of intracranial meningiomas after surgical treatment.J Neurol Neurosurg Psychiatry.1957; 20: 22–39.
4.
MirimanoffR.O., DosoretzD.E., LinggoodR.M.. Meningioma: analysis of recurrence and progression following neurosurgical resection.J Neurosurg.1985; 62: 18–24.
5.
MahmoodA., CaccamoD.V., TomecekF.J.. Atypical and malignant meningiomas: a clinicopathological review.Neurosurgery.1993; 33: 955–963.
6.
JaaskelainenJ., HaltiaM., ServoA.. Atypical and anaplastic meningiomas: radiology, surgery, radiotherapy, and outcome.Surg Neurol.1986; 25: 233–242.
7.
MilosevicM.F., FrostP.J., LaperriereN.J.. Radiotherapy for atypical or malignant intracranial meningioma.Intl J Radiat Oncol Biol Phys.1996; 34: 817–822.
8.
GoldsmithB.J., WaraW.M., WilsonC.B.. Postoperative irradiation for subtotally resected meningiomas: a retrospective analysis of 140 patients treated from 1967 to 1990.J Neurosurg.1994; 80: 195–201.
9.
RosenthalM.A., AshleyD.L., CherL.. Treatment of high risk or recurrent meningiomas with hydroxyurea.J Clin Neurosci.2002; 9: 156–158.
10.
HugE.B., DevriesA., ThorntonA.F.. Management of atypical and malignant meningiomas: role of high-dose, 3D-conformal radiation therapy.J Neurooncol.2000; 48: 151–160.
11.
BarnettG.H., SuhJ.H., CrownoverR.L.. Recent advances in the treatment of skull base tumors using radiation.Neurosurg Clin N Am.2000; 11: 587–596.
12.
SchrellU.M., RittigM.G., AndersM.. Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea.J Neurosurg.1997; 86: 840–844.
13.
MasonW.P., GentiliF., MacdonaldD.R.. Stabilization of disease progression by hydroxyurea in patients with recurrent or unresectable meningioma.J Neurosurg.2002; 97: 341–346.
14.
BlankensteinM.A., VerheijenF.M., JacobsJ.M.. Occurrence, regulation, and significance of progesterone receptors in human meningioma.Steroids.2000; 65: 795–800.
15.
CohenM.E., DuffnerP.K.. Long-term consequences of CNS treatment for childhood cancer, Part I: Pathologic consequences and potential for oncogenesis.Pediatr Neurol.1991; 7: 157–163.
16.
ShintaniT., HayakawaN., HoshiM.. High incidence of meningioma among Hiroshima atomic bomb survivors.Radiat Res (Tokyo).1999; 40: 49–57.
17.
EvansD.G., SainioM., BaserM.E.. Neurofibromatosis type 2.J Med Genet.2000; 37: 897–904.
18.
CaiD.X., BanerjeeR., ScheithauerB.W.. Chromosome 1p and 14q FISH analysis in clinicopathologic subsets of meningioma: diagnostic and prognostic implications.J Neuropathol Exp Neurol.2001; 60: 628–636.
19.
BostromJ., Meyer-PuttlitzB., WolterM.. Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas.Am J Pathol.2001; 159: 661–669.
20.
Lopez-GinesC., Cerda-NicolasM., Gil-BensoR.. Loss of 1p in recurrent meningiomas. A comparative study in successive recurrences by cytogenetics and fluorescence in situ hybridization.Cancer Genet Cytogenet.2001; 125: 119–124.
21.
NakasuS., LiD.H., OkabeH.. Significance of MIB-1 staining indices in meningiomas: comparison of two counting methods.Am J Surg Pathol.2001; 25: 472–478.
22.
HoD.M., HsuC.Y., TingL.T.. Histopathology and MIB-1 labeling index predicted recurrence of meningiomas: a proposal of diagnostic criteria for patients with atypical meningioma.Cancer.2002; 94: 1538–1547.
23.
LanzafameS., TorrisiA., BarbagalloG.. Correlation between histological grade, MIB-1, p53, and recurrence in 69 completely resected primary intracranial meningiomas with a 6 year mean follow-up.Pathol Res Pract.2000; 196: 483–488.
24.
KorshunovA., ShishkinaL., GolanovA.. DNA topoisomerase II-alpha and cyclin A immunoexpression in meningiomas and its prognostic significance: an analysis of 263 cases.Arch Pathol Lab Med.2002; 126: 1079–1086.
25.
PerryA., StaffordS.L., ScheithauerB.W.. The prognostic significance of MIB-1, p53, and DNA flow cytometry in completely resected primary meningiomas.Cancer.1998; 82: 2262–2269.
26.
KameiY., WatanabeM., NakayamaK.. Prognostic significance of p53 and p21WAF1/CIP1 immunoreactivity and tumor micronecrosis for recurrence of meningiomas.J Neurooncol.2000; 46: 205–213.
27.
AbramovichC.M., PraysonR.A.. Apoptotic activity and bcl-2 immunoreactivity in meningiomas. Association with grade and outcome.Am J Clin Pathol.2000; 114: 84–92.
28.
ComtesseN., HeckelD., RaczA.. Five novel immunogenic antigens in meningioma: cloning, expression analysis, and chromosomal mapping.Clin Cancer Res.1999; 5: 3560–3568.
29.
WeisbergS., AshkenaziE., IsraelZ.. Anaplastic and atypical meningiomas express high levels of Fas and undergo apoptosis in response to Fas ligation.Am J Pathol.2001; 159: 1193–1197.
30.
KilicT., BayriY., OzdumanK.. Tenascin in meningioma: expression is correlated with anaplasia, vascular endothelial growth factor expression, and peritumoral edema but not with tumor border shape.Neurosurgery.2002; 51: 183–193.
31.
MiralbellR., LingoodR.M., de la MonteS.. The role of radiotherapy in the treatment of subtotally resected benign meningiomas.J Neurooncol.1992; 13: 157–164.
32.
BarbaroN.M., GutinP.H., WilsonC.B.. Radiation therapy in the treatment of partially resected meningiomas.Neurosurgery.1987; 20: 525–528.
33.
LeeJ.Y., NiranjanA., McInerneyJ.. Stereotactic radiosurgery providing long-term tumor control of cavernous sinus meningiomas.J Neurosurg.2002; 97: 65–72.
OlsonJ.J., BeckD.W., SchlechteJ.. Hormonal manipulation of meningiomas in vitro.J Neurosurg.1986; 65: 99–107.
36.
MatsudaY., KawamotoK., KiyaK.. Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo.J Neurosurg.1994; 80: 527–534.
37.
OlsonJ.J., BeckD.W., SchlechteJ.A.. Effect of the antiprogesterone RU-38486 on meningioma implanted into nude mice.J Neurosurg.1987; 66: 584–587.
38.
KoperJ.W., FoekensJ.A., BraakmanR.. Effects of progesterone on the response to epidermal growth factor and other growth factors in cultured human meningioma cells.Cancer Res.1990; 50: 2604–2607.
39.
GrunbergS.M., WeissM.H., SpitzI.M.. Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone.J Neurosurg.1991; 74: 861–866.
40.
GrunbergS.M.. Role of antiprogestational therapy for meningiomas.Human Reprod.1994; 9(suppl 1): 202–207.
HanahanD.. Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.Cell.1996; 86: 353–364.
43.
FolkmanJ., IngberD.. Inhibition of angiogenesis.Semin Cancer Biol.1992; 3: 89–96.
44.
KabaS.E., De MonteF., BrunerJ.M.. The treatment of recurrent unresectable and malignant meningiomas with interferon alpha-2B.Neurosurgery.1997; 40: 271–275.
45.
KoperJ.W., ZwarthoffE.C., HagemeijerA.. Inhibition of the growth of cultured human meningioma cells by recombinant interferon-alpha.Eur J Cancer.1991; 27: 416–419.
46.
ZhangZ.J., MuhrC., WangJ.L.Interferon-alpha inhibits the DNA synthesis induced by PDGF and EGF in cultured meningioma cells.Anticancer Res.1996; 16: 717–723.
47.
Wober-BingolC., WoberC., MarosiC.. Interferon-alfa-2b for meningioma.Lancet.1995; 345: 331.
48.
MuhrC., GudjonssonO., LiljaA.. Meningioma treated with interferon-alpha, evaluated with [(11)C]-L-methionine positron emission tomography.Clin Cancer Res.2001; 7: 2269–2276.
49.
YazakiT., TakamiyaY., CastelloP.C.. Inhibition of angiogenesis and growth of human non-malignant and malignant meningiomas by TNP-470.J Neurooncol.1995; 23: 23–29.
HarlandS.P., KucR.E., PickardJ.D.. Expression of endothelin(A) receptors in human gliomas and meningiomas, with high affinity for the selective antagonist PD156707.Neurosurgery.1998; 43: 890–899.
52.
SalhiaB., RutkaJ.T., LingewoodC.. The treatment of malignant meningioma with verotoxin.Neoplasia.2002; 4: 304–311.
53.
LawrenceJ.H., TobiasC.A., LinfootJ.A.. Successful treatment of acromegaly: metabolic and clinical studies in 145 patients.J Clin Endocrinol Metab.1970; 31: 180–198.
54.
KhandwalaH.M., McCutcheonI.E., FlyvbjergA.. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth.Endocr Rev.2000; 21: 215–244.
55.
FriendK.E.. Cancer and the potential place for growth hormone receptor antagonist therapy.Growth Horm IGF Res.2001; 11(suppl A) S121–S123.
56.
McCutcheonI.E., FlyvbjergA., HillH.. Antitumor activity of the growth hormone receptor antagonist pegvisomant against human meningiomas in nude mice.J Neurosurg.2001; 94: 487–492.
57.
TrainerP.J., DrakeW.M., KatznelsonL.. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.N Engl J Med.2000; 342: 1171–1177.
58.
van der LelyA.J., HutsonR.K., TrainerP.J.. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.Lancet.2001; 358: 1754–1759.
59.
Garcia-LunaP.P., RelimpioF., PumarA.. Clinical use of octreotide in unresectable meningiomas: a report of three cases.J Neurosurg Sci.1993; 37: 237–241.
60.
SchulzS., PauliS.U., SchulzS.. Immunohistochemical determination of five somatostatin receptors in meningioma reveals frequent overexpression of somatostatin receptor subtype sst2A.Clin Cancer Res.2000; 6: 1865–1874.
61.
SchrellU.M., GauerS., KieswetterF.. Inhibition of proliferation of human cerebral meningioma cells by suramin: effects on cell growth, cell cycle phases, extracellular growth factors, and PDGF-BB autocrine growth loop.J Neurosurg.1995; 82: 600–607.
62.
TodoT.E., AdamsF., FahlbuschR.. Inhibitory effect of trapidil on human meningioma cell proliferation via interruption of autocrine growth stimulation.J Neurosurg.1993; 78: 463–469.
63.
JensenR.L., LeeY.S., GuijratiM.. Inhibition of in vitro meningioma proliferation after growth factor stimulation by calcium channel antagonists, Part II: Additional growth factors, growth factor receptor immunohistochemistry, and intracellular calcium measurements.Neurosurgery.1995; 37: 937–947.
64.
JensenR.L., OrigitanoT.C., LeeY.S.. In vitro growth inhibition of growth factor-stimulated meningioma cells by calcium channel antagonists.Neurosurgery.1995; 36: 365–374.
65.
JensenR.L., PetrM., WursterR.D.. Calcium channel antagonist effect on in vitro meningioma signal transduction pathways after growth factor stimulation.Neurosurgery.2000; 46: 692–703.
66.
MerryS., FetherstonC.A., KayeS.B.. Resistance of human glioma to adriamycin in vitro: the role of membrane transport and its circumvention with verapamil.Br J Cancer.1986; 53: 129–135.
67.
JensenR.L., LepplaD., RokoszN.. Matrigel augments xenograft transplantation of meningioma cells into athymic mice.Neurosurgery.1998; 42: 130–136.
68.
JensenRL, WursterR.D.. Calcium channel antagonists inhibit growth of subcutaneous xenograft meningiomas in nude mice.Surg Neurol.2001; 55: 275–283.
69.
BowlesA.P.Jr., PantazisC.G., WansleyW.. Use of verapamil to enhance the antiproliferative activity of BCNU in human glioma cells: an in vitro and in vivo study.J Neurosurg.1990; 73: 248–253.
70.
Cano-GauciD.F., RiordanJ.R.. Action of calcium antagonists on multidrug resistant cells: specific cytotoxicity independent of increased cancer drug accumulation.Biochem Pharmacol.1987; 36: 2115–2123.
71.
HelsonL.. Calcium channel blocker enhancement of anticancer drug cytotoxicity: a review.Cancer Drug Deliv.1984; 1: 353–361.
72.
InceP., AppletonD.R., FinneyK.H.. Verapamil increases the sensitivity of primary human colorectal carcinoma tissue to vincristine.Br J Cancer.1986; 53: 137–139.
73.
RobinsonB.A., ClutterbuckR.D., MillarJ.L.. Verapamil potentiation of melphalan cytotoxicity and cellular uptake in murine fibrosarcoma and bone marrow.Br J Cancer.1985; 52: 813–822.
74.
TsuruoT., IidaH., TsukagoshiS.. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil.Cancer Res.1981; 41: 1967–1972.
75.
JohnsonM.D., WoodardA., KimP.. Evidence for mitogen-associated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells.J Neurosurg.2001; 94: 293–300.
76.
ChauvetA.E., KesavaP.P., GohC.S.. Selective intraarterial gene delivery into a canine meningioma.J Neurosurg.1998; 88: 870–873.
77.
IkedaK., SaekiY., Gonzalez-AgostiC.. Inhibition of NF2-negative and NF2-positive primary human meningioma cell proliferation by overexpression of merlin due to vector-mediated gene transfer.J Neurosurg.1999; 91: 85–92.
78.
DirvenC.M., GrillJ., LamfersM.L.. Gene therapy for meningioma: improved gene delivery with targeted adenoviruses.J Neurosurg.2002; 97: 441–449.
