Chemotherapy: what is its role in meningioma?

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Oct 19, 2012 - Describe the role of hydroxyurea and somatostatin in treatment of progressive, ... recurrent, or inoperable meningiomas, based on a review.
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Expert Rev. Neurother. 12(10), 1189–1196 (2012)

WJ Sherman and JJ Raizer* Department of Neurology, Northwestern University, 710 North Lake Shore Dr. Abbott Hall, Room 1123, Chicago, IL 60611, USA *Author for correspondence: Tel.: +1 312 503 4724 Fax: +1 312 908 5073 [email protected]

While strong evidence exists for the standard therapy for meningiomas, inclusive of surgery and/or radiation therapy, for those tumors which recur, progress or are inoperable, the optimal medical therapies are yet to be elucidated. This article reviews the current literature for chemotherapeutic options for this subset of tumors, including cytotoxic agents, biologic agents, targeted molecular agents and hormonal agents. At this point in time, the most data is with hydroxyurea and somatostatin, although further trials with combination and targeted molecular therapies are still underway.

Keywords: bevacizumab • chemotherapy • erlotinib • gefitinib • hydroxyurea • imatinib mesylate • IFN-a • meningioma • mifepristone • octreotide • somatostatin • tamoxifen

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Release date: 19 October 2012; Expiration date: 19 October 2013

Learning objectives Upon completion of this activity, participants will be able to: • Describe the role of hydroxyurea and somatostatin in treatment of progressive, recurrent, or inoperable meningiomas, based on a review • Describe the potential utility of cytotoxic chemotherapy and hormonal therapy for progressive, recurrent, or inoperable meningiomas, based on a review • Describe the role of targeted molecular therapies for progressive, recurrent, or inoperable meningiomas, based on a review

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10.1586/ERN.12.108

© 2012 Expert Reviews Ltd

ISSN 1473-7175

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Financial & competing interests disclosure

Editor Elisa Manzotti Publisher, Future Science Group, London, UK Disclosure: Elisa Manzotti has disclosed no relevant financial relationships. CME Author Laurie Barclay Freelance writer and reviewer, Medscape, LLC Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships. Authors and Credentials Wendy J Sherman, MD Northwestern University Department of Neurology, Chicago, IL, USA Disclosure: Wendy J Sherman, MD, has disclosed no relevant financial relationships. Jeffrey J Raizer, MD Northwestern University Department of Neurology, Chicago, IL, USA

Disclosure: Jeffrey J Raizer, MD, has disclosed no relevant financial relationships.

Cytotoxic agents

Currently, cytotoxic agents have limited use in the management of recurrent or progressive meningiomas. Multiple ­studies have investigated a variety of agents, including temozolomide, dacarbazine, adriamycin, ifosfamide and irinotecan, all with disappointing results [1,2] . A Phase II study looking at the use of temozolomide prospectively enrolled 16 patients with refractory meningioma, administering temozolomide orally for 42 days every 10 weeks. No patients experienced a complete or partial radiographic response to therapy. Median time to progression was found to be 5 months (range: 2.5–5 months) and median survival 7.5 months (range: 4–9 months) [3] . It has been subsequently elucidated that the DNA repair enzyme O6methylguanine-DNA‑methyltransferase appears to be predominantly present in meningioma cell populations [4] , thus likely limiting temozolomide’s potential efficacy. Irinotecan was found to inhibit meningeal cell growth in vitro and in vivo in preclinical studies [5] ; however, a subsequent Phase II trial failed to demonstrate clinical efficacy [6] . A modest survival benefit was demonstrated in a small series of patients with malignant meningiomas treated with three to six cycles of a combination of cyclophosphamide, adriamycin and vincristine. The study included 14 patients, all of whom underwent surgical resection followed by radiation therapy. They were subsequently treated with cyclophosphamide, adriamycin and vincristine: three cycles for those with gross total resection versus six cycles for those with subtotal resections. The median time to tumor progression was 4.6 years (range: 2.2–7.1 years) and median survival was 5.3 years (range: 2.6–7.6 years). However, despite this modest survival benefit, patients suffered substantial toxicity following treatment, including four patients requiring dose reduction due to myelosuppression, and three of which had to discontinue treatment before planned course [7] . In addition, the true impact of this regimen is unclear as it was started postsurgery and ­postradiation therapy. Hydroxyurea, an oral ribonucleotide reductase inhibitor, has become a standard therapy in the treatment of meningiomas refractory to surgery and radiation. Hydroxyurea arrests 1190

menin­gioma cell growth through arrest of the S-phase of the cell cycle, thus inducing apoptosis [8] . The first evidence that meningiomas may respond to treatment with hydroxyurea was presented in a small study of four patients with recurrent and unresectable meningiomas. Patients received hydroxyurea at a dosage of approximately 20 mg/kg/day. Three patients demonstrated radiographic response (15–74% shrinkage on magnetic resonance imaging), with the fourth patient having stable disease, thought to indicate significant anti-tumor activity [9] . This was followed by a slightly larger study enrolling 17 patients, 16 of which were evaluable for response. Fourteen patients responded with stable disease (20–144+ weeks; median: 80 weeks) and two patients had progressive disease after only 10 weeks of therapy. Toxicity was mainly hematologic, with nine patients requiring a dose reduction [10] . Additional small studies showed disease stability with hydroxyurea treatments [11,12] ; however, whether these aforementioned studies represented true therapeutic responses or rather the natural disease course remains questionable. A subsequent study in 2004, enrolling 12 patients with regrowing, nonmalignant meningiomas, did not demonstrate the aforementioned treatment effectiveness of hydroxyurea. Patients received 2 years of continuous therapy with hydroxyurea at the standard dose of 20 mg/kg/day. Of the 12 patients enrolled, nine showed progressive disease, with a median time to progression of 13 months. One patient did show a small initial radiographic response with subsequent stabilization while the other two patients were removed early from the study due to hematologic toxicity [13] . Chamberlain published two recent retrospective case series. The first showed very limited benefit to therapy with hydroxyurea, with no radiographic response in any of 60 patients, with 35% having stable disease and 65% with progressive disease during follow-up [14] . The follow-up retrospective case series was subsequently published, enrolling 35 patients (22 with grade II and 13 with grade III meningiomas), all of whom had progressed radiographically despite surgery and radiation therapy, and were then treated with hydroxyurea. Of the 35 patients, 43% had stable radiographic disease and 57% had progressive disease, with no Expert Rev. Neurother. 12(10), (2012)

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Chemotherapy: what is its role in meningioma?

radiographic responses observed and an overall progression-free survival of 3% at 6 months [15] . Although toxicity was limited, hydroxyurea was found to have limited to no anti-tumor activity in both trials, suggesting hydroxyurea is not active in these tumors. Combination therapy of hydroxyurea and radiotherapy has also been assessed. Twenty one patients with recurrent or progressive meningiomas received hydroxyurea (20 mg/kg/day) with fractionated 3D-conformal radiation (55.8–59.4 Gy) for a median treatment duration of 3 months. Fourteen out of 21 patients achieved disease stabilization, as well as three patients who showed minimal radiographic response but marked improvement of their neurologic symptomatology. Progression-free survival rates were measured at 1 and 2 years after initiation of treatment with combined radiation and hydroxyurea, and were found to be 84 and 77%, respectively. Of the six patients with eventual progressive disease, median time to progression was 59 weeks. Combined therapy seemed to be well tolerated, with only one patient discontinuing treatment with hydroxyurea due to gastrointestinal symptoms [16] ; whether this approach is better than radiotherapy alone remains to be determined. Hormonal agents

Hormonal therapies were developed in response to the discovery of androgen receptors in meningiomas, which first came to light after the predominance of meningiomas in women during reproductive years was noted. There have been observational reports, in the form of both case studies and epidemiological studies, suggesting that administration of estrogens and progestins have resulted in the growth or development of meningiomas, although this correlation has been controversial [17–20] . Regarding the specific androgen receptors, estrogen receptors are expressed in approximately 10% of meningiomas, whereas progesterone and androgen receptors are present in approximately two-thirds of meningiomas. In addition, it was identified that progesterone receptors are most commonly found in benign meningiomas, as opposed to the more aggressive subtypes [21] . Estrogen receptor inhibitors, specifically tamoxifen, have not been shown to be effective in the inhibition of meningioma growth. This lack of efficacy has been typically explained by the presence of estrogen receptors in only 10% of meningiomas. Thus, as may have been expected, an initial Phase II study of 19 patients only saw a partial or minor response to tamoxifen therapy in only three of the study participants [22] . The predominance of progesterone receptors in the meningioma population has created great interest in the potential efficacy of progesterone receptor inhibitors, namely mifepristone (RU486). Initially some small studies demonstrated a modest potential benefit, but this was refuted by a large, prospective, randomized multi­center study enrolling 180 patients to either daily mifepristone or placebo, which failed to show a benefit of mifepristone over placebo [23] . It has been postulated that mifepristone may still be potentially efficacious as the majority of studies enrolled patients with meningiomas exhibiting increased proliferation index and of a higher histological grade, since it has been shown that the incidence of progesterone receptors is ­markedly decreased in these meningioma subtypes [24] . www.expert-reviews.com

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Biologic agents

With regard to the use of biologic agents, initial studies indicated a potential role for IFN-α which has been shown to inhibit meningioma cells in vitro [25] . However, repeated studies have shown a mixed response. In 2008, a Phase II study was published looking at the progression-free survival in patients with recurrent, treatment-refractory WHO grade I meningiomas treated with IFN-α. Thirty five patients were enrolled, receiving IFN-α at a dose of 10 million U/m 2 subcutaneously every other day. No patients experienced either a complete or partial radiographic response. Twenty six patients had stable disease after the first three cycles of treatment, whereas nine patients were found to have progressive disease. The progression-free survival was found to be 54% at 6 months and 31% at 12 months, with a median time to progression of 7 months (2–24 months) [26] . This is a modest response and, given the lack of control data, there is no consensus on the utility of IFN-α in the management of meningiomas [24] . Somatostatin is another biologic agent which, in vitro, has been found to inhibit meningioma growth due to the presence of somatostatin receptors within almost 90% of meningiomas [27] . The pilot prospective study investigating somatostatin’s potential use in the treatment of recurrent meningiomas proved promising. Sixteen patients were enrolled, all demonstrating overexpression of somatostatin receptors by octreotide scintigraphy. They received long-acting somatostatin on a monthly administration schedule. A partial radiographic response was achieved in 31% of patients, stable disease in 31% and progressive disease in 38%. They found that 44% of patients were free of progression at 6 months. These results, in combination with minimal toxicity during therapy, are suggestive of a potential therapeutic benefit for somatostatin in those patients with recurrent meningiomas which demonstrate somatostatin receptor positivity on octreotide scintigraphy [28] . Noting the efficacy of somatostatin, a recent Phase II study was published looking at the efficacy of octreotide, a somato­ statin receptor agonist, in recurrent meningiomas. Eleven patients with recurrent or progressive meningioma received subcutaneous octreotide with a goal dose of 500 µg three times per day, as tolerated, with one additional patient enrolled with meningeal hemangiopericytoma. No patients experienced a radiographic response. Eleven of the 12 patients enrolled showed disease progression, with a median time to progression of 17 weeks. Median survival was 2.7 years. Although octreotide appeared to be well tolerated (mainly mild gastrointestinal symptoms), this study failed to demonstrate an objective tumor response to octreotide therapy. It should be noted, however, that in contrast to somatostatin trials, this study did not perform octreotide scintigraphy to include patients, although they do note that they evaluated tissue for somatostatin receptor positivity in a subset of patients which did not appear to correlate with time to progression [29] . Pasireotide long-acting release (LAR), a long-acting somatostatin analog, was recently studied in a single-arm Phase II trial, utilizing the fact that pasireotide has a higher binding affinity for most somatostatin receptor subtypes than octreotide. Of the six patients accrued, 65% had atypical or malignant meningiomas. All patients underwent octreotide scintigraphy, with 22 tumors 1191

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demonstrating at least intermediate octreotide uptake. Twenty two patients were evaluable, 73% of which showed stable radiographic disease; no radiographic responses were observed. For those patients with atypical or malignant meningiomas, the median progression-free survival was 16 weeks [30] . Toxicity was mainly limited to hyperglycemia. Pasireotide has limited activity in grade II/III meningiomas, but data in grade I meningiomas has not yet been presented.

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Targeted molecular therapies

There are numerous aberrant signaling pathways which have been identified in meningiomas and implemented in their progression (Table 1) [31] . Dysregulated cell signaling has been implemented in meningioma cell proliferation, survival, invasion and angiogenesis. In particular, PDGF and its receptors (PDGFR) are frequently expressed in meningiomas, independent of histologic grade [32] . Activation of PDGFR is thought to result in aberrant cell signaling through either one of two pathways: PI3K AKT or ras-MAPK pathways [33,34] . Many novel agents that target PDGF, VEGF, and other components of the MAPK pathway are being investigated with variable activity. Imatinib mesylate, a PDGFR inhibitor, was investigated in patients with recurrent meningiomas. The study included 13 patients with grade I, five patients with grade II and five patients with grade III meningiomas. All patients were initiated on imatinib at a dose of 600 mg/day and then subsequently

increased to 800 mg/day after the first 4-week cycle, assuming toxicities remained tolerable. Nineteen of the 23 patients enrolled were evaluable for a response, which showed ten patients who progressed at the time of the first scan and nine patients with stable disease at that time. Median progression-free survival was found to be 2 months (0.7–34 months). Although therapy was well tolerated, they did not find imatinib to have significant efficacy with regard to progression-free survival in recurrent meningiomas [35] . This was subsequently followed by another Phase II study, which this time looked at a combination therapy of imatinib plus hydroxyurea. Of the 21 patients receiving dual therapy, no patients achieved a complete or partial radiographic response; best observed was stable radiographic disease, which was identified in 14 patients (67%). Progression-free survival at 6 months was found to be 61.9% in grade I, 87.5% in grade II and 46.2% in grade III meningiomas. As previously seen in the imatinib trial, therapy was well tolerated, but the combination of imatinib with ­hydroxyurea was only modestly better than imatinib alone in recurrent/progressive meningiomas [36] . The EGF receptor (EGFR) has also been found to be ­overexpressed in meningiomas, reported to be present in as many as 60% of tumors [37,38] . Similar to PDGFRs, EGFRs are thought to signal through the ras-MAPK and PI3K pathways, promoting meningeal cell proliferation in vitro [37] . This finding prompted investigational use of the EGFR inhibitors gefitinib and erlotinib

Table 1. Comparing current data on targeted agents.

Action

Imatinib (Wen et al. [2009] [35] )

Gefitinib/ erlotinib (Norden et al. [2010] [39] )

PDGFR inhibitor

EGFR inhibitor

Imatinib + HU (Reardon et al. [2012] [55] )

Sunitinib (Kaley et al. [2011] [56] )

PTK-787 (Raizer et al. [2010] [57] )

Avastin (Reardon et al., [2012] [47] )

Tyrosine kinase receptor inhibitor

VEGFR and PDGFR inhibitors

VEGF antibody

36

21

14

Patients (n) 22

25 (16 received gefitinib and 9 received erlotinib)

21

All-grade tumors

PFS-6: 30%

PFS-6: 28%

PFS-6: 61.9%

PFS-6: 47%

PFS-6: 85.7%

mPFS: 2 months

mPFS: 2.5 months

mPFS: 7.0 months

mPFS: 5.9 months

mPFS: 17.9 months

mOS: 23 months Grade I

PFS-6: 45%

PFS-6: 25%

mPFS: 3 months

mPFS: 2.25 months mPFS: 13.9 months

Grade II/III PFS-6: 0% mPFS: 2 months

RR

50% SD

PFS-6: 87.5%

PFS-6: 80% mPFS: 12.2 months

OS 13 months

mOS: 66 m

PFS-6: 29%

PFS-6: 46.2%

PFS-6: 36%

PFS-6: 39/43%

PFS-6: 87.5%

mPFS: 4 months

mPFS: 5.3 months

mPFS: 4.6 months

mPFS: 3.7/3.6 months

mPFS: 17.9 months

OS 33 months

mOS: 20.9 months

32% SD

31% SD

OS 22.9/19/6 months 61% SD

71% SD

3.6% PR

5% PR

HU: Hydroxyurea; mPFS: Median progression-free survival; OS: Overall survival; PDGFR: PDGF receptor; PFS-6: 6-month progression-free survival; PR: Progressive response; RR: Radiographic response; SD: Stable disease; VEGFR: VEGF receptor.

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in patients with recurrent meningiomas. In one study, 25 patients with recurrent meningioma received treatment with either gefitinib (64%) or erlotinib (36%). The 6-month progression-free survival was 25% for benign tumors and 29% for atypical and malignant tumors; 12-month overall survival was 50% for benign and 65% for the more aggressive tumors. Similar to the aforementioned targeted molecular therapies, treatment was well tolerated but did not appear to have significant activity against recurrent meningiomas [39] . There are multiple case reports indicating additional targeted therapies in incidental radiographic regression of meningiomas, including therapy with bevacizumab, a VEGF inhibitor [40] , and with CP-751,871 (an IGF-1R inhibitor) [41] . Meningiomas are well known to be hypervascular, which is believed to be the pathology behind the impact of VEGF inhibitors on meningioma growth. VEGF has clearly shown to contribute centrally to tumor angiogenesis [42,43] . It has been further found that the level of VEGF expression in meningiomas seems to correlate with tumor grade [44,45] . Finally, inhibition of tumor angiogenesis also reduces peritumoral edema, which is well known to contribute to the symptomatology of meningiomas, thus contributing to morbidity [46] . Reardon et al. recently released their retrospective review of 14 patients with recurrent meningioma treated with bevacizumab [47] . In this study, four patients with recurrent meningiomas were treated with bevacizumab alone, whereas the other ten patients were treated with bevacizumab in combination with etoposide and either sirolimus or temozolomide. Of those patients with grade II or III tumors, their 6-month progression-free survival was found to be 87.5%, with a median progression-free survival of 17.9 months. There also seemed to be a slightly better outcome in those patients in whom a chemotherapeutic agent was added to the bevacizumab regimen [48] . PTK-787, an inhibitor of both VEGF and PDGF receptors, was investigated in a recent Phase II trial of 21 patients with grade II or III meningiomas with prior radiation and surgery treatments. After three patients were withdrawn due to toxicity, of the 17 remaining patients, a partial response was seen in one patient, stable disease in 12 patients (70.6%) and progressive disease in five patients (29.4%). Median time to progression was 3.7 months for grade II tumors and 3.6 months for grade III tumors, with a median overall survival of 22.9 months for grade II and 19.6 months for those with grade III tumors [49] . From this initial study, it appears that the dual inhibition of VEGF and PDGF receptors in recurrent or progressive meningiomas can lead to disease stabilization and requires further investigation. Sunitinib, a tyrosine kinase receptor inhibitor, was recently studied, given that it targets both VEGF and PDGF receptors. In this Phase II trial, they administered 50 mg/day of sunitinib to 30 patients with grade II tumors and six patients with grade III tumors. This study found the 6-month progression-free survival to be 36%, with a median progression-free survival of 5.1 months [50] . Studies are currently undergoing or awaiting publication for these final results, as well as other, targeted therapies. Considerations

At this point in time, further trials are needed to better delineate the role of chemotherapy in the treatment of recurrent or www.expert-reviews.com

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­ rogressive meningiomas. The data currently available are limp ited due to multiple factors. The low power of the studies limits results, as most trials contain at most 20–30 patients. Given the low power, patient populations studied tend to be quite heterogeneous with regard to tumor grade, location, extent of resection and prior therapies. Beyond the heterogeneity of patient populations, response criteria used to evaluate treatment efficacy varies between studies, limiting comparability. All these issues limit data interpretability. In contrast to the limited trials looking at tissue responses to targeted agents, when these agents are used in actual patient populations, their lack of efficacy does not seem to correlate with tissue responses, as evidenced by the octreotide trials [29] . This hypothetically may be due to multiple factors, including inadequate drug penetration or possibly subtherapeutic drug levels. In addition, while identified targets have been implicated in tumor proliferation, they may not be the primary factor in progression, potentially requiring an additional target to be inhibited in order to improve progression-free survival. Expert commentary

Meningiomas represent the most common intracranial tumor. Meningiomas are classified according to the WHO histologic grading system into three grades. The majority (~80–85%) of meningiomas are benign (grade I), with low chance of recurrence following surgical resection with or without subsequent radiation. However, grade II and III meningiomas have a higher rate of recurrence, despite complete removal with surgery and then radiotherapy. In addition, there is a small subset of patients with grade I tumors who have shown to progress to high-grade pathology when they recur [51] . It is these more aggressive recurrent tumors, as well as some inoperable or incompletely operable grade II and III tumors that often require medical therapy beyond surgery and radiation. Initial treatment for symptomatic meningiomas commonly involves surgical resection if considered operable, which may be followed by either externalbeam radiation therapy or stereotactic radiosurgery, depending on their operable status and histologic grade [52,53] . Stereotactic radiosurgery is primarily used as adjunctive therapy following resection, particularly in grade II or III meningiomas, as well as skull-base tumors and areas of tumor incompletely resected due to proximity to important neurovascular structures [54] . Despite these treatment options, if or when these tumors recur, physicians must then often rely on medical treatment for these more aggressive tumors. The optimal medical therapies for these subsets of patients are yet to be determined. Many have been tried and others are under investigation as potential salvage therapy for recurrent or aggressive meningiomas, and include cytotoxic, hormonal and biologic agents. Five-year view

As new agents are investigated in the treatment of recurrent or progressive meningiomas, benchmarks for comparison need to be determined. Patient populations must also be segregated with regard to both histologic grades, as well as molecular profiles (e.g., 1193

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sporadic meningiomas vs those associated with neurofibromatosis). Perhaps trials enrolling homogenous patient populations need to be employed to address this issue. Ultimately, multi-arm,

multicenter trials would allow for rapid accrual of patients, as well as comparison of several agents at one time. Availability of genetic profiles should also help tailor individual therapies.

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Key issues • Progressive, recurrent or inoperable meningiomas pose a difficult challenge to the clinician, as optimal medical therapies have yet to be fully determined. • Cytotoxic chemotherapeutic agents appear to have only modest clinic effect, but in the setting of significant toxicity, do not play a significant role in management at this point in time. • Hydroxyurea appears to have the most clinical evidence at this time for the treatment of recurrent/progressive meningiomas; however, recent data suggest no real efficacy. Combination studies are currently underway. • Somatostatin appears to achieve a significant radiologic response in the subset of patients demonstrating somatostatin receptor positivity on octreotide scintigraphy. • Although meningiomas are well known to foster hormonal receptors, particularly progesterone receptors, thus far evidence with mifepristone (a progesterone receptor inhibitor) has failed to show benefit. • Targeted molecular therapies, including those that target PDGF receptor, VEGF, EGF receptor and MAPK pathway components appear promising in vitro, but further clinical evidence needs to be gained to delineate their potential role in the treatment of recurrent/progressive meningiomas.

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Koper JW, Zwarthoff EC, Hagemeijer A  et al. Inhibition of the growth of cultured human meningioma cells by recombinant interferon-alpha. Eur. J. Cancer 27(4), 416–419 (1991). Chamberlain MC, Glantz MJ. ­Interferon-alpha for recurrent World Health Organization grade 1 intracranial meningiomas. Cancer 113(8), 2146–2151 (2008). Arena S, Barbieri F, Thellung S et al. Expression of somatostatin receptor mRNA in human meningiomas and their implication in in vitro antiproliferative activity. J. Neurooncol. 66(1–2), 155–166 (2004). Chamberlain MC, Glantz MJ, Fadul CE. Recurrent meningioma: salvage therapy with long-acting somatostatin analogue. Neurology 69(10), 969–973 (2007). Johnson DR, Kimmel DW, Burch PA et al. Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma. Neuro-oncology 13(5), 530–535 (2011). Norden AD, Hammond S, Drappatz J  et al. Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma. J. Clin. Oncol. 29 (2011). Ragel BT, Jensen RL. Aberrant signaling pathways in meningiomas. J. Neurooncol. 99(3), 315–324 (2010).

•• Good review of the signaling pathways targeted by newer medical therapies in the treatment of recurrent meningiomas. 32

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Yang SY, Xu GM. Expression of PDGF and its receptor as well as their relationship to proliferating activity and apoptosis of meningiomas in human meningiomas. J. Clin. Neurosci. 8(Suppl. 1), 49–53 (2001). Johnson MD, Okedli E, Woodard A, Toms  SA, Allen GS. Evidence for phosphatidylinositol 3-kinase–Akt–p7S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in meningioma cells. J. Neurosurg. 97(3), 668–675 (2002). Johnson MD, Woodard A, Kim P, Frexes-Steed M. Evidence for mitogenassociated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells. J. Neurosurg. 94(2), 293–300 (2001). Wen PY, Yung WK, Lamborn KR et al. Phase II study of imatinib mesylate for

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Chemotherapy: what is its role in meningioma?

recurrent meningiomas (North American Brain Tumor Consortium study 01-08). Neuro-oncology 11(6), 853–860 (2009). 36

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Reardon DA, Norden AD, Desjardins  A et al. Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma. J. Neurooncol. 106(2), 409–415 (2012). Carroll RS, Black PM, Zhang J et al. Expression and activation of epidermal growth factor receptors in meningiomas. J. Neurosurg. 87(2), 315–323 (1997).

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Lou E, Sumrall AL, Turner S et al. Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series. J. Neurooncol. 109, 63–70 (2012).

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Lou E, Sumrall AL, Turner S et al. Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series. J. Neurooncol. 109(1), 63–70 (2012).

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Grimm SA, Chamberlain MC, Chandler J et al. A Phase II trial of PTK787/ZK 222584 (PTK787) in recurrent high-grade meningioma. J. Clin. Oncol. 29 (2011).

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Jones NR, Rossi ML, Gregoriou M, Hughes JT. Epidermal growth factor receptor expression in 72 meningiomas. Cancer 66(1), 152–155 (1990).

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Norden AD, Raizer JJ, Abrey LE et al. Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma. J. Neurooncol. 96(2), 211–217 (2010).

Kaley TJ, Wen PY, Schiff D et al. Phase II trial of sunitinib (SU011248) for recurrent meningioma. Neuro-oncol. 12(Suppl. 4), iv69–iv78 (2010).

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Goutagny S, Raymond E, Sterkers O, Colombani JM, Kalamarides M. Radiographic regression of cranial meningioma in a NF2 patient treated by bevacizumab. Ann. Oncol. 22(4), 990–991 (2011).

Al-Mefty O, Kadri PA, Pravdenkova S, Sawyer JR, Stangeby C, Husain M. Malignant progression in meningioma: documentation of a series and analysis of cytogenetic findings. J. Neurosurg. 101(2), 210–218 (2004).

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Collins IM, Beddy P, O’Byrne KJ. Radiological response in an incidental meningioma in a patient treated with chemotherapy combined with CP-751,871, an IGF-1R inhibitor. Acta Oncol. 49(6), 872–874 (2010).

Rogers L, Mehta M. Role of radiation therapy in treating intracranial meningiomas. Neurosurg. Focus 23(4), E4 (2007).

•• Excellent overview of conventional fractionated external-beam radiotherapy for meningiomas.

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Kerbel RS. Tumor angiogenesis. N. Engl. J. Med. 358(19), 2039–2049 (2008).

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Cook KM, Figg WD. Angiogenesis inhibitors: current strategies and future prospects. CA. Cancer J. Clin. 60(4), 222–243 (2010).

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Lamszus K, Lengler U, Schmidt NO, Stavrou D, Ergün S, Westphal M. Vascular endothelial growth factor, hepatocyte growth factor/scatter factor, basic fibroblast growth factor, and placenta growth factor in human meningiomas and their relation to angiogenesis and malignancy. Neurosurgery 46(4), 938–947; discussion 947 (2000). Provias J, Claffey K, delAguila L, Lau N, Feldkamp M, Guha A. Meningiomas: role of vascular endothelial growth factor/vascular permeability factor in angiogenesis and peritumoral edema. Neurosurgery 40(5), 1016–1026 (1997). Goldman CK, Bharara S, Palmer CA et al. Brain edema in meningiomas is associated with increased vascular endothelial growth factor expression. Neurosurgery 40(6), 1269–1277 (1997).

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McMullen KP, Stieber VW. Meningioma: current treatment options and future directions. Curr. Treat. Options Oncol. 5(6), 499–509 (2004).

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Pannullo SC, Fraser JF, Moliterno J, Cobb W, Stieg PE. Stereotactic radiosurgery: a meta-analysis of current therapeutic applications in neuro-oncologic disease. J. Neurooncol. 103(1), 1–17 (2011).

•• Very good meta-analysis of the role of stereotactic radiosurgery in meningiomas. 55

Reardon DA, Norden AD, Desjardins A et al. Phase II study of Gleevec plus hydroxyurea (HU) in adults with progressive or recurrent meningioma. J. Neurooncol. 106, 409–415 (2012).

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Kaley TJ, Wen PY, Schiff D et al. Phase II trial of sunitinib in patients with recurrent or inoperable meningioma. Neurooncol. 11, 625 (2011) (abstract 264).

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Raizer J, Grimm S, Chamberlain MC. PTK787 for recurrent and progressive meningioma. Neurooncol. 12(iv1–iv136), iv50 (2010).

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Chemotherapy: what is its role in meningioma?

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Your patient is a 54-year-old woman with recurrent meningioma after resection and radiation therapy. Based on the review by Drs. Sherman and Raizer, which of the following statements about the potential role of hydroxyurea and somatostatin in her treatment is most likely correct?

£ A Hydroxyurea is an oral ribonucleotide reductase inhibitor that has become a standard treatment for meningiomas £ B £ C £ D

refractory to surgery and radiation Recent studies have proven the efficacy of hydroxyurea in treating meningiomas refractory to surgery and radiation Somatostatin has been shown to achieve a significant radiologic response in all patients regardless of octreotide scintigraphy findings In patients with overexpression of somatostatin receptors, long-acting somatostatin given monthly achieved 6-month progression-free survival in 88% of patients

2. Based on the review by Drs. Sherman and Raizer, which of the following statements about the potential utility of cytotoxic chemotherapy and hormonal therapy for the patient described in question 1 is most likely correct?

£ A Cytotoxic chemotherapy should be first-line treatment £ B Temozolomide and dacarbazine have been shown to be helpful £ C Estrogen receptors are expressed in about 10% of meningiomas, and progesterone and androgen receptors in about two thirds

£ D Mifepristone, a progesterone receptor inhibitor, is highly effective for treatment of refractory meningiomas 3. Based on the review by Drs. Sherman and Raizer, which of the following statements about the role of targeted molecular therapies for progressive, recurrent, or inoperable meningiomas would most likely be correct?

£ A Laboratory evidence does not support a potential role for targeted molecular therapies £ B Efficacy of targeted molecular therapies is well proven in clinical trials £ C Targeting platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor (VEGF), epidermal £ D 1196

growth factor receptor (EGFR), and mitogen activated protein kinase (MAPK) pathway components could potentially be a helpful strategy but requires further development Platelet-derived growth factor (PDGF) and PDGFR are seldom expressed in meningiomas

Expert Rev. Neurother. 12(10), (2012)