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Meningiomas are primary central nervous system (CNS) tumorsthat constitute more than 20 % of adult primary brain tumors.

Complete surgicalresection offers the best chance of cure but unfortunately it is not safelypossible for all tumors. Histological grading is important because it helps topredict the likelihood of recurrence with benign meningiomas (WHO grade 1) havinga recurrence risk of 7–20% after gross total resection and atypical meningiomas(grade 2) having a 40% recurrence rate despite resection. Malignant meningiomas(grade 3) represent 1–3% of meningiomas but recur in 50–80% of patients.Despite maximal surgical resection and radiotherapy, a subset of these patientswill recur and require additional treatment. Treatment of these surgery andradiation refractory recurrent meningiomas require systemic therapy butunfortunately currently there is no effective systemic therapy that stands outas standard of care despite a number of agents including chemotherapies,hormonal and biologic therapies have been investigated.

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Recently there has been increasing use of targeted therapiesdirected at recognized mutations of meningioma oncogenesis, such as receptortyrosine kinases (RTK). The RTKs believed to be most relevant for meningiomagrowth and proliferation are EGFR, PDGF, VEGF and recently FGFR. We would liketo summarize the findings of available prospective trials and infer itssignificance in terms of present role of receptor tyrosine kinase inhibitors inrecurrent meningiomas. All these trials used six- month PFS as their primaryendpoint for evaluating outcomes with secondary outcome being overall survivaland radiological response. However there is paucity of data regarding thenatural history of untreated recurrent meningiomas making it hard to interpretresults of these trials.Trials involving imatinib and erlotinib/geftinib failed todemonstrate effectiveness given the low 6PFS and lack of radiological responsehowever there were limitations of these studies which have been summarized inthe table below that could have contributed to the outcome.

Along with the lownumber of subjects recruited in both of these trails to draw statically robustconclusions, receptor status evaluation was not done for all patients. AlthoughPDGFR is expressed in majority of meningiomas and EGFR in more than 60% ofmeningiomas but subjects chosen may have had a different phenotype. Inaddition, the subjects were heterogenous with regard to pretreatment.

The 6PFSin Imatinib trial in Grade 2/3 meningioma was 0 % whereas it was 29% ingeftinib/erlotinib trial. This could be because in the imatinib trial thesubjects were heavily pretreated as there was no limitation in the number ofprior therapies, which could already signify a more advanced disease resultingin poorer outcome whereas in the geftinib/erlotinib trial patients havinggreater than 2 recurrences were excluded resulting in less heavily pretreatedcohort selection. Another possible explanation could be the inhibition of PDGFRor EGFR alone is insufficient to prevent growth of meningiomas and that othertyrosine kinases such as VEGF/IGF/FGF, may play a greater role in maintainingthe transformed phenotype.

Kaley et al evaluated sunitinib in recurrent meningiomas andit is the first prospective trial to demonstrate efficacy of a medicaltreatment for patients with aggressive meningioma. Primary efficacy endpointwas reached, with PFS6 of 42% in the primary study cohort of atypical andanaplastic meningioma. Although subject were heterogenous with regard toearlier trials with other tyrosine kinase inhibitors, sunitinib being amulti-tyrosine kinase inhibitor (PDGFRa, PDGFRb, VEGFR2, and KIT) mighttherefore have been more effective by blocking multiple pathways. However, considerabletoxicity to sunitinib was observed with 30 patients (60%) experiencing grade 3or higher toxicity but overall toxicity was rather similar to the priorliterature on sunitinib with the exception of the CNS hemorrhages.

Correlationof receptor status with PFS and OS was also done. In 28 patients of meningiomas( 3 grade 1 and 25 grade 2/3) VEGFR2 expression predicted median PFS of 1.4months in VEGFR2-negative patients versus 6.4 months in VEGFR2- positivepatients (P ¼ .005). Similarly, VEGFR2 expression predicted median OS of 9.1months in VEGFR2-negative patients versus 24.6 months in VEGFR2-positivepatients (P ¼ .

002). Tumors were variably positive with a wide range for PDGFRaand PDGFRb, but no significant correlation was noted of PDGFRa or PDGFRbexpression with outcome measures in meningioma. However, it can not beconcluded that VEGF+ is a good prognostic marker as VEGF+ patients who did notreceive sunitinib were not evaluated.Another recent trial with PTK787 (Vatalanib) also shows anti-tumoractivity of this molecule in recurrent meningiomas with acceptable toxicityprofile. Wen et al. suggested that a positive trial for recurrent Grade II andIII meningiomas would demonstrate a PFS-6 greater or equal to 30%. ThePFS-6 for Grade II/III patients combined was 54.4 % suggesting PTK787 is an active agentfor high-grade meningiomas but this trial could not be concluded as positivebecause pre-specified statistical analysis was powered for Grade I meningiomasbased on the assumption that most of the patients enrolled would be grade 1 but22 out of 25 patients enrolled were grade 2/3.

In conclusion, there have been only a handful of studiesthat met their predetermined statistical criteria in evaluating this promisingtargeted therapy, although one is currently enrolling and utilizing bevacizumab(NCT01125046) and would be completed by this year. But there are issuesregarding interpreting data on role of receptor tyrosine kinase inhibitors inmeningiomas due to paucity of trials published, heterogeneity of patients onthese various trials with respect to prior treatment, the variability of tumorgrade, the small numbers of patients treated on a trial, the lack of controlsto which to compare treatment, no standardized response criteria or”benchmark” for activity (for example PFS-6, ORR or OS) and the absence ofprospective randomized clinical trials.  Also, response assessment is challenging inthis patient population. Macdonald criteria were used measuring the largestcross-sectional area of the enhancing tumor but as many of these tumors haveirregular shapes, this measurement may be inaccurate. Improved responseassessment criteria for meningioma specifically are needed for morestandardized trial designs in the future. Sunitinib and Valatanib have shownefficacy against high grade meningiomas and warrant further investigation inrandomized setting.

Though, long term durable anti-tumor activity was notpresent as all patients finally progressed highlighting that there may be activationof other pathways, incomplete target suppression or the target not being thesole driver of meningiomagenesis. Recently AKT and SMO mutations have also beenshown in meningioma so the need of the hour is to either come with a targetedtherapy that block at multiple levels the growth of tumor or try combinationtherapy in randomized setting like combining PI3K inhibitor with an mTORinhibitor or an AKT inhibitor with an anti-angiogenic agent to more effectivelyblock alternate pathway activation and to improve the already grim prognosis inthis subgroup of patients.

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