**4. Medical treatment for meningioma**

The classical first-line treatment for all MNs is surgery. However, high grade meningiomas have a high recurrence rate; up to 60% of tumors may recur after 15 years of complete resection [12, 61]. Unfortunately, at the moment there are no standard effective treatments determined because of lack of existent evidence [12]. The use of systemic treatments as standard care remains experimental and is reserved for cases of recurrent/progressive disease not suitable for surgery or radiotherapy [62]. Hereafter we are going to present some of the systemic strategies currently in used and under study. A summary of the main therapies that have shown some benefit in MN treatment can be seen in **Table 1,** and a summary of current active clinical trials is shown in **Table 2.**

#### **4.1 Chemotherapy**

It is known that chemotherapy is poorly effective as adjuvant treatment after surgery and radiotherapy. Some clinical trials and case series have shown a minimal or no impact in patients' outcomes. However, some agents are being tested in several clinical trials [63].

Hydroxyurea is a ribonucleotide reductase inhibitor that was initially developed to treat myeloproliferative disorders and chronic myelogenous leukemia [64]. It induces apoptosis in meningioma cells, arresting meningioma cells in the S-phase of the cell cycle [63]. In pre-clinical trials from Schrell et al., they demonstrated that hydroxyurea prevent recurrence for 24 months in patients who had complete resection [65, 66]. However, clinical trials, failed to provide similar results showing that 50% of the patients achieve stable disease, a median PFS of 44–176 weeks and acceptable toxicity [63, 65–71]. Other retrospective studies with small sample sizes, have shown a median PFS of 10–80 weeks [64]. Weston et al. also found that hydroxyurea may prevent progression, but does not reduce tumor size and causes significant side effects [72]. It is important to emphasize that in these trials many patients did not received radiotherapy or that radiotherapy was administered concurrently, making data interpretation difficult [73]. In addition, a retrospective study of 60 patients from Chamberlain et al. reported a disease progression in 65% of the patients and a median PFS of 4 months in patients treated with hydroxyurea after recurrence (Chamberlain and Johnston, 2011). Finally, some studies suggest hydroxyurea may have outcomes equivalent to those when radiation therapy was used [74].

Additionally, some studies reported reduction of hydroxyurea efficacy when other concomitant therapies are administrated [64]. In a study by Reardon et al., hydroxyurea and imatinib were used to treat patients with recurrent refractory meningiomas, a good tolerance was reported; however, the combination did not affect survival [75]. Other authors suggest that chemotherapy should be based on expression of drug resistance genes, in patients whose mRNA analysis predicted sensitivity to chemotherapy. In these cases, a concomitant treatment with mitoxantrone and hydroxyurea reported long-term efficacy [61]. Currently, some investigators are


Tipifarnib Farnesyl transferase inhibitor

Farnesyl transferase inhibitors


### **Table 1.**

*A summary of different agents with promising evidence in the treatment of high-grade meningioma.*



#### **Table 2.**

*A summary of currently ongoing clinical trials that assess the effectiveness and safety of different systemic therapies in high-grade meningiomas.*

looking for the role of hydroxyurea as an adjunct to other therapies, such as calcium channel blockers, as calcium channel antagonists have an inhibitory effect on meningioma growth in culture [76]. For this matter, Ragel et al. reported that calcium channel antagonists can block stimulatory effects of growth factors on meningioma cell cultures and increase hydroxyurea effectiveness [77]. Evidence of hydroxyurea treatment in patients with high grade meningioma varies widely across patients. Demonstrating that this treatment is generally well-tolerated but evidence in tumor control is not conclusive to establish a standard treatment in high-grade MNs.

Trabectedin it is an alkylating agent used in soft tissue sarcomas. It inhibits transcription, its mechanism is not completely understood but some studies reported decreased cell proliferation, induction of apoptosis and inhibition of transcription factor binding by binding to the minor groove of the DNA helix [78]. In the randomized phase II clinical trial NCT02234050 by EORTC Brain Tumor Group (EORTC-1320-BTG)**,** treatment with trabectidin in grade II/III meningiomas did not improve PFS or OS and it was associated with significantly higher toxicity as compared to local standard care. A median PFS of 4.17 months was reported in the local standard care arm and of 2.43 months in the trabectedin arm (hazard ratio [HR] for progression, 1.42; 80% CI, 1.00–2.03; *p* = 0.204). Also, the median OS was 10.61 months in the local standard care arm and was 11.37 months in the trabectedin arm (HR for death, 0.98; 95% CI, 0.54–1.76; *p* = 0.94). In 44.4% of the local standard care arm patients occurred adverse events (4 serious adverse events, 0 lethal events) and 59% of the trabectidin arm presented adverse events (57 serious adverse events and 2 toxic deaths) [79]. Trabectedin did not improve PFS and OS and was associated with significantly higher toxicity. Evidence is not conclusive to establish a standard treatment in high grade meningiomas. However, the data future clinical trials are needed.

Temozolomide another alkylating agent, used as standard care in management of glioma. It does not prolong PFS in clinical trials of recurrent meningioma [80]. It is believed that the no effect on meningioma could be due to intact activity of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) [63, 81, 82].

Chamberlain et al. reported a median time tumor progression of 4.6 years and median OS of 5.3 years in patients treated with cyclophosphamide, doxorubicin, and vincristine. They also reported high toxicity and very low response. However, without a control group the results are difficult to interpret [83]. Some small case series also reported results by administrating cyclophosphamide, adriamycin, vincristine, isofosfamide/mesna or adriamycin/dacarbazine, but the evidence is limited [84]. In some in vitro an in vivo animal studies, was reported that irinotecan has an anti-meningioma effect. However, it did not show benefits in phase II clinical trials [81, 82, 85].

Finally, some preclinical studies evaluated the response of Plant-Derived Chemotherapeutic Agents. Curic et al. described an antitumorigenic properties from curcumin (from the spice plant *Curcuma longa*) [86]. Additionally, Park et al. reported a cytotoxic effect of acetyl-11-keto-beta-boswellic acid (substance isolated from the *Boswellia serrata*), by inhibition of microsomal prostaglandin E synthase–1 and the serine protease cathepsin G [87]. Overall, traditional chemotherapy has demonstrated limited clinical efficacy in treating meningiomas. Additionally, it may lead to complications as immunosuppression, myelosuppression, gastrointestinal distress, organ damage, and fatigue [88].

#### **5. Targeted therapy**

Unlike other solid tumors, MN presents with a low mutation rate of approximately 3.5 mutations per megabase [25]. However, the case of high-grade MNs

*High Grade Meningiomas: Current Therapy Based on Tumor Biology DOI: http://dx.doi.org/10.5772/intechopen.100432*

has been evaluated recently. Bi et al. analyzed 39 samples of high-grade MN and found an average of 23 (range 1–223) nonsynonymous coding alterations. This number of alterations is similar to that of craniopharyngioma and thyroid cancer, but considerably lower than other aggressive tumors like head and neck carcinoma, colorectal carcinoma and melanoma [34]. Because of its relatively low mutational burden, very few potential molecular targets have been identified. Interestingly, Bi et al. found that non-NF2 driver mutations in high-grade MN was considerably lower than in low grade MN, which reduces the number of possible targets than can be addressed. In the other hand, NF2 is usually altered in high-grade MN (80% of cases) more frequently than in low grade MN (40%). Most of genetic and regulatory alterations that have been described in high grade MN occur downstream to a disrupted NF2 protein. Some of the pathways altered might involve Rac1/ Cdc42, Ras/JNK and the master regulator AP-1 [89]. Furthermore, one of the main pathways associated with NF2 is the mTOR signaling cascade. NF2 naturally acts as a repressor of the mTORC1 and mTORC2, and when it is mutated, unregulated activation of this pathway occurs. Based on this, mTOR and some of its upstream/ downstream effectors (Akt/PI3K) have been identified as potential targets. Other pathways regulated by receptor tyrosine kinases (RTKs) like EGFR, PDGFR and VEGFR (angiogenesis) are also being studied.
