**7. Other therapies**

is an increased risk of radiation necrosis. This may lead to neurological dysfunction, edema and mass effect. Radiation necrosis is very difficult to distinguish from progressive disease solely by imaging techniques. Histology remains the gold standard for diagnosis. Combs et al. investigated the role of re-irradiation using the fractionated stereotactic approach and demonstrated a median survival of 8 months and a progression-free survival of 5 months for

**Stereotactic radiosurgery** offers the potential of providing a "boost" radiation to a portion of the radiation field in newly diagnosed patients or treating a small recurrence, being an alternative to open surgery [63]. However, its applicability remains very limited in absence of

**Intracavitary brachytherapy** using the GliaSite system can be used in selected newly diagnosed patients or in recurrent disease, intending to deliver an additional radiation to the surgical cavity wall. It is a medical device, composed of a balloon that will contain a radioactive solution with 125I during the period of irradiation, connected through a catheter to an infusion port. The balloon is placed in the resection cavity during surgery and the radioactive solution is injected later. Re-irradiation of recurrent GBM with GliaSite Radiation Therapy System after resection seems to provide a median survival of approximately 9 months [64, 65].

For the time being, **TMZ** is considered the first-line chemotherapy drug in GBM. It is an oral systemic drug with a good penetration of the BBB and limited side effects. The mechanism of action is based on its ability to alkylate/methylate DNA. This alkylation damages the DNA

a DNA-repair enzyme that rescues glioma cells from damages induced by alkylating agents like TMZ or carmustine. High activity of MGMT in tumor cells creates resistance to chemotherapy with alkylating agents and may determine treatment failure. Epigenetic silencing of the MGMT gene by promoter methylation is associated with decrease of DNA-repair activity and thus tumor cells will be more responsive to TMZ. In other words, the methylation status of MGMT promoter is associated with a benefit from alkylating agent-based chemotherapy in GBM. Numerous studies have confirmed that carriers of the methylated form of MGMT promoter with GBM treated with TMZ and RT have a prolonged overall survival [66–68]. Hegi et al. found that their median survival was 21.7 months as compared with 15.3 months among those who were assigned to only RT [69]. Furthermore, assessing MGMT methylation status in a cohort of patients with GBM who underwent radiation treatment but did not receive chemotherapy, Rivera et al. have demonstrated an 50% reduction in the rate of tumor progression during RT in methylated tumors versus those that were unmethylated. These data suggest that MGMT promoter methylation may predict a better response to any form of therapy, including RT [70]. Consequently, MGMT promoter methylation status has been established as an important prognostic biomarker, helping in performing a risk stratification of cases. National Comprehensive Cancer Network (NCCN) guidelines consider MGMT pro-

moter methylation status in clinical management of the patients with GBM.


studies which could demonstrate a statistically significant benefit.

patients with GBM [62].

22 Brain Tumors - An Update

**6. Chemotherapy**

and triggers the death of tumor cells. *MGMT* (O6

**Optune (formerly NovoTTF-100A) is a device that delivers tumor-treating fields (TTFields)**, meaning low-intensity, intermediate-frequency, alternating electric fields that have antiproliferative properties with minimal toxicity. It has been approved (FDA 2015) as an alternative treatment for adult patients having a newly diagnosed supratentorial GBM following debulking surgery and completion of RT, with concomitant SoC chemotherapy. It has also been approved (FDA, 2011) for the treatment of adult patients with supratentorial confirmed recurrences of GBM, to be used as a monotherapy, as an alternative to standard medical therapy after surgical and radiation options have been exhausted (Novocure, 2017). Current evidence supports the use of TTFs as a therapeutic option. Stupp et al. analyzed 315 patients with GBM who had completed standard chemoradiation therapy, adding TTFields to maintenance TMZ chemotherapy and found a significantly prolonged progression-free survival and overall survival. Median progression-free survival was 7.1 months in the TTFields plus TMZ group and 4 months in the TMZ alone group. Median overall survival was 20.5 months in the TTFields plus TMZ group and 15.6 months in the TMZ-alone group [78].

**VEGF** is a key factor implicated in tumor neoangiogenesis. GBM is a highly vascular tumor, that depends on vascular proliferation for growth. Recent evidence suggests vasculogenic mimicry in GBM, meaning formation of vessel-like network by tumor cells, allowing a blood supply for tumor growth. This process differs from angiogenesis, it is happening without the presence of endothelial cells. Angiogenesis is driven primarily by tumor-secreting VEGF-A (one member of the VEGF family), but there are many secreted proangiogenic factors [82]. The level of VEGF in HGG is greater than 10-fold compared with LGG [83]. Thus, drugs have been developed to interfere with angiogenesis by directly blocking ligand (VEGF) or receptor (VEGFR) or by targeting proangiogenic molecules that function by alternative mechanisms [84]. Of all targeted biological agents, only **bevacizumab** (Avastin) has demonstrated efficacy. It is a humanized monoclonal antibody that selectively blocks VEGF and so the BBB becomes more stable, with a resultant decrease in vascular permeability and edema, such that the corticosteroid doses can be reduced or suspended. Bevacizumab may be useful during and after RT, because of reduction of peritumoral edema, sometimes refractory to corticosteroid drugs and because of reduction of radiation necrosis rate following improving oxygenation. It has been approved by FDA (2009) as a single agent in the treatment of recurrent GBM following prior therapy, based on improvement in progression-free survival (that however did not translate into an improvement in overall survival) and a modest toxicity profile. Patients treated with bevacizumab inevitably relapse and sometimes an aggressive, invasive "gliomatosis" pattern of recurrence, unresponsive to subsequent therapy is observed. In addition to bevacizumab, there are many inhibitors of VEGF/VEGFR and other relevant targets under investigation, including: vatalanib, cediranib, sunitinib, sorafenib, vandetanib, VEGF trap, ramucirumab, pazopanib, etc. Dually targeted VEGFR/PDGFR inhibitors may prove useful,

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049 25

Other antiangiogenic approach targets **the integrins** *α***v***β***3 and** *α***v***β***5** that are overexpressed by tumor endothelial cells. They are transmembrane receptors that interact with extracellular matrix proteins to facilitate angiogenesis and invasion. Cilengitide inhibits these integrins. There are clinical studies focused on **substances that inhibit intracellular signaling molecules**. Overactivation of the PI3K/Akt/mTOR signaling in GBM has been observed, because of receptor tyrosine kinase overactivity, mutated oncogenic PI3K subunits, and/or loss of PTEN tumor suppressor activity. Several mTOR inhibitors are currently tested, including sirolimus, temsirolimus, everolimus, and ridaforolimus. Enzastaurin is an inhibitor of protein kinase C-β2 that suppresses PI3K/Akt pathway. Overactivation of RAS/RAF/mitogen-activated protein kinase pathway in malignant glioma has provided the rationale to study farnesyl transferase inhibitors (farnesylation is a critical step in activation of RAS). Tipifarnib, lonafarnib and sorafenib may inhibit farnesyltransferase. Histone deacetylase inhibitors (vorinostat, romidepsin, valproic acid, etc.) prevent gene transcription, resulting in cell cycle arrest, dif-

**Immunotherapy** has become a promising cancer treatment, which allows for synergistic multimodal strategies. There are different immunotherapeutic approaches in GBM, including active immunotherapy (tumor vaccination therapy) and passive immunotherapy (antibodybased immunotherapy, adoptive cell therapy and other immune-modulatory therapy). **Tumor** 

ferentiation, and/or apoptosis of tumor cells. Clinical trials are in progress.

because of role of PDGFR in pericyte recruitment.
