**6. Chemotherapy**

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 and triggers the death of tumor cells. *MGMT* (O6 -methylguanine-DNA methyltransferase) is 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 promoter methylation status in clinical management of the patients with GBM.

**For newly diagnosed GBM,** TMZ is typically given following surgical resection, concurrent and adjuvant, in addition to RT. It is administered daily at a dose of 75 mg/m2 for 6 weeks during irradiation, followed by a rest period of about 1 month after RT is completed (concurrent treatment). When restarted, TMZ is dosed at 150 mg/m2 daily for 5 days every 4 weeks for 6 cycles (adjuvant treatment). If tolerated, the dose of the adjuvant treatment can be escalated up to 200 mg/m2 daily. This is the well-known Stupp regimen. In common practice, some medical centers have attempted to prolong TMZ administration for 12–18 months. Some evidence suggests that long-term therapy with TMZ in selected patients is superior to Stupp regimen [71–73], but there is no definitive data to prove this.

The use of standard or hypofractionated RT plus concomitant and/or adjuvant TMZ has been extended to **elderly** (> 70 years old) with a good performance status (KPS ≥ 60). For patients >70 years old with a poor performance status (KPS < 60), TMZ alone can be an option.

At the time of **recurrence**, reoperation should be proposed if the tumor is resectable and if prognostic factors suggest a benefit. Local chemotherapy can be administered during surgery by implantation of Gliadel wafers. Second-line chemotherapy is indicated based on MGMT promoter methylation, time to disease recurrence and toxicity profile. The nitrosourea-based regimen is the preferred choice. Restarting therapy with TMZ may be an option in MGMTmethylated patients. Other agents, such as carboplatin, etoposide, irinotecan may be tried as single agents or in regimens.

**Gliadel wafers** are composed of a biodegradable polymer impregnated with carmustine (BCNU), an alkylating agent of the nitrosourea family. During the surgery, after removal of the tumor, up to 8 wafers (containing a maximum of 61.6 mg BCNU) are deposited along the wall of the resection cavity and left in situ. BCNU will be release over a period of 2–3 weeks, the tumor cells being directly and efficiently exposed to high levels of drug starting immediately after surgery. Gliadel has received FDA (USA) approval for use in both newly diagnosed GBM and recurrences. Studies have consistently reported an increase of median survival by about 2 months [74–76]. Local delivery of carmustine reduces systemic adverse events, but sometimes induces complications: cerebral edema, seizure, poor wound healing, cerebrospinal fluid (CSF) leak, infection, headache, hemiparesis, hydrocephalus, particularly in patients with recurrent GBM. Combining local and systemic chemotherapy offers advantages that may explain the prolonged survival. First, systemic TMZ is most effective in regions of the tumor that are most vascular, whereas local release of BCNU allows direct access to relatively avascular areas of walls of the surgical cavity. Second, following the Stupp protocol, between surgery and chemoradiotherapy there is a period without treatment. Gliadel allows treatment of residual tumor cells within this period. Therefore, the combination of different treatment modalities allows continuous therapy up to 9 months, beginning immediately following surgery [77].
