**8. Signaling pathways in high grade glioma**

survival, and EOR [34]. There are, however, some retrospective studies (volumetric and nonvolumetric) that have shown no survival benefit with increased EOR. However, the aggregate of evidence does support the thesis that patients with high-grade gliomas do show survival

After maximally-safe surgical resection, the standard of care for GBM is a 6 week course of External Beam Focused Radiation Therapy with concurrent chemotherapy followed by 6

With the support of Level IA evidence, fractionated focal radiotherapy (60 Gy, 30-33 fractions of 1.8-2 Gy) is the established radiation regimen after resection or biopsy of malignant gliomas [37]. The fundamental nature of the ionizing radiation utilized has, needless to say, not changed; however, leaps and bounds have been made in efforts to focus the beam, tailor it to the highly-serrated and convoluted contours of tumor, and limit the dose to nearby critical structures/tissue by the use of intensity-attenuated and image-guided technologies, all with

The single first-line chemotherapeutic agent for GBM is temozolomide, an oral alkylating agent that exerts its anti-tumorigenic effect by methylating/alkylating DNA at the N-7/O-6 positions of guanine residues, thereby causing irreparable damage to (tumor) DNA and instigating the process of tumor cell death. The benefits of the addition of concurrent with adjuvant chemo‐ therapy to the foundation of radiation therapy were demonstrated by a seminal landmark study by Stupp *et al* that showed a 14.6 to 12.1 month median overall survival benefit and showed a sustained survival advantage of 9.8% vs 1.9% at 5 year analysis (Figure 7) [35].

High-dose corticosteroids have a role to play in reduction of tumor-associated edema and associated symptoms but are not indicated for long periods of time [37]. There is an established role for anti-seizure therapy in patients who present with seizures, but the role for seizure prophylaxis after surgery is only indicated in symptomatic patients. It ought to be kept in mind

benefit with increased EOR.

**7. Standard adjuvant therapy**

**Figure 7.** EORTC/NCIC Trial 5-Yr Follow-up [35]

12 Tumors of the Central Nervous System – Primary and Secondary

months of adjuvant chemotherapy.

positive effect.

To understand the fundamentals of GBM oncogenesis, it is essential to understand that that there are certain cellular signal transduction pathways responsible for cell proliferation that are normally highly regulated. However, in malignant gliomas, these pathways aberrantly lose regulatory control and end up constitutively activated to disastrous consequence. This occurs mainly through anomalies in the receptors that initiate the signal transduction cascades for growth factors. In one common mechanism, epigenetic mutations result in overexpression or amplification of the genes that encode growth factor receptors. Increased expression of these growth factor receptors results in increased activation of signal transduction cascades. This ultimately yields exponentially increased expression of growth factors which begets malignant cellular proliferation [16].

Some of the best-characterized growth factor mutations in GBM oncogenesis are, as previously introduced, EGFR in primary GBM and PDGFR in secondary GBM. In upwards of 40% of cases of primary GBM, EGFR is amplified to significant pathologic effect (27). Most cases have a genetic lesion of EGFR from deletion of exons 2-7 that results in the anomalous gene *EGFR‐ vIII*. The normal gene product of the wild-type *EGFR* gene is the EGFR receptor. This receptor, by default, is phosphorylated at the intracellular domain which sets in motion a cascade of signal transduction events that culminates in cell proliferation and survival. In normal cells, the EGFR receptor is regulated by binding of extracellular ligands to the extracellular domain which acts to antagonize phosphorylation at the intracellular domain and thereby downregulate the mitogenic function of the growth factor cascade. The mutant gene *EGFRvIII* generates the aberrant gene product EGFRvIII that is constitutively phosphorylated/activated due to lacking a down-regulating extracellular ligand-binding domain that would otherwise have been coded by the missing exons 2-7 [16].

There is an ever-burgeoning body of information with the molecular features of malignant gliomas that casts the WHO system in a stark light for the limitations it makes apparent. This molecular information has allowed for determination of discrete subtypes of gliomas within each WHO grade that, through the rigors of clinical trials, have borne out true clinical utility for diagnosis, prognostication and treatment [13]. Within one grade, molecular signatures have identified subtypes that respectively take demonstrably different clinical courses and have discrete treatment responses. Another aspect illuminated by molecular markers is that, when placing a new specimen into one of the 4 WHO grades, there still remains, considerable variability between pathologists/centers. This is particularly so for Grades III and IV [17].
