**6. Role of surgical resection**

The standard treatment for newly-diagnosed GBM has remained relatively staid as evinced by the relatively abysmal prognosis over the aggregate of decades. However, caveat emptor must once again be invoked as there is a sea change in elucidation of the molecular features of GBM that promises much in the way of therapeutic potential on the horizon. This will be discussed in detail in content to follow.

The first modality in treatment is maximally safe surgical resection. This, it needs bearing in mind, is not curative. At the time of diagnosis, newly-found GBM has invariably infiltrated extensively into normal brain parenchyma. GBM is almost always diagnosed after it has grown large enough to elicit symptoms due to mass effect and parenchymal disruption. However, the benefits of maximally-safe surgical resection of tumor are manifold: sampling of tissue for pathological diagnosis, palliation of mass effect, and some indication of improvement in survival [16]. Though rote surgical resection has remained somewhat limited due to the intricate insinuation of the tumor into brain tissue, new surgical technologies have allowed for more elegant and discriminating extrication of malignant tissue. One example is neuroendo‐ scopy, use of an endoscope deployed through the ventricles for a minimally-invasive approach to allow for biopsy, resection and alleviation of lesions causing obstructive hydrocephalus [13]. Another surgical technology is fluorescence-guided resection. This involves the administra‐ tion of a non-fluorescent prodrug 5-aminolevulinic acid (ALA) that, when taken up by tumor tissue, is converted to fluorescent metabolite protoporyphyrin IX (PpIX) and accumulates to a marked degree in Grade III and IV gliomas. The neurosurgeon intra-operatively deploys "blue light" which allows tumor tissue to be visualized as "red" due to the fluorescent biomarker. This, in turn, has been shown to allow for more optimal and extensive tumor resection [13] (See Figure 6).

**Figure 6.** Flourescence/ALA-Guided Surgical Resection of GBM [13]

**Figure 5.** (A) T1 pre-contrast images exhibit a hypointense lesion in the left frontal lobe region (arrow). (B) Axial T1 post-contrast images, after injection of 20 cc of intravenous MultiHance®, demonstrate a focus of enhancement in left frontal lobe. (C) Axial T2 FLAIR images show increase in FLAIR signal in the left frontal lobe, which demonstrates en‐

The gold standard for diagnosis, of course, remains procurement of tissue for histological confirmation that can either be accomplished either diagnostically through stereotactic biopsy or, more commonly, diagnostically and therapeutically with tissue samples obtained during

The standard treatment for newly-diagnosed GBM has remained relatively staid as evinced by the relatively abysmal prognosis over the aggregate of decades. However, caveat emptor must once again be invoked as there is a sea change in elucidation of the molecular features of GBM that promises much in the way of therapeutic potential on the horizon. This will be

The first modality in treatment is maximally safe surgical resection. This, it needs bearing in mind, is not curative. At the time of diagnosis, newly-found GBM has invariably infiltrated extensively into normal brain parenchyma. GBM is almost always diagnosed after it has grown large enough to elicit symptoms due to mass effect and parenchymal disruption. However, the benefits of maximally-safe surgical resection of tumor are manifold: sampling of tissue for

hancement. (D) T2 FSE images also demonstrate increase in signal in the region of the left frontal lobe.[30]

craniotomy for the purposes of tumor resection or debulking.

**6. Role of surgical resection**

10 Tumors of the Central Nervous System – Primary and Secondary

discussed in detail in content to follow.

An important concept to invoke here in the discussion of surgical treatment is Extent Of Resection (EOR), i.e. the extent of tumor tissue that can be safely resected. There is, as would be intuited, a likely positive association between (EOR) and patient survival/patient outcome. Data from the ALA-glioma Study Group out of Germany provided the highest level of evidence--2b--for a positive association between patient outcome, i.e. progression free


that many anti-epileptics, particularly of the first generation (e.g. phenytoin, carbamazepine), may decrease the serum concentration of certain chemotherapy agents by dint of inducing

High Grade Glioma — Standard Approach, Obstacles and Future Directions

http://dx.doi.org/10.5772/58548

13

As evinced by the yet-sobering statistics on overall GBM survival/patient outcome, there are many-a-challenge and obstacle that remain in treatment, especially regarding the development

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

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

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].

of resistance to both radiation therapy and, more so, to temozolomide chemotherapy.

increased hepatic metabolism [37].

cellular proliferation [16].

have been coded by the missing exons 2-7 [16].

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

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

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 benefit with increased EOR.
