**11. Hypoxia as means of resistance and poor outcome**

improved vessel perfusion, a reduction in tumor interstitial pressure, and improved tumor oxygenation. Summarily, these changes all translate into an observed improvement in the delivery and efficacy of cytotoxic chemotherapy. A newer and exceedingly compelling hypothesis is that antiangiogenic agents appear to exercise antagonism to Glioblastoma stemlike cells (GSCs). GSCs play an inextricable part in the angiogenic potentiation of malignant gliomas. They appear to contribute to the resistance that glioblastoma is known to have to cytotoxic chemotherapy treatment by augmenting the repair of DNA damaged by cytotoxic agents and activating the DNA damage checkpoint response system. Antiangiogenic therapy appears to antagonize the functionality of GSCs by merit of GSCs embodying a categorically structural and functional vascular niche in the tumoral micro-milieu. GSCs have been found to upregulate VEGF expression, instigate formation of very angiogenic tumors in animal models, and bear a predilection for stem cell hot beds in areas around endothelial cells. In the self-same animal models, antiangiogenic agents appear to fundamentally disrupt the struc‐ tural framework of the hot beds in which GSCs reside and resultantly provoke GSC death.

18 Tumors of the Central Nervous System – Primary and Secondary

The canonical agent that has garnered the most investigation and use is the humanized anti-VEGF monoclonal antibody bevacizumab, originally used for treating colorectal cancer and also used routinely for metastatic lung adenocarcinoma. Its use for CNS tumors, recurrent gliomas in particular, was conceived of after improved outcomes were noted when it was used in conjunction with chemotherapy for colorectal and lung cancers. Recurrent gliomas have historically had a low radiographic response rate after re-exposure to temozolomide after failing initial therapy, ranging from only 5-8%. However, in the very first published study of the use of bevacizumab with irinotecan, a radiographic response rate of 66% (19 of 29 patients) was found [40]. This was followed by a number of retrospective studies on recurrent gliomas which showed progression free survival at 6 months (PF6) of 32-64% with bevacizumab vs. 21% PF6 rate for temozolomide [13]. The aggregate of these very positive results prompted two phase 2 trials designed for the purposes of fast track FDA approval of bevacizumab for the indication of recurrent gliomas. These two trials corroborated the prior results--a signifi‐ cant radiographic response rate and increase in PF6. The largest bevacizumab trial to date, designated the BRAIN trial and conducted by Freidman et al in 2009, randomized patientswith glioblastoma either after first or second recurrence to be treated with bevacizumab alone(n=85) or bevacizumab plus irinotecan (n=82). Both response rates (using MacDonald response criteria) and six month progression free survival were markedly higher when compared to historical controls in both groups (higher response rate in bevacizumab plus irinotecan group). However, overall survival was not statistically significant between the two groups at 9.2 months for bevacizumab alone and 8.7 months for the combination regimen. Bevacizumab was well tolerated. The most common or significant adverse events included thromboembo‐

It is important to remind the reader here of the interdependence between angiogenesis and the propagation of peritumoral edema in malignant gliomas. In fact, the original name for VEGF was vascular permeability factor due to its increasing the permeability of tumor vessels, which leads to the phenomenon of vasogenic brain edema. Vasogenic brain edema is a telltale hallmark of malignant gliomas and qualifies much of the morbidity associated with them. It

licevents, hypertension and proteinuria.

Despite the many promising aspects of antiangiogenic therapy outlined above, there have recently come to the fore many challenges that remain to the use of antiangiogenic agents for the treatment of malignant gliomas. One challenge that has become evident is based upon, in a matter of speaking, "tipping the balance" too far towards antiangiogenesis by significant use of antiangiogenesis agents. Animal and human biopsy results have showed that when used overzealously, antiangiogenic therapy actually works to promote a hypoxic environment within the tumor bed. Tumor hypoxia has been well established as a formidable means of resistance to chemotherapy and radiation [38]. Pre-clinical data obtained from xenograft models suggests that hypoxia and the hypoxia-inducible factors (HIFs) play a central role in maintaining the stem-like fraction in gliomas. This is achieved by providing the essential cellular interactions and signals needed to arrest differentiation of these stem-like cells. These interactions lead to stem-like cell survival and self-propagation. Upregulation of HIF-1alpha also activates autophagy, a lysosomal degradation pathway which may promote tumor cell survival.

with hyper-intense T2 FLAIR MRI signal. Due to this new understanding, a revised response criteria was developed that, in addition to post-gadolinium sequences, incorporates FLAIR MRI sequences, steroid dependence and clinical stability. This new set of criteria is known as the RANO criteria (Response Assessment in Neuro-Oncology) and now is standard in clinical

High Grade Glioma — Standard Approach, Obstacles and Future Directions

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

21

An important concept to invoke at this juncture, and one unique to the treatment of Glioblas‐ toma with chemotherapy and radiation, is that of Pseudoprogression. A few months after completion of concurrent temozolomide with radiation, many patients show increased contrast enhancement and T2/FLAIR hyperintensity in the radiation treatment field. This generally occurs about 3 months after completion of chemo-radiation and sometimes persists for about 6 months. The MacDonald criterion does not take this phenomenon into account when defining disease progression. The more contemporary RANO criteria defines progres‐ sion at less than 12 weeks after chemoradiotherapy as the development of a new area of enhancement outside of the prior radiation field, confirmed tumor via biopsy, or clinical decline. Pseudoprogression, as the name implies, denotes these changes that are not due to tumor progression, but rather due to unique cytotoxic effects on the tumor and its microen‐ vironment. Approximately ⅓ of patients with pseudoprogression are found to be symptomatic due to associated inflammation and edema and require treatment with corticosteroids. There is preliminary evidence at hand that indicates that administration of an anti-VEGF agent with standard of care concurrent temozolomide and radiation may reduce the incidence of pseu‐ doprogression [45]. As in the case of vasogenic cerebral edema, this may spare, if not limit, the ill effects of heavy corticosteroid use in many patients. Distinguishing pseudoprogression and true disease progression is very challenging and new imaging techniques (i.e. MR spectrosco‐ py, MR perfusion study) are being developed to help with this dilemma and guide treatment approach. Accumulating data shows promise using these new techniques but have yet to be

practice.

validated in large clinical studies.

Though clinical trials have largely focused on VEGF-A antagonism through bevacuzimab, there are a multitude of other pro-angiogenic factors/cytokines that contribute to glioma angiogenesis, including basic FGF (bFGF), angiopoietins, PDGF, interleukin-8 (IL-8), and hepatocyte growth factor/scatter factor (HGF/SF). It is thought that the contribution of these alternative mediators of angiogenesis mediate the phenomenon of antioangiogenic therapy resistance. In other words, these alternative proangiogenic factors are thought to allow for continuing angiogenesis in the face of VEGFR inhibition. Quite sobering is the harsh reality that though antiangiogenic therapy does prolong PFS and response rates are high in patients with recurrent GBM/gliomas, progression of disease inevitably occurs and once tumor burden breaks through, no therapeutic recourse presently exists. Confoundingly, patients with recurrent GBM die very shortly after failing antiangiogenic therapy (figure 8) [44].


### **12. Response criteria and pseudoprogression**

Anti-angiogenic agents also have made assessing response and progression a nebulous task. Prior to the era of anti-angiogenic agents, response assessment was performed via the MacDonald criteria which only utilized post-gadolinium MRI sequences. It was previously accepted that a decrease in enhancement represents eradication of tumor but this has proven not to be entirely valid with the use of anti-angiogenic agents. The development of a posttreatment hypoxic microenvironment favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain that is not represented by MRI contrast enhancement. Pre-clinical data suggests that Anti-VEGF treat‐ ment reduces vessel contrast leakage, reduces vessel density and promotes invasiveness of tumor cells which can be observed by an incongruent decrease in contrast enhancement along with hyper-intense T2 FLAIR MRI signal. Due to this new understanding, a revised response criteria was developed that, in addition to post-gadolinium sequences, incorporates FLAIR MRI sequences, steroid dependence and clinical stability. This new set of criteria is known as the RANO criteria (Response Assessment in Neuro-Oncology) and now is standard in clinical practice.


also activates autophagy, a lysosomal degradation pathway which may promote tumor cell

Though clinical trials have largely focused on VEGF-A antagonism through bevacuzimab, there are a multitude of other pro-angiogenic factors/cytokines that contribute to glioma angiogenesis, including basic FGF (bFGF), angiopoietins, PDGF, interleukin-8 (IL-8), and hepatocyte growth factor/scatter factor (HGF/SF). It is thought that the contribution of these alternative mediators of angiogenesis mediate the phenomenon of antioangiogenic therapy resistance. In other words, these alternative proangiogenic factors are thought to allow for continuing angiogenesis in the face of VEGFR inhibition. Quite sobering is the harsh reality that though antiangiogenic therapy does prolong PFS and response rates are high in patients with recurrent GBM/gliomas, progression of disease inevitably occurs and once tumor burden breaks through, no therapeutic recourse presently exists. Confoundingly, patients with

recurrent GBM die very shortly after failing antiangiogenic therapy (figure 8) [44].

Anti-angiogenic agents also have made assessing response and progression a nebulous task. Prior to the era of anti-angiogenic agents, response assessment was performed via the MacDonald criteria which only utilized post-gadolinium MRI sequences. It was previously accepted that a decrease in enhancement represents eradication of tumor but this has proven not to be entirely valid with the use of anti-angiogenic agents. The development of a posttreatment hypoxic microenvironment favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain that is not represented by MRI contrast enhancement. Pre-clinical data suggests that Anti-VEGF treat‐ ment reduces vessel contrast leakage, reduces vessel density and promotes invasiveness of tumor cells which can be observed by an incongruent decrease in contrast enhancement along

**Figure 8.** Post-Bevacizumab Salvage Therapy [44]

**12. Response criteria and pseudoprogression**

survival.

20 Tumors of the Central Nervous System – Primary and Secondary

An important concept to invoke at this juncture, and one unique to the treatment of Glioblas‐ toma with chemotherapy and radiation, is that of Pseudoprogression. A few months after completion of concurrent temozolomide with radiation, many patients show increased contrast enhancement and T2/FLAIR hyperintensity in the radiation treatment field. This generally occurs about 3 months after completion of chemo-radiation and sometimes persists for about 6 months. The MacDonald criterion does not take this phenomenon into account when defining disease progression. The more contemporary RANO criteria defines progres‐ sion at less than 12 weeks after chemoradiotherapy as the development of a new area of enhancement outside of the prior radiation field, confirmed tumor via biopsy, or clinical decline. Pseudoprogression, as the name implies, denotes these changes that are not due to tumor progression, but rather due to unique cytotoxic effects on the tumor and its microen‐ vironment. Approximately ⅓ of patients with pseudoprogression are found to be symptomatic due to associated inflammation and edema and require treatment with corticosteroids. There is preliminary evidence at hand that indicates that administration of an anti-VEGF agent with standard of care concurrent temozolomide and radiation may reduce the incidence of pseu‐ doprogression [45]. As in the case of vasogenic cerebral edema, this may spare, if not limit, the ill effects of heavy corticosteroid use in many patients. Distinguishing pseudoprogression and true disease progression is very challenging and new imaging techniques (i.e. MR spectrosco‐ py, MR perfusion study) are being developed to help with this dilemma and guide treatment approach. Accumulating data shows promise using these new techniques but have yet to be validated in large clinical studies.
