**14. Patterns of recurrence**

As we gain more experience using anti-angiogenic agents in high grade gliomas, we also learn more about what occurs after treatment failure. Mancuso et al. conducted a pre-clinical study using a mouse xengraft model to address the reversibility of VEGF inhibition after cessation of anti-VEGF therapy. It was noted that even after a 50–60% reduction of tumour vascularity, ''empty sleeves of basement membrane were left behind.'' By day 7 after drug cessation, tumours were fully re-vascularized, suggesting that these remaining empty sleeves of basement membrane and pericytes are responsible for this tumor revascularization. These basement membranes also serve as storage sites for angiogenic growth factors as well as ''tracks'' for tumor vascular regrowth. This "rebound" phenomenon has also been observed in clinical studies (figure 9) [46]. This phenomenon appears to be associated with rapid clinical demise and dismal prognosis.

**Figure 9.** Rebound progression after discontinuation of bevacizumab: Original tumor area seen on post-Gd T1 weighted (a) and FLAIR MRI (e) sequences prior to initiating therapy with bevacizumab in a patient with recurrent high-grade glioma. Post-Gd T1 weighted (b) and FLAIR MRI (f) sequences that demonstrate partial response after 1 six-week cycle of treatment with bevacizumab. Post-Gd T1 weighted (c) and FLAIR MRI (g) sequences at the time of bevacizumab failure and subsequent cessation of bevacizumab therapy. Post-Gd T1 weighted (d) and FLAIR MRI (h) sequences at the time of "rebound" progression demonstrating a dramatic increase in area of enhancement and ab‐ normal FLAIR signal 6 weeks after cessation of therapy with bevacizumab. [44]

## **15. MicroRNA – Potential target**

**13. Bevacizumab as first line therapy**

22 Tumors of the Central Nervous System – Primary and Secondary

maker for overall survival.

bevacizumab group.

**14. Patterns of recurrence**

Two large phase III double-blinded randomized studies published in NEJM in February, 2014 evaluated the use of bevacizumab in the first line setting in patients with glioblastoma. Gilbert et al, led a study that randomized 637 patients with newly diagnosed glioblastoma to standard six weeks of chemo-radiotherapy (adjuvant temozolomide and concurrent radiotherapy) followed by up to twelve months or until disease progression of maintenance temozolomide, with or without bevacizumab starting at week four of chemo-radiotherapy [46]. The results were disappointing in that no survival benefit was determined between the two groups. The bevacizumab group reported a median overall survival (OS) of 15.7 months and the placebo group had an OS of 16.1 months. Progression-free survival favored the bevacizumab group at 10.7 months vs. 7.3 months in the placebo group. Interestingly, over time the patients who received bevacizumab did not benefit from a quality of life standpoint despite better response rates. These points further reinforce the question as to whether PFS is an appropriate surrogate

A second published in the same issue of NEJM performed by Chinot et al, studied the use of bevacizumab in the front line setting as well [49]. Similar conclusions were reported in this study compared to the performed by Gilbert et al. The treatment regimen used in the study differed in that after 6 months of maintenance temozolomide with or without bevacizumab were continued with bevacizumab alone or placebo until disease progres‐ sion or until suffering from intolerable side effects. The results were again disappointing in that the addition of bevacizumab to standard chemo-radiation and maintenance therapy with this anti-angiogenic agent did not provide a survival benefit (72% and 33.9% one and two year survival rate respectively in the bevacizumab group versus 66.3% and 30.1%) despite a significantly better PFS (10.6 months in bevacizumab group vs. 6.2 months in placebo group). Baseline quality of life was maintained for a longer period of time in the

These results, in particular the study by Gilbert et al, appears to possibly support the use of maintenance temozolomide for twelve months instead of traditional standard therapy with six months as conducted in the landmark study by Stupp et al now considered standard of care. This is a question that every neuro-oncologist has to address when treating patients with newly diagnosed glioblastoma. Although difficult to extrapolate data from two separate studies, no large scale study has been performed making a direct comparison of twelve months versus six months of maintenance temozolomide. However, this data suggests that twelve months of maintenance temozolomide leads to an improvement in OS reporting 16.1 months

As we gain more experience using anti-angiogenic agents in high grade gliomas, we also learn more about what occurs after treatment failure. Mancuso et al. conducted a pre-clinical study

versus14.6 months reported in the EORTC trial led by Stupp et al.

MicroRNAs (miRNAs) are molecules of RNA numbering 20-23 nucleotides that function to interfere with messenger RNA (mRNA) translation into protein, the final step in gene expression. Through a complex and elegantly-characterized molecular sequence of steps, miRNAs function to "flag" mRNAs for decay, translational inhibition, or cleavage prior to the process of translation. This, in turn, results in a decreased level of encoded proteins, which in turn affects a myriad of essential cell functions, i.e. growth, proliferation, metabolism, apoptosis, etc. [43] Interestingly, though miRNA constitutes roughly 1-3% of

the human genome, it is postulated that these molecules have influence on as much as ~30% of all gene expression [44]. The expression of one mRNA may be affected by numerous miRNAs; on the same token, one miRNA may affect the expression of multiple mRNAs [44]. The deregulation of miRNA has been pivotally implicated in tumorigenesis; a positive association has been found between those sites in the human genome associated with cancer and areas of miRNA expression [44]. Furthermore, miRNAs have been found to exempli‐ fy both oncogenic and tumor suppressor functions in the tumorigenesis of pancreatic cancer, prostate cancer, thyroid cancer, ovarian cancer, colon cancer, breast cancer, and melano‐ ma. Of recent, the same has also been found in GBM wherein a multitude of miRNAs have been reported to have roles in tumor suppression or oncogenesis. Therapeutic strategies with respect to miRNA aim to augment tumor suppression or antagonize oncogenesis, respectively. In the former case, it is postulated that viral vectors may be utilized to deliver gene therapy to increase the *in situ* expression of tumor suppressive miRNAs. In the latter case, studies pursuing anti-miRNA therapies, e.g. the use of anti-miRNA oligonucleoti‐ des, are underway for downregulation of oncogenic miRNAs [44].
