**2. Current standard of care for patients with glioblastoma**

Glioblastoma is the most frequently encountered astrocytic brain tumor in adults and accounts for more than 50% of all gliomas (Reardon, D.A. & Wen, 2006). The tumor rapidly infiltrates normal surrounding brain tissue. Patients with glioblastoma typically encounter tumor progression or recurrence, and median survival is only 14.6 months (Stupp et al., 2005). Neurologically safe, maximal surgical tumor resection is generally considered the first therapeutic measure for the treatment of newly diagnosed glioblastoma. However, localization of the tumor in or near eloquent brain areas will impose considerable restrictions on the radicality of the surgical procedure in order to avoid severe postoperative neurological deficits. Radiotherapy in combination with concomitant and adjuvant chemotherapy with temozolo‐ mide (Temodar®/Temodal®, Schering Corporation, Kenilworth, NJ, U.S.A.) is a viable postop‐ erative treatment option. Whole brain irradiation (50-60 Gy) was shown by several randomized studies to increase survival by 14-36 weeks (Walker et al., 1980). While the chemotherapeutics that were initially used for the adjuvant treatment of glioblastoma were only of minor benefit, a randomized controlled trial in patients with newly diagnosed glioblastoma showed that administration of temozolomide concomitantly with and subsequently to radiation therapy significantly increased two-year survival from 10.4% to 26.5% and median survival from 12.1 to 14.6 months when compared to adjuvant radiation therapy alone (Stupp et al., 2005). With this study, a new therapeutic standard was established. Nevertheless, a progression-free survival and overall survival of only 6.9 and 14.6 months, respectively, strongly emphasize that further improvement of glioblastoma therapy is urgently needed.

Currently, a standard of care for the treatment of *recurrent* glioblastoma does not exist. In general, repeated gross tumor resection should be attempted. However, this strategy might not always be appropriate, especially when considering the fact that progressive tumor invasion may significantly increase the risk of provoking neurological deficits. Chemothera‐ peutics that were especially used before the temozolomide era upon tumor relapse include nitrosoureas such as carmustine (BCNU) or lomustine (CCNU) and alkylating agents such as procarbazine. However, the antineoplastic activity of these agents in clinical trials was shown to be rather modest (Rodriguez et al., 1989; Newton et al., 1990; Brandes et al., 2004). Irinotecan (Camptosar®, Pfizer Pharmaceuticals, New York, NY, U.S.A.), an inhibitor of topoisomerase I (Raymond et al., 2003; Reardon, DA et al., 2005), or bevacizumab (Avastin®, Genentech Inc., San Francisco, CA, U.S.A.), a humanized monoclonal antibody targeted to vascular endothelial growth factor (VEGF), represent two compounds that have been introduced more recently for the treatment of recurrent glioblastoma and that showed anti-glioblastoma activity (Stark-Vance, 2005).

genesis, angiogenesis and invasion (Halatsch et al., 2006). Dysregulated HER1/EGFR signaling may be caused by different mechanisms such as gene amplification resulting in HER1/EGFR overexpression as shown for 40-50% of glioblastoma (Salomon et al., 1995). Mutational changes of the intrinsic receptor structure constitute another mechanism that may lead to pathologically altered HER1/EGFR signaling. The so-called EGFRvIII accounts for approximately 60% of all HER1/EGFR mutants and is characterized by a constitutive activation (Frederick et al., 2000; Karpel-Massler et al., 2010). The expression of EGFRvIII was shown to confer cellular trans‐

Despite recent improvements, the clinical efficacy of existing therapeutic modalities remains disappointing. Hence, in light of accumulating evidence for HER1/EGFR-mediated promotion of tumor growth and malignant transformation, substantial interest in the realization of HER1/ EGFR-targeted therapeutic strategies developed. Small molecule tyrosine kinase inhibitors such as erlotinib (Tarceva®, Genentech Inc., San Francisco, CA, U.S.A.), a combined inhibitor of both, HER1/EGFR and EGFRvIII, are the clinically most advanced HER1/EGFR-targeted agents (Karpel-Massler et al., 2009). After promising results derived from experimental studies using erlotinib in a single agent approach were not confirmed by clinical trials, hopes now are set on the identification of other targeted agents enhancing the antineoplastic activity of

Glioblastoma is the most frequently encountered astrocytic brain tumor in adults and accounts for more than 50% of all gliomas (Reardon, D.A. & Wen, 2006). The tumor rapidly infiltrates normal surrounding brain tissue. Patients with glioblastoma typically encounter tumor progression or recurrence, and median survival is only 14.6 months (Stupp et al., 2005). Neurologically safe, maximal surgical tumor resection is generally considered the first therapeutic measure for the treatment of newly diagnosed glioblastoma. However, localization of the tumor in or near eloquent brain areas will impose considerable restrictions on the radicality of the surgical procedure in order to avoid severe postoperative neurological deficits. Radiotherapy in combination with concomitant and adjuvant chemotherapy with temozolo‐ mide (Temodar®/Temodal®, Schering Corporation, Kenilworth, NJ, U.S.A.) is a viable postop‐ erative treatment option. Whole brain irradiation (50-60 Gy) was shown by several randomized studies to increase survival by 14-36 weeks (Walker et al., 1980). While the chemotherapeutics that were initially used for the adjuvant treatment of glioblastoma were only of minor benefit, a randomized controlled trial in patients with newly diagnosed glioblastoma showed that administration of temozolomide concomitantly with and subsequently to radiation therapy significantly increased two-year survival from 10.4% to 26.5% and median survival from 12.1 to 14.6 months when compared to adjuvant radiation therapy alone (Stupp et al., 2005). With this study, a new therapeutic standard was established. Nevertheless, a progression-free survival and overall survival of only 6.9 and 14.6 months, respectively, strongly emphasize

formation and enhanced tumorigenicity (Nishikawa et al., 1994).

**2. Current standard of care for patients with glioblastoma**

that further improvement of glioblastoma therapy is urgently needed.

erlotinib in a multi-targeted approach.

224 Tumors of the Central Nervous System – Primary and Secondary
