This is a randomized (2:1), explorative, parallel-group, open-label, phase II trial in elderly patients with newly diagnosed glioblastoma. In the control arm, patients will receive radiotherapy, in the experimental arm, patients will receive bevacizumab during and after radiotherapy until progression.

Background:

For decades, neurosurgical resection and postoperative radiotherapy have been the cornerstones of treatment for patients with glioblastoma. Most chemotherapeutic agents showed little or no activity in malignant glioma patients, with the possible exception of nitrosoureas. This has changed with the introduction of temozolomide, first shown to be active in recurrent disease (Yung et al. 2000) and more recently in newly diagnosed glioblastoma (Stupp et al. 2005, 2009). This EORTC 26981-22981 NCIC CE.3 trial demonstrated an increase in median survival from 12.1 to 14.6 months and of the 2 year survival rate from 10% to 26% in patients receiving radiotherapy plus temozolomide compared with radiotherapy alone. Notably patients with tumors exhibiting methylation of the promoter region of the O6-methylguanine DNA methyltransferase (MGMT) gene showed a striking benefit from temozolomide (Hegi et al. 2005). Yet, inclusion in this trial was limited to patients up to the age of 70, and subgroup analyses demonstrated that younger patients were more likely to derive benefit from combined modality treatment than older patients. Thus, radiotherapy alone is still the standard of care in the elderly. The value of radiotherapy has been confirmed in a small randomized trial comparing best supportive care versus radiotherapy alone: median survival was 29 weeks with radiotherapy compared with 16.9 weeks with supportive care only (Keime-Guibert et al. 2007). Based on the overall shorter survival in elderly patients, hypofractionated radiotherapy has been explored and shown to be equieffective in patients aged 65-70 years and more (Roa et al. 2004). Two randomized trials presented in abstract form at the Annual Meeting of the American Society of Clinical Oncology in June 2010 failed to show superiority of primary temozolomide chemotherapy alone over radiotherapy alone in elderly patients (Malmstrom et al. 2010, Wick et al. 2010a). In fact, the German NOA-08 trial even showed that primary temozolomide alone is not non-inferior to primary radiotherapy alone (Wick et al. 2010a). A concomitant treatment strategy is currently evaluated in a NCIC-EORTC randomized trial. Further, the Nordic trial corroborated the equieffectiveness of an accelerated radiotherapy protocol of 40 Gy administered in 15 fractions versus the standard fractionation of 30 x 2 Gy. Altogether, these clinical data justify the exploration of new, temozolomide-free first-line treatment strategies in glioblastoma.

Glioblastomas express high levels of vascular endothelial growth factor (VEGF) and are highly vascularized tumors. The VEGF antibody, bevacizumab, has recently gained approval in patients with recurrent glioblastoma in the USA and in Switzerland in 2009, but not in the EU. Its role in the first-line treatment of glioblastoma is currently being evaluated in randomized trials. There is limited data on the safety and efficacy of bevacizumab in elderly patients with glioblastoma, although the safety profile of bevacizumab in elderly patients with other types of cancer, e.g., lung cancer is favorable. There are ample rationales for combining bevacizumab with radiotherapy, including the induction of VEGF by radiotherapy and the concept of vascular normalization resulting in increased oxygenation and thus sensitivity to radiotherapy. Thus, bevacizumab is not only expected to inhibit angiogenesis, but may also exhibit additive or synergistic interactions with radiotherapy and further impair tumor growth. Altogether, this study seeks to explore, using a dedicated neuroimaging protocol, the possibility that bevacizumab enhances the effects of radiotherapy via the process of vascular normalization.

The purpose of this study is to explore the efficacy of bevacizumab combined with radiotherapy compared with radiotherapy alone in the treatment of newly diagnosed glioblastoma in the elderly.