Trial Information

Avastin Plus Radiotherapy in Elderly Patients With Glioblastoma

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.