Key words: temozolomide; glioblastoma; clinical trial; neurotherapeutics; radiotherapy; quality of life.

Introduction and Overview

Glioblastoma multiforme is the most common and devastating of all primary brain tumors, with median survival typically in the range of 9–12 months with multi-modality treatment (DeAngelis, 2001; Burger & Scheithauer, 1994). Even with aggressive therapeutic approaches to prevent and manage tumor progression, and intense efforts to develop better treatments, survival for patients with glioblastoma has changed little in 30 years. Most patients experience local tumor progression, and usually succumb within months of recurrence. Standard accepted initial therapy for this disease has been maximal feasible surgical resection followed by conformal fractionated radiotherapy. Although not generally considered a chemosensitive tumor, glioblastoma occasionally responds to chemotherapeutic agents, particularly when these drugs are administered for recurrent disease (Brada et al., 2001; Yung et al., 2000). However, no drugs are predictably active against this disease, and most patients with glioblastoma who receive chemotherapy are usually treated with alkylating agents, historically nitrosoureas and most recently temozolomide (Lesser & Grossman, 1994).

Efforts to improve survival for patients with glioblastoma have included advances in surgical techniques that enable more complete tumor resection, and more sophisticated ways of delivering radiotherapy to the tumor bed while comparatively sparing normal brain; these technical advances have made treatment safer, but have not had a definitive impact on extending survival. Chemotherapy has also been evaluated as initial treatment with surgery and radiotherapy in an attempt to improve dismal survival statistics for glioblastoma. The choice of potential agents for evaluation in glioblastoma has been limited by concerns surrounding effective drug penetration into the central nervous system (CNS), which is protected by a blood–brain barrier that renders tumors at least partly impervious to most drugs.