New Directions in the Treatment of Glioblastoma

Zachary J. Reitman, MD, PhD; Frank Winkler, MD, PhD; Andrew E. H. Elia, MD, PhD


Semin Neurol. 2018;38(1):50-61. 

In This Article

Other Therapies in the Primary Setting

GBMs are highly vascular tumors, which has led to the study of angiogenesis inhibition as a treatment strategy. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A that showed progression-free survival benefit but not overall survival benefit in two phase III randomized trials (Table 1). In one trial, RTOG 0825, bevacizumab was added to the standard regimen of radiation with concurrent and adjuvant temozolomide. There was no difference in overall survival between the group that received bevacizumab and the group that did not. A progression-free survival benefit was noted in the bevacizumab group (median 10.7 versus 7.3 months), which did not meet the prespecified efficacy target.[19] In the other randomized trial, AVAglio, the addition of bevacizumab to radiation and temozolomide did not confer an advantage in terms of overall survival, but there was a statistically significant increase in progression-free survival from 6.2 to 10.6 months.[20] These two trials highlighted several hallmarks of bevacizumab therapy: (1) the agent reduces vascular permeability and alters contrast-enhancement in MR imaging, confounding interpretation of surveillance scans and raising problems with progression-free survival endpoints that may be driven by imaging findings; (2) there is a slight increase in the rate of adverse events, especially thromboembolic and hemorrhagic events, among patients taking bevacizumab. These and other data have relegated bevacizumab to use in carefully selected patients in the newly diagnosed setting. The integrin inhibitor cilengitide is another agent with antiangiogenic activity that failed to improve overall survival when added to standard therapy in the CENTRIC trial (Table 1). Cilengitide was administered intravenously on a biweekly schedule with both radiation and temozolomide and then administered again after radiation for up to 18 months, with no improvement in survival.[21]

Two adjuvant therapies have resulted in increased overall survival but have not been routinely adopted in clinical practice. Carmustine wafers (Gliadel) implanted in the resection cavity at the time of surgery to deliver local adjuvant chemotherapy have demonstrated an overall survival benefit in two randomized trials (median 13.9 versus 11.6 months in one trial).[22,23] However, when non-GBM cases were removed from the analysis in one of these trials, the benefit was no longer statistically significant.[23] Concern regarding adverse effects, including cerebrospinal fluid leakage and intracranial hypertension, and challenges in interpretation of imaging findings after wafer placement have prevented wide adoption of this adjuvant therapy. Tumor-treating fields (TTFs) have also emerged as a novel therapy, with randomized evidence supporting an overall survival benefit. TTFs involve placement of a specialized helmet worn for >18 hours/day that delivers continuous alternating electric fields via transducers placed on the shaved scalp. The EF-14 phase III trial randomized patients to standard radiation with concurrent and adjuvant temozolomide with or without TTF maintenance treatment following radiation completion. The trial was closed early after an overall survival benefit was observed at the first interim analysis and ultimately yielded a benefit of 20.9 versus 16.0 months in the final analysis.[24] The therapy has subsequently gained in popularity, but some authorities have raised concern over the lack of a sham placebo device in the trial, the invasive nature of the device in terms of the patient experience, and the incompletely understood antitumor mechanism.[25]