Howard A. Fine, MD, Chief of Hematology/Oncology at New York University Langone Medical Center and Director of the NYU Brain Tumor Center, served as formal discussant of the RTOG 0825 study at the Plenary Session. He noted the strong rationale for studying bevacizumab in glioblastoma, which is a highly vascular tumor that overexpresses vascular endothelial growth factor (VEGF). Promising phase II studies in recurrent glioblastoma led to FDA approval of bevacizumab in 2009, but the upfront setting may present unique challenges.

“Glioblastoma progression through bevacizumab is often associated with increased tumor cell invasiveness that appears to be VEGF- and largely angiogenesis-independent,” he said. “This may, in part, be the reason why the data do not currently support the routine use of bevacizumab as part of upfront treatment in most patients with newly diagnosed disease.”

In addition, bevacizumab affects the biology and imaging of glioblastomas, making interpretation of trial data challenging, he said.

Confounding Factors

Also discussing the bevacizumab studies was Albert Lai, MD, PhD, Assistant Clinical Professor in the Adult Brain Tumors section at the University of California, Los Angeles, Medical Center. “Most of us believe that bevacizumab does help patients, but how do we show it?” he asked.

The potential for an overall survival benefit, which has not yet been demonstrated, would be confounded by crossovers in the studies so far, he pointed out. “If bevacizumab crossover is unavoidable, then the overall survival question becomes an issue of the timing of bevacizumab use, and it will be difficult to show a benefit,” he predicted.

“For progression-free survival we have some positive results, but what do they mean clinically?” he added.

He suggested that maintenance of function may be the most relevant endpoint, and, if so, “we need to thoroughly and rigorously evaluate this,” he said. He further suggested that while bevacizumab is steroid-sparing, “we may be trading a steroid toxicity signal for a bevacizumab toxicity signal.… We still need to understand the biology to pin down the antitumor vs antiedema activity.”

Research Recommendations

Dr. Fine and Dr. Lai suggested that in the future, researchers should attempt to:

• define radiographic, genetic, molecular and clinical biomarkers of glioblastomas that will most likely benefit from bevacizumab
• include primary endpoints other than progression-free and overall survival
• explore bevacizumab in combination with new agents that inhibit anti-VEGF–associated invasiveness
• share data from all studies to resolve the discrepancies in quality-of-life and neurocognitive outcomes, as shown in RTOG 0825 and AVAglio

“Despite these new data demonstrating its limitations, bevacizumab represents the single most important therapeutic agent in glioblastoma multiforme since temozolomide. Ongoing and future trials will better define how and when it should be optimally used in these patients,” Dr. Fine concluded. ■

Disclosure: Drs. Fine and Lai reported no potential conflicts of interest.