Gilbert and colleagues reported a phase 3 trial conducted by the Radiation Therapy Oncology Group, North Central Cancer Treatment Group and Eastern Cooperative Oncology Group that included 637 patients. It addressed whether the addition of bevacizumab to standard therapy improves survival for patients with newly diagnosed glioblastoma multiforme, the most common malignant brain tumor in adults. The study showed that bevacizumab produced a statistically significant improvement in PFS; however, OS was not improved. Of concern, patients with the best overall prognosis — as predicted by gene profiling — had a worse survival trend, although this observation was of questionable statistical significance.

This study, once again, highlights the difficulties and frustrations associated with the treatment of glioblastoma. More than a decade ago, bevacizumab — initially in combination with irinotecan — was shown to have promising activity in patients with recurrent glioblastoma multiforme. The combination resulted in radiographic objective responses and an encouraging prolongation of 6-month PFS. Subsequent studies demonstrated that the drug combination had only a modest effect on prolonging OS and that bevacizumab alone was essentially equal to the use of the drug with irinotecan. There was also concern that the use of bevacizumab altered the pattern of disease relapse, as some patients experienced progression in a more diffuse pattern than was usually encountered. However, since bevacizumab had some degree of efficacy in this disease, which has been highly recalcitrant to treatment, it was hoped that adding the drug to radiation and temozolomide would prolong survival and possibly result in a greater percentage of long-term survivors.

The study by Gilbert and colleagues demonstrated — in a large, well-powered randomized clinical trial — a modest prolongation of PFS for those treated on the bevacizumab arm (which did not reach statistical significance), but the addition of bevacizumab did not improve OS. Actually, in the best prognostic group, those patients with MGMT methylation and a favorable 9-gene profile, patients treated with bevacizumab actually had a worse survival trend. Although the bevacizumab was relatively well tolerated, as could have been expected, bevacizumab was associated with some degree of toxicity; primarily neutropenia, hypertension and deep vein thrombosis/pulmonary embolus.

Clearly, the study does not support the use of bevacizumab for patients with newly diagnosed glioblastoma multiforme, although it may still have a role for those with recurrent disease. The search for more effective therapies for glioblastoma multiforme continues. Temozolomide, primarily in patients with methylated MGMT, has resulted in some improvements in disease control.

To date, the use of biologic agents has not demonstrated any reproducible survival advantage. The identification of molecular subgroups of glioblastoma has opened a new window into insights of the genetic alterations that underlie glioblastoma development, progression and invasiveness. Such information has led to renewed hope that molecularly-guided precision therapies can be developed to improve outcome in subsets of patients with this disease. Although work is ongoing by the study group to determine if there are patients who benefit from bevacizumab, it seems that other directions will be required to make a significant impact on improving disease control and survival for patients with glioblastoma.

This study has a significant impact for our patients. The addition of more therapy did not extend survival and in fact was associated with increased toxicity. Although bevacizumab has a role in the treatment of glioblastoma, further research is required to better define the patient population that will benefit the most from this exciting drug.