By Michael Spiotto, MD, PhD
We have tried almost everything to treat glioblastoma without much progress.
For the last 10 years, the treatment for malignant glioma has remained the same: surgery, if possible, followed by radiation and temozolomide, an oral alkylating agent.
Previous attempts using higher total radiation doses and daily treatment sizes, more toxic chemotherapies and other agents showed inconsistent results.
By contrast, approximately 10 years ago, groups added temozolomide to radiation to provide an incremental benefit where median overall survival increased by 2 months (14.6 months with temozolomide vs. 12.1 months without) 1.
Recently, bevacizumab (Avastin) has risen in prominence for the treatment of recurrent glioblastoma 2.
Bevacizumab inhibits angiogenesis which may be indirectly tumoricidal. In addition, it induces vascular remodeling to improve chemotherapeutic drug delivery or better oxygenate tumors to improve the impact of radiation.
Bevacizumab when given alone or with other chemotherapeutics, such as irinotecan, showed improved response rates and, in some phase II studies, better overall survival.
The mechanism by which bevacizumab improved outcomes still remains unclear. In addition to potential tumoricidal effects, bevacizumab also decreased vasogenic edema associated with the tumor that impacts the measurement of the disease.
Since bevacizumab alters the edema and contrast enhancement on imaging, tumor responses to bevacizumab may also have been overestimated, as glioblastoma was forced to grow along the blood vessels which could not be assessed by these imaging characteristics.
Given these promising responses, the Radiation Therapy Oncology Group initiated a trial to assess the impact of bevacizumab in combination with radiation. Here, patients with newly diagnosed glioblastoma were started on temozolomide and radiation.
Bevacizumab was added during week four of radiation and continued for 6 to 12 months afterwards. Initial results of this trial, RTOG 0825, were reported last month at ASCO 2013 3.
Bevacizumab improved progression free survival (10.7 months with bevacizumab vs. 7.3 months without bevacizumab; p = 0.004). However, patients treated with bevacizumab trended to worse overall survival (15.7 months vs. 25 months; p = 0.08) potentially due to ineffective treatments as well as increased toxicity. Furthermore, this improved progression free survival with bevacizumab came at a cost of increased toxicity.
Similar results were observed in a recent European trial using an analogous design (AVAglio trial). Despite the promise, bevacizumab unfortunately will not likely be incorporated into the initial treatment of glioblastoma.
Where do we go from here?
The standard of care for newly diagnosed glioblastoma will remain surgery followed by chemoradiation with temozolomide.
After sorting through all the clinical samples collected, researchers are looking to identify a subset of tumors with molecular profiles that predicted a favorable response to bevacizumab.
Furthermore, this serves as a reminder that agent with much promise still require randomized trials and caution using such agents “off protocol”.
Hopefully, we can identify patients who have tumors with favorable molecular profiles who may eventually benefit from incorporating bevacizumab for the initial therapy of glioblastoma but that will require further study.
Michael Spiotto, MD, PhD, is an Assistant Professor of Radiation & Cellular Oncology at the University of Chicago Medicine. He specializes in treating patients with head and neck cancer. Whenever possible, he uses image-guided radiation therapy to target a tumor more precisely while reducing damage to surrounding tissue.
3.Gilbert MR, al. e. RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). J Clin Oncol. 2013;31:(suppl; abstr 1).