Imaging Studies May Predict Tumor Response to Antiangiogenic Drugs


Key Points

  • All but one of the study participants showed evidence of vascular normalization and reduced edema, but only half of the patients who had had advanced brain imaging were found to have persistent improvement in vessel perfusion.
  • Vessel architectural imaging revealed that patients with improved perfusion survived an average of 9 months longer than did those with stable or worsened perfusion levels.
  • The study provides evidence that vascular normalization–induced increased vessel perfusion is the mechanism of benefit in glioblastoma patients treated with antiangiogenic drugs.

Advanced imaging techniques may be able to distinguish which patients' tumors will respond to treatment with antiangiogenic drugs and which will not. In a report published online in PNAS, researchers studied patients with newly diagnosed glioblastoma who were treated with the antiangiogenic agent cediranib and found that those patients for whom cediranib rapidly "normalized" abnormal blood vessels around their tumors and increased blood flow within tumors survived significantly longer than did patients in whom cediranib did not increase blood flow.

“Two recent phase III trials of another antiangiogenic drug, bevacizumab [Avastin], showed no improvement in overall survival for glioblastoma patients, but our study suggests that only a subset of such patients will really benefit from these drugs," explained co-lead and corresponding author Tracy Batchelor, MD, Director of the Pappas Center for Neuro-Oncology at the Massachusetts General Hospital Cancer Center. "Our results also verify that normalization of tumor vasculature appears to be the way that antiangiogenic drugs enhance the activity of chemotherapy and radiation treatment."

Vasculature Normalization Hypothesis

?Antiangiogenic drugs were first introduced for cancer treatment under the theory that they would act by "starving" tumors of their blood supply. Since that time, however, new evidence has suggested that the drugs' benefits come through their ability to "normalize" the abnormal, leaky vessels that usually surround and penetrate tumors, improving delivery of both chemotherapy drugs and the oxygen that is required for effective radiation therapy. This hypothesis was first proposed and has subsequently been developed by Rakesh K. Jain, PhD, senior author of the current study and Director of the Steele Laboratory for Tumor Biology in the MGH Department of Radiation Oncology.

A 2007 clinical study led by Dr. Batchelor found evidence suggesting that cediranib could temporarily normalize tumor vasculature in recurrent glioblastoma, but it was not clear what role normalization might have in patients' survival. In the past few years, several research teams lead by Drs. Batchelor, Jain, and other coauthors of the current paper reported evidence that cediranib alone improved blood perfusion within recurrent glioblastoma tumors in a subset of patients and improved their survival. A Nature Medicine study published earlier this year used vessel architectural imaging to reveal that cediranib alone improved the delivery of oxygen within tumors of some patients with recurrent glioblastoma.

Study Details

Patients in the current study were participants in a clinical trial of cediranib plus radiation and chemotherapy for postsurgical treatment of newly diagnosed glioblastoma. Among participants in that trial, 40 also had advanced brain imaging with vessel architectural imaging and other magnetic resonance imaging techniques. Although all but one of the participants in the overall trial showed some evidence of vascular normalization and reduced edema, only 20 of 40 patients were found to have persistent improvement in vessel perfusion. 

Vessel architectural imaging also revealed improved oxygen delivery only in the patients with improved perfusion. Those patients survived on average 9 months longer—26 months, compared with 17 months—than did those whose perfusion levels remained stable or worsened. A comparison group of glioblastoma patients treated with radiation and chemotherapy only survived an average of 14 months.

Role of Imaging Techniques

"It's quite likely that the results we've found with cediranib will apply to other antiangiogenics," Dr. Batchelor said. "In fact, a presentation at a recent meeting showed that patients with improved perfusion from bevacizumab were also the ones in that study who lived longer. More research is needed, but these findings suggest that magnetic resonance imaging techniques should play an essential role in future studies of antiangiogenic drugs in glioblastoma and possibly other types of solid tumors.  We've received National Cancer Institute funding to study this approach with bevacizumab treatment, and we will also be investigating tumor delivery of chemotherapy and oxygen status using combined magnetic resonance/PET techniques.”?

Dr. Jain added, "We originally introduced the normalization hypothesis for antiangiogenic treatment in 2001, but it's taken more than a decade to confirm that vascular normalization actually increases tumor perfusion and that increased perfusion, rather than tumor starvation, is what improves survival. This study provides compelling evidence that normalization-induced increased vessel perfusion is the mechanism of benefit in glioblastoma patients."

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.