Researchers from Massachusetts General Hospital (MGH) report that advanced imaging modalities may possess the ability to differentiate between which patients' tumors will in fact respond to treatment with anti-angiogenic drugs and which will not.
For those patients who have been newly diagnosed with the life-threatening brain tumor glioblastoma, researchers say those for whom treatment with the anti-angiogenic drug cediranib quickly 'normalized' irregular blood vessels around their tumors and increased blood flow within tumors survived considerably longer than did patients in whom cediranib did not increase blood flow. The report has been featured in PNAS Early Edition.
"Two recent phase III trials of another anti-angiogenic drug, bevacizumab, 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. Our results also verify that normalization of tumor vasculature appears to be the way that anti-angiogenic drugs enhance the activity of chemotherapy and radiation treatment," said director of the Pappas Center for Neuro-Oncology at the MGH Cancer Center and co-lead and corresponding author of the current study, Tracy Batchelor, MD.
Anti-angiogenic drugs, which obstruct the action of determinants that fuel the growth of blood vessels, were first introduced for cancer treatment based on the theory that they would act by 'starving' tumors of their blood supply. Since then, however, new evidence has revelaed that the drugs' benefits come through their capability to 'normalize' the atypical, leaky vessels that typically enclose and penetrate tumors, improving delivery of both chemotherapy drugs and the oxygen that is needed for effectual radiation therapy.
This theory was first suggested and has later been expanded upon by senior author of the current study and director of the Steele Laboratory for Tumor Biology in the MGH Department of Radiation Oncology, Rakesh Jain, PhD.
A 2007 clinical study conducted and led by Batchelor uncovered evidence suggesting that cediranib, which has not yet been awarded FDA approval, could provisionally normalize tumor vasculature in recurrent glioblastoma, but it remained unclear as to what role normalization might have in patients' survival. In the past few years, several research teams under the guidance from Batchelor, Jain, and other co-authors of the current study reported evidence that cediranib on its own improved blood perfusion within recurrent glioblastoma tumors in a subset of patients and improved their overall survival.
A Nature Medicine study published earlier this year employed an approach called vessel architectural imaging (VAI), developed at the Martinos Center for Biomedical Imaging at MGH, to show that cediranib alone improved the delivery of oxygen within tumors of some patients with recurrent glioblastoma.
Patients in the current study participated in a clinical trial of cediranib along with radiation and chemotherapy for postsurgical treatment of newly diagnosed glioblastoma. Among participants in that trial, 40 also had advanced brain imaging with VAI and other MR imaging modalities. While all but one of the participants in the overall trial exhibited some evidence of vascular normalization and reduced edema, tissue swelling that can be hazardous within the brain, of the 40 who had imaging studies, only 20 were discovered to have constant improvement in vessel perfusion.
VAI also demonstrated improved oxygen delivery only in the patients with improved perfusion. Those patients managed to survive for about 9 months longer, 26 months, as opposed to 17 months, than those whose perfusion levels remained stable or worsened. A comparison group of glioblastoma patients treated with radiation and chemotherapy only survived a median of 14 months.
"It's quite likely that the results we've found with cediranib will apply to other anti-angiogenics. "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 MR imaging techniques should play an essential role in future studies of anti-angiogenic 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 MR/PET techniques at the Martinos Center's MR/PET facility," said Batchelor.
"We originally introduced the normalization hypothesis for anti-angiogenic 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," Jain added.