Research Update

RTOG® reveals next steps to optimize radiation therapy.research update

Participants at the American Society of Clinical Oncology 2013 Annual Meeting received updates on scientific questions investigated by RTOG®-sponsored research involving advances in the science underlying radiation oncology.

Among the 13 RTOG presentations was a plenary session report of the highly anticipated primary aim results of RTOG 0825, a phase-III trial evaluating the use of anti-angiogenic therapy with frontline chemoradiation for glioblastoma. Three other related analyses of the trial's secondary and tertiary aim results were presented in other oral abstract sessions

The Role of Anti-Angiogenic Targeted Therapy

RTOG 0825, a phase-III double-blind placebo-controlled trial evaluating bevacizumab in patients with newly diagnosed glioblastoma, was designed to test the primary hypothesis that "anti-angiogenic targeted therapies would normalize the tumor's rapidly forming and underdeveloped blood vessels, resulting in improved oxygen and chemotherapy delivery to the tumor and potentially enhancing radiotherapy and chemotherapy treatment," according to Mark R. Gilbert, MD, professor of neuro-oncology at the University of Texas MD Anderson Cancer Center in Houston, who led the trial. The multicenter trial enrolled 637 participants, all of whom received standard RT (60 Gy) and daily temozolomide. Beginning at week four of RT, participants were randomized to receive bevacizumab or placebo every two weeks until disease progression, severe treatment-related toxicity, or completion of adjuvant therapy. Unblinding of the experimental arm at the time of disease progression allowed for follow-on treatment with or without bevacizumab.

Data analysis performed in May 2011, 18 months after completion of enrollment, found no statistical difference in overall survival (OS) between the experimental and standard study arms (16.1 months versus 15.7 months, respectively). Although there was a difference in progression-free survival (PFS) between the experimental and standard arms (10.7 months versus 7.3 months, respectively), the established level of benefit for PFS was not reached. In clarifying the relevant result, Gilbert states, "The upfront use of bevacizumab does not prolong survival. We now know that by administering bevacizumab later rather than earlier in treatment, you avoid the risk of toxicity, and that may be relevant."

Molecular Predictors of Outcome and Response

A secondary objective of the trial was to determine whether the tumor molecular profile would be associated with increased OS or PFS from the addition of bevacizumab. Toward that end, study participants were stratified equally across study arms by prognostic molecular markers of tumor O6 methylguanine-DNA methyltransferase methylation status and a tumor-based 9-gene assay. Erick P. Sulman, MD, PhD, from the University of Texas MD Anderson Cancer Center, reported that no subgroup of participants surviving longer with first-line administration of bevacizumab was revealed by the analysis.

Patient-Reported Outcomes

Terri S. Armstrong, PhD, ANP-BC, from the University of Texas Health Science Center, and co-principal investigator for the trial's quality of life (QOL) component, presented the analysis on the impact of treatment on patient-reported outcomes in the trial's two arms. Analysis of QOL and brain tumor symptom questionnaires completed at baseline and at weeks 10, 22, and 34 by randomized participants with continued PFS revealed more deterioration in symptoms and QOL in the bevacizumab arm compared with the placebo arm, with persistent significant differences in treatment-associated symptoms. Questionnaire-identified symptoms occurring at baseline and at week 10 were prognostic for OS and PFS.

Neurocognitive Function Outcomes

Jeffrey S. Wefel, PhD, ABPP, from the University of Texas MD Anderson Cancer Center, reported on the analysis of tests of verbal learning, memory, processing speed, executive function, and verbal fluency completed by participants at baseline and at weeks 10, 22, and 34. Mean test performance at baseline was equivalent between study arms, and there were no statistically significant between-arm differences in frequency of improvement through week 34. Neurocognitive function test performances at baseline and at week 10 were prognostic for OS and PFS.

Trial Impact

"Study participants' consent allowing the collection of tumor tissue and blood samples, as well as imaging examination, longitudinal symptom, QOL, and neurocognitive function data provides RTOG investigators a rich archive of data to support ongoing investigations of potential molecular markers to identify subgroups of patients who may benefit from early bevacizumab," says study Co-principal Investigator Minesh P. Mehta, MD, chair of the RTOG Brain Tumor Committee and a radiation oncologist at the University of Maryland Marlense and Stewart Greenebaum Cancer Center.

"I congratulate the entire RTOG 0825 team on the design of an innovative trial that has provided important insight about the use of anti-angiogenic therapies with standard front-line treatment and on the unprecedented collection of specimens and associated outcome data that will continue to provide significant future information. I also thank our Eastern Cooperative Oncology Group and the North Central Cancer Treatment Group colleagues for their trial support," says Walter J. Curran, RTOG chair and executive director of the Winship Cancer Center at Emory University in Atlanta.

By Nancy Fredericks, MBA, and Julie Catagnus, MSW, ELS

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