ACRIN and RTOG Research in the Spotlight
Exciting new findings lead to advances in patient care.
The annual meetings of the American Society for Radiation Oncology (ASTRO) and RSNA provide an excellent venue to showcase RTOG® and ACRIN® research.
Affiliated investigators have the opportunity to present study findings on behalf of RTOG and ACRIN research teams, which have often invested years of effort to bring the research results to fruition. Spotlighted here are examples of the practice-changing research presented at the 2012 meetings.
Memantine Delays Cognitive Dysfunction
ASTRO's 54th Annual Meeting, held October 28–31 in Boston, examined how innovation in technology and patient-care delivery can lead to improved patient outcomes. This theme set the stage for the plenary session presentation of the results of RTOG 0614 (A Randomized, Phase III, Double-Blind, Placebo-Controlled Trial of Memantine for Prevention of Cognitive Dysfunction in Patients Receiving Whole-Brain Radiotherapy). The results determined that patients who received the drug memantine during the course of whole-brain radiotherapy (WBRT) for metastatic brain tumors experienced significant overall delay in the onset of cognition-function decline. This is the first trial to evaluate the efficacy of memantine, a drug currently used in the treatment of dementia, as a neuroprotective agent from vascular injury and cognitive dysfunction caused by radiotherapy.
Trial participants receiving memantine were found to be 55 percent less likely to experience cognitive decline at six months. Nadia N. Laack, MD, the trial's modality co-chair and assistant professor of radiation oncology at the Mayo Clinic in Rochester, Minn., presented the results demonstrating that patients who received the drug had a delay in both the onset and the rate of cognitive decline as measured by multiple cognition tests administered during and up to 24 weeks after WBRT. "We believe adults receiving whole-brain radiotherapy should now receive this medication," she says.
As part of the trial, nearly 140 predominantly community-based cancer research sites enrolled 554 participants with pathologically proven solid tumor malignancy and MRI- or CT-verified brain metastases. Participants were randomized to receive memantine or placebo at the start of the three-week WBRT treatment and for 21 weeks post treatment. At weeks 8, 16, and 24 and at 12 months from treatment commencement, participants completed quality-of-life questionnaires and underwent physical and neurological examination, blood tests, MRI of the brain, and memory testing.
The results of RTOG 0614 have the potential to improve the quality of life of 10 to 30 percent of patients with cancer who develop brain metastases, a condition that appears 10 times more often than primary brain tumors each year. Improved detection and multimodality cancer treatments are thought to account for the higher rate of incidence. Paul D. Brown, MD, the principal investigator of RTOG 0614 and a professor of radiation oncology at the MD Anderson Cancer Center in Houston, Texas, is encouraged by the implications of the study results. "In addition to the confirmatory results," he explains, "no differences in toxicity or survival were found between the two arms, so we know memantine is safe to administer in this patient population and does not adversely affect treatment."
Collaboration Combats Glioblastoma
One of several ACRIN clinical trial results reported at RSNA 2012 was the product of an RTOG-ACRIN research collaboration. The ACRIN 6677 trial, an imaging sub-study of the RTOG 0625 trial (A Randomized Pahse II Trial of Bevacizumab With Irinotecan or Bevacizumab with Temozolomide in Reccurent Glioblastoma), collected standard and advanced images from patients prior to starting therapy, two weeks following treatment initiation, and thereafter every two treatment cycles. The purpose was to assess local versus central interpretation of standard images and the role of perfusion MRI and MR spectroscopy for providing insight into treatment response. This archived image collection also enabled researchers to evaluate whether standard MR imaging sequences could provide reliable prognostic information about a patient's outcome when treatment included the antiangiogenic drug bevacizumab. Assessing whether a patient's tumor is responding to a therapeutic regimen with bevacizumab has presented MRI interpretation challenges due to the drug's potential for decreasing tumor enhancement independent of tumor changes.
“Working in tandem with a treatment group proved very helpful for addressing questions of mutual interest to oncologists and radiologists and holds much promise for the science to be carried out within the future National Clinical Trials Network” — Daniel P. Barboriak, MD
"We sought to determine if disease progression as seen on MRI using post-Gd 2-D- or 3-D-T1 or fluid-attenuated inversion-recovery (FLAIR) sequences can reliably predict patient outcome," says Jerrold L. Boxerman, MD, PhD, assistant professor at the Warren Alpert Medical School at Brown University in Providence, R.I., and vice chair for brain cancer research of the ACRIN Head and Neck/Neuro Committee, who presented the results. "Our study results demonstrate that even though tumor enhancement may diminish with the use of bevacizumab, a finding of progressive enhancement on the T1-weighted images highly correlates with worse patient outcome. Knowing that a patient is not benefiting from a treatment could permit a timely switch to a clinical trial evaluating an alternate therapeutic strategy," explains Boxerman, who also reported that a similar correlation was not found between patient outcome and either improved enhancement on T1-weighted images or tumor progression on FLAIR images.
In a central review of the 123 cases carried out at the ACR Imaging Core Laboratory in Philadelphia, two radiologists with Certificate of Additional Qualification (CAQ) in neuroradiology serially measured 3-D FLAIR hyperintensity images and bi-dimensional (2-D) and volumetric (3-D) enhancement on post-Gd T1-weighted images. Progression status on all post-treatment MR images was determined using MacDonald Criteria. A third CAQ-credentialed neuroradiologist adjudicated interpretation discrepancies. The median overall survival rate, measured in days, of patients whose tumor had progressed after two cycles and four cycles of treatment (at 8 and 16 weeks, respectively) was significantly lower than that for patients whose tumor did not progress on the 2-D-T1 and 3-D-T1 images or on the FLAIR images.
"Given the widespread use of bevacizumab for treating recurrent glioblastoma, establishing a highly-predictive marker of treatment response would be extremely valuable for patient care. These study results suggest that the standard imaging techniques employed in the joint RTOG-ACRIN trial can provide important clinical information," says Daniel P. Barboriak, MD, professor of radiology at Duke University Medical Center in Durham, N.C., and chair of the ACRIN Head and Neck/Neuro Committee. "Working in tandem with a treatment group proved very helpful for addressing questions of mutual interest to oncologists and radiologists and holds much promise for the science to be carried out within future National Clinical Trials Network," adds Barboriak, co-chair of the Brain Tumor Working Group within the ECOG-ACRIN Cancer Research Group.
By Nancy Fredericks, MBA, and Julie Catagnus, MPH, ELS