Use of an intensity-modulated radiotherapy (IMRT) technique that avoids radiation dose to the hippocampus during whole-brain radiotherapy appears to safeguard patients’ memory, according to results of a single-arm, phase II Radiation Therapy Oncology Group (RTOG) Community Clinical Oncology Program (CCOP) trial presented today at the American Society for Radiation Oncology (ASTRO) 55th Annual Meeting. Study participants with brain metastases in whom the hippocampal region was avoided during whole-brain radiotherapy (HA-WBRT) had, on average, a 7 percent memory score decline at 4 months post-treatment as measured by the Delayed Recall scale of the Hopkins Verbal Learning Test (HVLT). In comparison, a historical control group of patients with brain metastases who underwent conventional WBRT without avoiding the hippocampus had a 30 percent memory score decline.

“Although we expected to observe some benefit, we were surprised and excited by the results suggesting that, by minimizing radiation dose to the hippocampus during WBRT, patient memory function can essentially be preserved,” says Vinai Gondi, M.D., co-director of the Cadence Health Brain Tumor Center, associate research director at the Cadence Health Proton Center, and co-principal investigator (co-PI) for the RTOG 0933 trial, who presented the trial results. Gondi reported that a 7 percent memory decline score is within the standard error of measurement for the HVLT Delayed Recall scale, suggesting that HA-WBRT had minimal impact on patients’ memory. By 6 months post-treatment, study participants’ memory score decline was 2 percent, on average. 

“Radiation oncologists often face the dilemma of weighing the therapeutic benefits of whole-brain radiotherapy against the treatment’s known side effects,” says Gondi. He cites, as an example, the use of WBRT for patients with multiple brain metastases and the associated memory loss that clearly impacts their quality of life. “Preclinical and clinical evidence has suggested that the dose of radiation received by the hippocampus during WBRT may play a role in radiation-induced cognitive decline. That led us to investigate if employing a hippocampal avoidance technique with IMRT would achieve the therapeutic benefits of whole brain radiotherapy while still preserving memory function,” explains Gondi.

In addition to testing the technique’s efficacy, the trial presented the opportunity to carry out a rigorous educational program to confirm a site’s HA-WBRT treatment planning competency prior to enrolling a patient on to the trial. RTOG 0933 also included a rapid central review of all treatment plans prior to the start of treatment to ensure adherence to the specified HA-WBRT technique. “The educational component was critical.  Should the trial results have been negative, we would be left wondering if it was due to poor technique. The educational efforts also helped to demonstrate that the technique could be successfully performed in a community-based setting where the majority of patients receive care,” says Deborah W. Bruner, R.N., Ph.D., FAAN, Principal Investigator of the RTOG CCOP Research Base and associate director of outcomes at the Winship Cancer Institute of Emory University in Atlanta. Bruner pointed to the rapid successful completion of the trial.  More than 80 RTOG-affiliated sites were credentialed and 113 physicians certified to participate in the trial, which accrued 113 study participants (15 percent at CCOP sites) in approximately 19 months.

“Highlighting the significance of the hippocampus as a cognitive-specific anatomic structure for memory function and confirming its sensitivity to radiotherapy, this trial presents important considerations for the delivery of radiation to the brain for other indications. The strong positive results also confirm that the next step is to conduct a phase III trial to obtain Level 1 evidence, and that’s where we’re headed,” says study Co-PI Minesh Mehta, M.D., chair of the RTOG Brain Tumor Committee, a professor of radiation oncology at the University of Maryland School of Medicine, and a radiation oncologist at the University of Maryland Marlene and Stewart Greenebaum Cancer Center.

“The RTOG 0933 trial team is to be congratulated on this achievement that involved innovation in both science and the development of a model for ensuring success of clinical trials incorporating a new radiotherapy technique,” says Walter J. Curran, Jr, M.D., RTOG Group Chairman and Executive Director of the Winship Cancer Institute.