Protecting Hippocampus During Whole-Brain Radiation Substantially Reduces Rate of Cognitive Decline 

Get Permission

Protecting the stem cells that reside in and around the hippocampus substantially reduces the rate of cognitive decline in patients during whole-brain radiotherapy without a significant risk of recurrence in that area of the brain, a new study shows. Results of the phase II clinical trial of patients with brain metastases were presented recently by co–principal investigator Vinai Gondhi, MD, of Central DuPage Hospital Cancer Center in Warrenville, Illinois, at the American Society for Radiation Oncology’s 55th Annual Meeting.1

“Memory loss, especially short-term recall, is an important consideration for patients receiving whole-brain radiotherapy,” said co–principal investigator, Minesh P. Mehta, MB, ChB, Professor of Radiation Oncology at the University of Maryland School of Medicine. “We found that reducing the radiation dose to the stem-cell niches surrounding the hippocampus during treatment was clearly associated with memory preservation without an inordinate risk of relapse in that portion of the brain. The findings far exceeded our expectations.”

Significant Decline in Memory Loss

Based on previous research, the predicted rate of cognitive decline at 4 months for patients receiving whole-brain radiation for brain metastases was 30%. Researchers designed the clinical trial so that a positive result would be a rate reduced by half, to 15%. The observed rate in the trial was actually 7%—significantly better than the baseline rate. With a third fewer patients to evaluate, the rate of decline observed at 6 months was 2%, although comparable data from the historic control study were not available. 

“These phase II results, while not absolutely conclusive, offer very important insights which we hope to validate in a larger, randomized phase III clinical trial,” said Dr. Mehta, who is also a radiation oncologist at the University of Maryland Marlene and Stewart Greenebaum Cancer Center and chairs the Brain Tumor Committee of the Radiation Therapy Oncology Group (RTOG).

Study Details

Patients in the study, the majority of them with lung cancer that had metastasized to the brain, were treated with intensity-modulated radiation therapy, which enabled doctors to shape the radiation beams to avoid the hippocampus. Researchers used a standardized cognitive function assessment—the Hopkins Verbal Learning Test (HVLT)—to measure patients’ baseline memory, such as their ability to recall information immediately or after a delay, with follow-up at 2, 4, and 6 months.

A total of 113 patients were recruited between 2011 and 2013; investigators were able to evaluate 42 patients at 4 months and 29 patients at 6 months. The median survival for the participants was 6.8 months. Three patients (4.5%) experienced progression of their disease in the hippocampal region, which was within the expected range.

Dr. Mehta said that the radiation affects cognitive function by damaging nerve cells as well as stem cells, which help to regenerate nerve cells that support memory formation. “These stem-cell niches are exquisitely sensitive to radiation and are involved in neurogenesis.… Although we call it hippocampal-avoidance radiotherapy, we really are targeting the stem-cell niches in and around the hippocampus,” he said.

He noted that factors other than radiation may also contribute to cognitive decline in patients with brain metastases, including medicines to control seizures or swelling in the brain. The cancer itself may also have an effect.

The research was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute. ■

Disclosure: The study authors reported no potential conflicts of interest.


1. Gondi V, Mehta MP, Pugh S, et al: Memory preservation with conformal avoidance of the hippocampus during whole-brain radiotherapy for patients with brain metastases: Primary endpoint results of RTOG 0933. American Society for Radiation Oncology 55th Annual Meeting. Abstract LBA1. Presented September 23, 2013.