Results of the Phase II clinical trial of patients with brain metastases presented today at the American Society for Radiation Oncology (ASTRO) annual meeting shows the benefits of protecting the stem cells that reside in and around the hippocampus. The hippocampus is a C-shaped area in the temporal lobe on both sides of the brain associated with the ability to form and store memories. Protecting the hippocampus substantially reduces the rate of cancer patients’ memory loss during whole-brain radiotherapy without a significant risk of recurrence in that area of the brain.

“Memory loss, especially short-term recall, is an important consideration for patients receiving whole-brain radiotherapy,” explained the study’s co-principal investigator, Minesh P. Mehta, M.B., Ch.B., 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.”

[The result of] reducing the radiation dose to the stem-cell niches surrounding the hippocampus… far exceeded our expectations.

Based on previous research, the predicted rate of cognitive decline at four months for patients receiving whole-brain radiation for brain metastases was 30%. Researchers designed this clinical trial, which was supported by RTOG grants from the National Cancer Institute (NCI), in such a way that a positive result would be a rate of cognitive decline reduced by half – to 15%. The observed rate in the trial was actually 7%. This was significantly better than the baseline rate of 30%. With a third fewer patients to evaluate, the rate of decline observed at six months was 2%. However, comparable data from the historic control study were not available.


Important insights
“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,” Mehta, a radiation oncologist at the University of Maryland Marlene and Stewart Greenebaum Cancer Center who chairs the Radiation Therapy Oncology Group (RTOG) brain tumor committee, noted. The RTOG, which managed the Phase II trial, also plans to manage the Phase III Study.

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Mehta’s co-principal investigator, Vinai Gondi, M.D., will present the findings at the plenary session at the ASTRO annual meeting in Atlanta. Gondi practices at Central DuPage Hospital Cancer Center in Warrenville, Ill.

Commenting on the study, Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and Dean of the University of Maryland School of Medicine, said, “Preserving neurocognitive function is extremely important in treating patients with brain metastases, and the results of this latest study on hippocampal-avoidance radiotherapy led by Mehta are very encouraging. This technique, if validated in a randomized clinical trial, will give physicians a significant new tool to help maintain patients’ quality of life while aggressively treating their cancer.”

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

Between 2011 and 2013 a total of 113 patients were recruited to participate in this study. Investigators were able to evaluate 42 patients at four months and 29 patients at six 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.

Hippocampal-avoidance radiotherapy
Mehta noted that the radiation affects cognitive function by damaging nerve cells as well as stem-cells. These stem-cells are designed to help to regenerate nerve cells that support memory formation. “These [stem-cell] niches are exquisitely sensitive to radiation and are involved in neurogenesis ? the process of generating new neurons, or nerve cells. Although we call it hippocampal-avoidance radiotherapy, we really are targeting the stem-cell niches in and around the hippocampus,” Mehta explained.

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

For more information:
Educational Session 413:Difficult Cases in CNS
Date: September 25, 2013
Time: 1:00 p.m. – 2:30 p.m.
Location: Georgia World Congress Center
Room Number: B405
Track: Central Nervous System

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