'Practice-Changing' Study on WBRT for Patients With Brain Mets

Fran Lowry

March 09, 2020

A better way of using radiation in patients with brain metastases is now established with the publication of data from a phase 3 trial.

The trial compared whole-brain radiotherapy (WBRT) plus memantine with and without hippocampal avoidance (HA), and showed that sparing the hippocampus resulted in less deterioration of executive function, learning, and memory, as well as less fatigue.

The study was published online February 14 in the Journal of Clinical Oncology.

"This study is practice-changing," commented Joseph P. Weiner, MD, a radiation oncologist at Rutgers Cancer Institute of New Jersey, New Brunswick, who wrote an accompanying editorial.

"As radiation oncologists, brain metastases are one of the most common things we treat. So the implications of this study are very wide," he told Medscape Medical News.  

"We knew from an earlier phase 2 study that sparing the hippocampus was beneficial, but because that evidence was from a phase 2 study, insurance companies would deny coverage," he commented. "They would say get phase 3 data and then they'll approve coverage. This was going on for years, and it was terrible. As a healthcare provider, I was so frustrated, knowing that I could do better for my patients but was not allowed to," he said.

No insurance company is going to argue with these results.    Dr Joseph Weiner

"So when this paper came out, I was really excited that we finally have these data. These results confirm what we knew from the phase 2 trial, that adding hippocampal avoidance to WBRT plus memantine does benefit patients. Now that we have phase 3 data from a randomized trial, no insurance company is going to argue with these results," he said.

HA Technique "Takes Some Learning"

The multicenter phase 3 NRG CC001 trial compared WBRT with hippocampal avoidance (HA-WBRT) plus memantine (the investigational group) or WBRT plus memantine.

"Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist that blocks pathologic excessive stimulation of NMDA receptors and has been shown to be beneficial in dementia and neuroprotective in preclinical models of brain irradiation. It is now a standard of care for patients receiving WBRT," explained lead author Paul D. Brown, MD, Mayo Clinic, Rochester, Minnesota.

Mastering the HA technique takes some learning and may send radiation oncologists back to their anatomy textbooks, Brown said.

"The hippocampus is not a structure that we learn about as radiation oncologists. We do learn about it in medical school but then we don't hear much about it in the rest of our oncology training, so all of the radiation oncologists in this trial had to relearn their anatomy to be able to locate the hippocampus on imaging. My coauthor, Vinai Gondi, MD, [Northwestern Medicine Cancer Center, Warrenville, Illinois], has created an atlas that helps the radiation oncologist walk through the anatomy of the brain and make sure they can contour it correctly," he said.

HA-WBRT will become the standard of care for patients with brain metastases, provided the tumors are not in or near the hippocampus, Brown told Medscape Medical News.

The fact that HA-WBRT did not worsen the patient's condition is also encouraging, Weiner added.

"Any time we are de-escalating our treatment, as we do here with sparing the hippocampus, we need to make sure we are not causing our patients some unintended problem," he said.

"And this paper shows that we're not. Although we are not prolonging their overall survival, we are maintaining the quality of their remaining time. I think we're going to see a lot more of this being done around the country and around the world to the betterment of patients' outcomes," Weiner said.

This study has opened the door for this to become primetime treatment.    Dr Joseph Weiner

"This study validates what we thought was the right thing to do," he continued. "I have already been able to treat two patients using hippocampal avoidance. So this study has opened the door for this to become primetime treatment. It really is a practice-changing paper. And it has wide implications. It's not like some little niche tumor, this is one of the most common things we as radiation oncologists do," he said.

Study Details

The trial was conducted in 518 patients with brain metastases outside a 5-mm margin around the hippocampus. All patients were over 18 years of age, had a Karnofsky performance score of 70 or greater, and a pathologically proven diagnosis of solid tumor malignancy.

Before being randomized, each patient underwent a baseline evaluation that included a history and physical examination, neurologic examination, performance status, thin-slice MRI, and a battery of cognitive tests. They also reported their quality of life and symptom burden.

These evaluations were repeated at month 2, 4, 6, and 12.

The primary endpoint was time to cognitive function failure.

Baseline characteristics were similar between the two groups. Median age was 61.5 years (range, 20-91 years), and most patients (57.7%) had primary lung cancer.

Median follow-up was 7.9 months (range, 0-15.6 months).

Cognitive failure risk was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine.

After adjusting for variables including age, prior radiosurgery, and prior surgical resection, the adjusted hazard ratio was 0.74 (95% CI, 0.58 - 0.95; P = .02).

At 2 months, there was no difference in cognitive deterioration rates between the groups.

However, at 4 months, patients in the HA-WBRT plus memantine group had less deterioration in executive function, as measured by the Trail Making Test Part B (TMT-B) compared with patients who received WBRT plus memantine (23.3% vs 40.4%; P = .01).

They also had less deterioration in learning (11.5% vs 24.7%; P = .049) and memory (16.4% vs 33.3%; P = .02) at 6 months, as measured by the Hopkins Verbal Learning Test – Revised (HVLT-R).

Patients in the HA-WBRT plus memantine group also had less fatigue (P = .04), less difficulty remembering things (P = .01),  less difficulty speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008), and fewer cognitive symptoms (P = .01).

There were no differences in overall survival, intracranial progression-free survival, or toxicity.

The study was funded by the National Cancer Institute. Weiner and Brown have reported no relevant financial relationships.

J Clin Oncol. Published online February 14, 2020. Abstract, Editorial

For more from Medscape Oncology, join us on Twitter and Facebook.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.