People who experience side effects from cranial radiation therapy may recover full neurocognitive function within months

A substantial number of patients with brain metastases who experience cognitive side effects following radiation therapy may fully regain cognitive function, according to a pooled analysis of three large, Phase III clinical trials.

Recovery was more likely for people treated with conformal, or highly targeted, radiation techniques, compared to standard whole-brain treatment. The findings were presented at the American Society for Radiation Oncology (ASTRO) Annual Meeting.

“No longer should we be viewing cognitive dysfunction as a permanent endpoint for patients,” said Hua-Ren Ryan Cherng, MD, lead author of the study and a radiation oncology resident at the University of Maryland Medical Center in Baltimore.

“Our research finds that the cognitive side effects of radiation treatment for people with brain metastases appear to be fully reversible, and patients appear to be able to sustain that recovery over the long-term.”

An estimated 30% of all people with cancer—about 600,000 people each year—are diagnosed with brain metastases at some point in the course of their disease.

Standard treatment for brain metastases, or cancer that has spread to the brain, often includes either whole-brain radiation therapy (WBRT) or more conformal radiation techniques, which target the radiation dose more precisely to the tumor site and minimize exposure to healthy brain tissue.

Cerebral radiation therapy helps prevent the cancer from spreading further inside the brain, but patients may experience cognitive side effects, such as declines in executive function, learning and memory.

The two most common types of conformal radiation are stereotactic radiosurgery (SRS), which delivers fewer, but higher doses of radiation per treatment to the tumor site, and hippocampal avoidance WBRT, which limits radiation exposure to the parts of the brain known to contribute to neurocognitive side effects that occur following treatment. Conformal radiation techniques have been shown in previous research to cause fewer cognitive side effects than traditional WBRT.

Advances in radiation therapy, systemic therapies and other cancer treatments, as well as better imaging that detects disease earlier, have significantly extended survival times for many people whose cancer spreads to the brain. While overall survival rates vary widely among cancer types, some patients with brain metastases live for several years following treatment.

Researchers are now able to focus on a patient’s quality of life for a longer amount of time than was previously possible, Dr. Cherng said.

“There’s been a focus in the last decade on approaches to decrease or delay the cognitive side effects of cranial irradiation. We had a lot of data looking at the onset of cognitive changes, but not much data and no randomized trials looking at how these patients fare down the road after developing cognitive side effects.”

“What remained unclear were the long-term outcomes for these patients. Is this permanent, or can they recover cognitive function? People are living years longer now, and there is a growing need for knowledge on how to counsel our patients about their long-term cognitive recovery prospects.”

Cognitive recovery is “a novel concept that has not been fully defined” for these patients, he said.

To fill that gap, Dr. Cherng and his colleagues pooled retrospective data from 288 patients with long-term cognitive testing data who participated in three large, randomized Phase III clinical trials comparing WBRT to different types of conformal radiation in brain metastases.

Cognitive outcomes were the primary endpoint for all three trials. Two of the trials were conducted by the North Central Cancer Trials Group (N107C and N0574) and compared WBRT to SRS; the third, from NRG Oncology (CC001), compared standard WBRT to WBRT with hippocampal avoidance.

To measure cognitive recovery, researchers analyzed results from a battery of cognitive tests administered to the patients before treatment and again at six and 12 months after the onset of neurocognitive function loss.

Six months following the first signs of cognitive decline, 38% of patients experienced full cognitive recovery, rising to 42% of patients at one year. Cognitive recovery was defined as a patient no longer having a significant decrease from baseline cognition scores on every cognitive test.

In other words, Dr. Cherng said, patients had to have a complete absence of cognitive failure after initial neurocognitive toxicity to meet the requirements of full cognitive recovery.

And although not all patients made a full recovery, roughly three-fourths recovered at least some lost cognitive function. Six months after treatment, 73% demonstrated improvement on one or more cognitive tests, rising to 76% at 12 months. Among the subset of patients who continued cognitive testing for two years of follow-up (n=65), two-thirds demonstrated sustained cognitive recovery.

“That’s a staggering amount,” said Dr. Cherng, who added that these findings will be useful in counseling patients with brain metastases as they consider treatment options.

“Our data suggest these side effects are not necessarily permanent but potentially reversible. We were able to define this novel concept of cognitive recovery, and we saw that a sizable portion of patients, after experiencing cognitive side effects, actually got better,” he said. “And not just better but fully recovered, showing no evidence of any lingering decline according to their cognitive testing.”

Patients treated with conformal radiation techniques were significantly more likely to demonstrate full cognitive recovery. The cumulative incidence of full cognitive recovery was higher among patients who received SRS compared to WBRT (HR 2.68, p=0.002) and those who received SRS alone compared to SRS with WBRT (HR 2.35, p=0.008).

There was also a nearly significant trend toward greater likelihood of cognitive recovery among people who received WBRT with hippocampal avoidance, compared to people who received WBRT alone (HR 1.57, p=0.059).

“These data show that what sounds good in theory is being borne out with more conformal types of radiation therapy. Not only do these techniques potentially help delay the onset of cognitive changes, but, downstream from treatment, the conformal techniques yielded a higher prevalence of cognitive recovery,” Dr. Cherng said.