Neurocognitive Side Effects of Brain Radiation Subside for Many, Analysis Shows

Patients with brain metastases who experienced cognitive side effects following radiation therapy often fully regain cognitive function, according to a pooled analysis of three phase III trials.

Of 288 patients who experienced neurocognitive failure after treatment, the pooled cumulative incidence of full cognitive recovery was about 38% at 6 months and 42% at 12 months, reported Hua-Ren Ryan Cherng, MD, of the University of Maryland Medical Center in Baltimore.

“Our analysis reveals that a sizeable proportion of patients experience full neurocognitive function failure reversal,” said Cherng during a session at the American Society for Radiation Oncology annual meeting in Washington, D.C. Considering the sensitivity of tests evaluating cognition, “clinically meaningful improvements in cognition are probably higher than 40%,” he added.

The findings may help counsel patients about their likelihood of meaningful cognitive improvement after radiation and underscore that neurocognitive decline is not necessarily permanent, which “has potential implications for how we think about and design clinical trials moving forward,” Cherng suggested.

During a press briefing at which Cherng presented the study’s results, discussant Lia Halasz, MD, of the University of Washington and Fred Hutchinson Cancer Center in Seattle, noted that radiation therapy “understandably … does come with some cognitive decreases, and this is very concerning to people. We all know … anecdotally that a lot of times this does pass. But we didn’t necessarily always have the data on how often it does.”

“I’m excited about this analysis because it took three cooperative group trials with many patients who were randomized to different types of radiation therapy to really figure out what is better in terms of cognitive outcomes,” she said. “I think an analysis such as this I can bring into my clinic and really help our patients understand what they may go through.”

The three randomized trials included in the analysis were NCCTG N107C/CEC.3, which compared postoperative stereotactic radiosurgery (SRS) versus whole-brain radiation therapy (WBRT) for patients with resected metastatic brain disease; NCCTG N0574, which compared SRS versus SRS plus WBRT for patients with one to three brain metastases; and NRG Oncology CC001, which compared hippocampal-avoidance WBRT plus memantine versus WBRT plus memantine for patients with brain metastases.

“The way in which these trials were set up, once you met the definition of cognitive failure you met the endpoint of the trial,” Cherng explained. “But the researchers continued to collect longitudinal testing data for these patients, so this is specifically an analysis looking at those patients who had longitudinal testing data beyond their time point of cognitive failure on these trials.”

Patients in the studies underwent a batch of cognitive tests administered before treatment and again at 6 and 12 months. Full cognitive recovery was defined as no longer exhibiting a ≥1 standard deviation (SD) decline from baseline on any cognitive test, while recovery on individual tests was defined as at least a 1-SD improvement on a previously failed test.

Longer longitudinal cognitive testing data beyond 12 months was available for 65 patients in these trials, and showed that about two-thirds were able to sustain cognitive recovery and had no evidence of neurocognitive toxicity.

When looking at cognitive recovery by trial, the cumulative incidence of full cognitive recovery was significantly greater among patients who received SRS versus WBRT in the NCCTG N107C/CEC.3 and NCCTG N0574 trials (HR 2.42, 95% CI 1.70-3.45, P<0.0001).

There was also a trend toward an increase in the cumulative incidence of full cognitive recovery among patients who received hippocampal-avoidance WBRT versus WBRT alone in the NRG Oncology CC001 trial (HR 1.56, 95% CI 0.98-2.48, P=0.061).

During a Q&A period, Cherng was asked about disease control in these patients in the context of weighing the potential benefit of therapy with its impact on cognition and quality of life.

“That is always something we are considering — how to balance neurocognitive outcomes versus intracranial brain control,” Cherng said. “Those data are reported in the primary manuscripts of these trials, but … distant brain control is always worse with more of a focal SRS approach as opposed to whole-brain radiation.”