A substantial number of patients with brain metastases who experience cognitive side effects after radiation therapy may fully regain cognitive function, according to recent findings presented by Cherng et al at the 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting (Abstract 150). The study results suggested that patients treated with conformal radiation techniques were most likely to achieve neurocognitive recovery compared with those treated with standard whole-brain treatment.
Background
An estimated 30% of all patients with cancer—about 600,000 per year—are diagnosed with brain metastases during the course of their disease. Standard treatment of brain metastases typically includes either whole-brain radiation therapy or more conformal radiation techniques that target the radiation dose more precisely to the tumor site and minimize exposure to healthy brain tissue. Although cerebral radiation therapy helps prevent the cancer from spreading further inside the brain, 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, which delivers fewer but higher doses of radiation per treatment to the tumor site, and hippocampal avoidance whole-brain radiation therapy, 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 whole-brain radiation therapy.
Advances in radiation therapy, systemic therapies, and other cancer treatments—as well as better imaging to detect disease earlier—have effectively extended survival times in patients with brain metastases. Although overall survival rates may vary widely among cancer types, some patients with brain metastases can survive for several years after treatment.
“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?” stressed lead study author Hua-Ren Ryan Cherng, MD, a radiation oncology resident at the University of Maryland Medical Center. “[Patients] 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 [in these patients]. No longer should we be viewing cognitive dysfunction as a permanent endpoint for patients,” he continued.
Study Methods and Results
In the recent pooled analysis, investigators examined the long-term cognitive testing data of 288 patients who participated in three large, randomized phase III clinical trials comparing whole-brain radiation therapy with different types of conformal radiation in brain metastases. Two of the trials—conducted by the North Central Cancer Trials Group (N107C and N0574)—compared whole-brain radiation therapy with stereotactic radiosurgery; the third trial, conducted by NRG Oncology (CC001), compared standard whole-brain radiation therapy with hippocampal avoidance whole-brain radiation therapy. Cognitive outcomes were the primary endpoint of all three trials.
To measure cognitive recovery, the investigators analyzed the results from a large number of cognitive tests administered to the patients prior to treatment and again at 6 and 12 months after the onset of neurocognitive function loss. They found that at 6 months and 12 months following the first signs of cognitive decline, 38% and 42% of the patients experienced full cognitive recovery, respectively. Cognitive recovery was defined as a patient no longer having a significant decrease from baseline cognition scores on every cognitive test. This required the patients to have a complete absence of cognitive failure following initial neurocognitive toxicity to meet the criteria for full cognitive recovery.
Even though not all of the patients made a full recovery, about 75% of them recovered at least some lost cognitive function. At 6 months after treatment, 73% of them demonstrated improvement on one or more cognitive tests, and 76% of them showed improvement at 12 months. Among the subset of patients (n = 65) who continued cognitive testing for 2 years of follow-up, approximately 67% of them demonstrated sustained cognitive recovery.
“That’s a staggering amount,” emphasized Dr. Cherng. “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—and not just better but fully recovered, showing no evidence of any lingering decline according to their cognitive testing,” he detailed.
The 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 the patients who received stereotactic radiosurgery compared with whole-brain radiation therapy (hazard ratio [HR] = 2.68, P = .002) and those who received stereotactic radiosurgery alone compared with stereotactic radiosurgery plus whole-brain radiation therapy (hazard ratio [HR] = 2.35, P = .008). There was also a nearly statistically significant trend toward greater likelihood of cognitive recovery among the patients who received hippocampal avoidance whole-brain radiation therapy compared with those who received whole-brain radiation therapy alone (HR = 1.57, P = .059).
Conclusions
The investigators suggested that the findings could be useful in counseling patients with brain metastases as they consider treatment options.
“Our research finds that the cognitive side effects of radiation treatment for [patients] with brain metastases appear to be fully reversible, and patients appear to be able to sustain that recovery over the long term,” Dr. Cherng highlighted. “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,” he concluded.
Disclosure: The research in this study was supported by a grant from the National Cancer Institute. For full disclosures of the study authors, visit astro2024.eventscribe.net.
