The risk for neurocognitive decline as an adverse effect of whole- brain radiotherapy (WBRT) is significantly reduced by using a hippocampal sparing technique and the neuroprotective agent memantine (multiple brands), say researchers reporting results from a phase 3 trial.
The hippocampal sparing technique should now be a standard of care for patients who require WBRT, said an expert not involved in the trial when the results were presented here at the American Society for Radiation Oncology (ASTRO) 2018.
"Quality of life for patients with brain metastases can be largely driven by their cognitive function," lead author Vinai Gondi, MD, Northwestern Medicine Cancer Center, Warrenville, Illinois, told Medscape Medical News.
"And we've come to understand that WBRT can significantly impact that cognitive function outcome as well as the quality of life associated with it," he added.
"So we have sought within energy oncology to try to identify safer approaches to treating patients with WBRT, first by establishing that memantine can be a very effective neuroprotective agent, and now with this study establishing that hippocampal avoidance using technological approaches of IMRT [intensity-modulated radiotherapy] can also provide very meaningful improvements," Gondi explained.
Study Details
The NRG Oncology CC001 trial stratified adult patients with brain metastases by recursive partitioning analysis of prognostic factors and by whether or not they had previously undergone radiosurgery or surgical resection.
"Patients were randomized to memantine and WBRT [at a dose of] 30 Gy in 10 fractions vs memantine plus WBRT plus hippocampal avoidance, WBRT again given at a dose of 30 Gy in 10 fractions," Gondi reported.
The primary endpoint was time to cognitive function failure, as assessed using a battery of cognitive tests. Cognitive function failure was defined as a decline in scores on any one of the battery of cognitive tests used, he added.
A total of 518 patients participated in the trial. There were no differences between treatment arms in age, sex, race, education level, primary tumor site, performance status, or neurologic symptoms at baseline.
Failure Rates at 6 Months
At 6 months, cognitive function failure rates were 24% lower in the hippocampal avoidance arm, at 59.5%, than in the control arm, at 68.2% (unadjusted hazard ratio [HR], 0.76; P =.03), Gondi reported.
"Cognitive function failure curves began to separate at 3 months and were maintained through the follow-up period for a median follow-up of 7.9 months for alive patients," Gondi added.
After adjustsment for treatment factors and age, the additional use of hippocampal avoidance techniques led to a 26% relative risk reduction in cognitive failure compared with WBRT plus memantine, Gondi noted (HR, 0.74).
Hippocampal avoidance was equally effective for patients aged 61 years and younger and 61 years and older.
"We showed that conformal avoidance of the hippocampal dentate gyrus using IMRT during WBRT plus memantine preserves cognitive function in patients with brain metastases with no difference in toxicity, intracranial progression-free survival rates, or overall survival," Gondi said.
These results contribute significantly to the evolving debate over WBRT.Dr Vinai Gondi
"And these results contribute significantly to the evolving debate over whether WBRT and/or radiosurgery should be used in the management of patients with brain metastases, since prior trials of radiosurgery with or without WBRT did not include cognitive protection strategies, including memantine or hippocampal avoidance," he concluded.
Gondi commented that it is important to take into account the neuroprotective effect of the combination of memantine, a neuroprotective agent used in the treatment of Alzheimer's disease, and the hippocampal-sparing radiation techniques.
For example, a previous study showed that the use of memantine reduced the risk for cognitive toxicity during WBRT by 22% (HR, 0.78) compared to WBRT alone.
That trial established use of memantine as standard of care during WBRT.
In the current study, hippocampal avoidance in conjunction with use of memantine during WBRT led to an additional 26% relative risk reduction of cognitive toxicity compared to WBRT and memantine alone (HR, 0.74).
"Thus, the combined benefit of both strategies can be estimated by the product of these HRs for a 42% relative risk reduction in cognitive toxicity compared with WBRT alone, which is comparable to contemporary trials favoring radiosurgery over WBRT," Gondi emphasized.
Common WBRT Effects
Discussant Christina Tsien, MD, Washington University in St. Louis, Missouri, told delegates that among the most common effects seen after WBRT are short-term memory loss and deficits in executive function and attention.
However, it is the late, progressive cognitive decline that is life-changing for patients who survive long enough after WBRT, Tsien emphasized.
"Since there are no effective treatments for these losses, this is a badly needed trial," she said.
She and Gondi both emphasized that the hippocampus is a highly radiosensitive structure, so by sparing the hippocampus during WBRT, "we probably delay or reduce some of the short-term memory loss as well as the long-term effects we see with WBRT on its own," she observed.
Patients who might benefit from hippocampal sparing techniques must be candidates for WBRT and have a good performance status. In addition, the patient's expected survival must be at least 4 months, both speakers pointed out.
"The benefits of this new approach have to be weighed against potential protection of microscopic disease in this area," Tsien cautioned.
"But the key thing here is that we really need to improve outcomes in patients with brain metastases," she said.
"And in patients who require WBRT, hippocampal sparing should be considered standard of care," Tsien concluded.
Dr Gondi has a partnership in Radiation Oncology Consultants, Ltd. Dr Tsien has received honoraria and travel expenses from Merck and speaker's bureau fees from Varian.
American Society for Radiation Oncology (ASTRO) 2018. Abstract LBA9, presented October 23, 2018.
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