Stereotactic radiosurgery (SRS) for cancer patients with four to 15 brain metastases staved off cognitive decline better than conventional whole-brain radiation therapy (WBRT), while yielding similar survival outcomes, a randomized trial found.
For the primary endpoint of memory function at 4 months, patients in the SRS group had an average z-score increase of 0.21 from baseline (standard deviation [SD] 1.15) on the Hopkins Verbal Learning Test-Revised Total Recall, as compared to a decline of 0.74 (SD 1.31) in the WBRT-treated group (P=0.041), reported Jing Li, MD, PhD, of MD Anderson Cancer Center in Houston.
Statistically significant and clinically meaningful advantages in memory function for SRS were seen as well at 1 month and 6 months, she said during a press briefing for the virtual American Society for Radiation Oncology (ASTRO) annual meeting.
With a median follow-up of 6.6 months, overall survival in the intent-to-treat population was not significantly different, at 7.8 months (95% CI 6.1-14.6) in the SRS arm compared with 8.9 months (95% CI 6.4-26.4) in the WBRT arm (P=0.59), though multiple patients in each arm received SRS or WBRT off protocol.
Phase III trials have established SRS as the standard of care in patients with up to three brain metastases, replacing WBRT due to better preservation of cognitive function and similar overall survival, said Li, but many patients present with four or more lesions. With increasing numbers, microscopic tumor burden becomes a concern, which cannot be addressed by SRS.
“There’s controversy over whether stereotactic radiation should be used for a patient who has numerous metastases in the brain,” said press briefing moderator Sue Yom, MD, PhD, of the University of California San Francisco. “This study showed clearly improved results on neurocognitive testing in those patients who had stereotactic radiation instead of conventional whole-brain radiation therapy.”
From 2012 to 2019, the phase III trial randomized 72 patients 1:1 with four to 15 brain metastases (median 8 at baseline) to SRS or WBRT. Most patients in the study were white (83%), about half were 60 years or older, and 58% were women.
Patients with up to 20 lesions at the time of treatment were allowed to stay on trial. All patients underwent detailed cognitive testing at baseline and at each follow-up for up to 1 year. Tests examined patients’ memory, learning, verbal fluency, executive function, attention, processing speed, and fine motor skills.
Use of memantine (Namenda), a dementia drug that helps preserve cognitive function, was encouraged in the control arm based on findings from RTOG 0614 — 62% received the NMDA receptor antagonist.
The study was stopped early, however, following results of the phase III NRG-CC001 trial, which showed that in patients receiving WBRT along with memantine, avoiding radiation to the hippocampus preserved patients’ cognitive function without detriment to survival. A phase III trial, CCTG CE.7, will directly compare SRS against WBRT plus memantine in patients with five to 15 brain metastases
Still, said Yom, “a lot of places aren’t using memantine or hippocampal sparing yet, so I would still say that the [current] study has really high relevance for the current standard practice today, which is typical whole-brain radiation therapy.”
Li noted that far more patients in the WBRT arm experienced a clinically meaningful decline in cognitive function (50% vs 6% with SRS).
Patients on SRS also had improved mean z-scores compared with WBRT at 1, 4, and 6 months on the Clinical Trial Battery Composite, which combines six cognitive function tests:
- 1 month: median -0.12 vs -0.71 (P=0.024)
- 4 months: median 0.28 vs -0.57 (P=0.004)
- 6 months: median 0.31 vs -0.16 (P=0.027)
Four-month local control rates were 95% with SRS versus 87% with WBRT (P=0.79), while distant brain control rates were 60% and 80%, respectively (P=0.37). Patients on SRS went on to systemic therapy a median 1.7 weeks after treatment versus 4.1 weeks with WBRT (P=0.001).
“Although it’s true that the stereotactic patients may have had more relapses occur in the untreated areas of the brain, they lived as long … with better neurocognitive function than the patients who got conventional radiation,” said Yom.
“Stereotactic treatment allowed those patients to resume their other treatments, such as chemotherapy or their systemic therapies, more promptly without an extended interruption,” she added.
Grade ≥3 toxicities occurred in 8% of patients in the SRS arm compared to 15% with WBRT, with radiation necrosis occurring in 17% of patients on SRS (4% per lesion).
Li reported research funding from Bristol Myers Squibb and Medtronic, and honoraria from Novocure and Monteris.