KEY POINTS
- This prospective, double-blind, placebo-controlled single-centre trial randomized 130 patients with brain metastases to memantine (n=66) or placebo (n=64) during and after cranial RT. Seventy-five patients received SRS and 55 received WBRT with or without hippocampal avoidance.
- Memantine was started with RT and escalated to 10 mg twice daily, continuing for six months. WBRT was generally 30 Gy in 10 fractions, while SRS regimens ranged from 20-24 Gy in one fraction to 25-30 Gy in five fractions, depending on lesion size and location.
- At six months, cognition clearly separated between groups. Mean ACE score was 83.9 with memantine versus 72.9 with placebo (p=0.005); in change-from-baseline analysis, median ACE improved by 4 points with memantine versus a 9-point decline with placebo (p<0.001).
- Cognitive preservation extended beyond the global score, with significant benefits in memory, delayed recall and verbal fluency. The HA/WBRT subgroup showed a statistically significant global treatment effect, while the SRS subgroup showed encouraging domain-specific preservation but was not powered for definitive subgroup testing.
- The SRS signal is particularly interesting because memantine has historically been studied mainly with WBRT. In the SRS subgroup, median 6-month ACE change was +4 with memantine versus -6 with placebo, although the formal global subgroup treatment-effect estimate remained underpowered and exploratory.
- Quality of life also favored memantine among six-month completers. Global health status improved by a median 33.3 points versus no change with placebo, while cognitive functioning improved by 16.7 points versus a 16.7-point decline.
- Treatment was not toxicity-free. 21% required a 50% dose reduction, appetite loss occurred in 25.7% versus 12.5%, including grade 3 events in 17.6% versus 0%, and gastric irritation occurred in 7.5% versus 0%. There was no significant difference in OS or PFS.
- The main limitation is attrition. The six-month primary analysis used available cases rather than all randomized patients, and completers had somewhat better baseline cognition than non-completers. Randomization was also not stratified by RT modality or cognitive-reserve factors, and this was a single-centre study.
CLINICAL TAKEAWAY
Memantine produced a meaningful cognitive-preservation signal after radiotherapy for brain metastases and reinforces its role alongside WBRT. The novel SRS finding is clinically provocative, particularly for longer-surviving patients, but substantial attrition and underpowered modality-specific analyses mean that routine memantine after SRS still requires independent confirmation.
SOURCE
International Journal of Radiation Oncology, Biology, Physics