Memantine in radiation-induced cognitive dysfunction in brain metastases: A double-blinded, randomized, placebo-controlled trial (CTRI/2022/01/039599).

Abstract

2036 Background: Prospective double-blinded, placebo-controlled randomized study to evaluate the role of memantine in brain metastasis (BM) in preserving cognitive function. Methods: Clinic-radiologically diagnosed of BM patients planned for radiation therapy (RT) (SRS or whole brain RT) were randomized to receive memantine or placebo (20 mg/day) over 24 weeks. Cognitive function assessed by Addenbrooke’s Cognitive Examination (ACE). Secondary outcomes included QoL, white matter volume changes (MRI T2 FLAIR), and plasma memantine levels (by LC-MS/MS). Safety was assessed using CTCAE v5.0 criteria. Results: 130 BM patients were enrolled after randomization [placebo 64 & memantine (experimental arm n = 66]. In placebo and memantine arm mean age was 56.5 & 56.7; female 39 & 40; high school education status 39 (30%) & 37 (28%); SRS in 40 (30%) & 35 (27%); frontal lobe lesion 43 (33%) & 55 (42%); PS 0-1 55 (42%) & 54 (41%) respectively. In the placebo arm, ACE scores at baseline in placebo and memantine arm 83.0 ± 10.1 and 77.7 ± 12.7 (p = 0.78) respectively. At 4 months, ACE score in placebo and memantine arm 76.2 ± 14.3 and 82.2 ± 12.7 (p = 0.04). At 6 months in placebo and memantine arm were 72.9 ± 20.2 and 83.9 ± 10.8 (p = 0.005). At 24 weeks, ACE scores change was +4.0 in memantine & -9.5 in placebo arm; p = 0.001. Memantine arm had better preservation of memory (-3 vs. -2.5, p < 0.001), delayed recall (-1 vs. -1, p < 0.001), and verbal fluency (-1 vs. 0, p = 0.007). In the SRS subgroup, ACE scores in placebo and memantine at baseline, 4 and 6 month was 83.5 (± 9.5) & 79.7 (± 12.5); 76.6 (± 14.7) & 85.3 (± 10.6); 72.5 (± 23.1) & 86.4 (± 9.5) respectively. At 24 weeks, memantine arm improved ACE scores by +4 (0 to 12) compared to placebo -8 (-15.5 to -2.5) (p < 0.001). At 24 weeks in WBRT, memantine arm sustained cognitive improvement (ACE score +3) compared to further decline in placebo (-9.5, p < 0.001). At 24 weeks, percentage change in global health status in placebo & memantine arms were -5.57%. & +63.3% respectively. 21% required dose reductions due to adverse events. Loss of appetite (25.7% vs. 12.5%, p = 0.05); gastric irritation (0 vs 7.5%; p = 0.02) were higher in memantine arm. White matter volume changes in the placebo group correlated negatively with cognitive decline (r = -0.544, p = 0.055), suggesting a potential role of edema in radiation-induced cognitive dysfunction. Memantine at a 5 mg BID dose achieved a median trough concentration of 118.06 ng/mL (IQR: 68–211), within the desirable therapeutic range (70–150 ng/mL). 10 mg BID dose trough was 172 (85-290) and peak concentration 397 (258-499 ng/mL) exceeded alert threshold of 300 ng/mL. Conclusions: Memantine preserved cognitive function and QoL in RT for BM. Cognitive benefits were more in SRS than HA/WBRT. White matter volume change was negatively correlated to cognitive outcomes. 5 mg BID dose optimally balances efficacy with tolerability. Clinical trial information: CTRI/2022/01/039599 .