Memantine in the Prevention of Radiation-Induced Brain Damage: A Narrative Review

Abstract

Preserving cognitive functions is a priority for most patients with brain metastases. Knowing the mechanisms of hyperglutamatergic neurotoxicity and the role of some hippocampal areas in cognitive decline (CD) led to testing both the antiglutamatergic pharmacological prophylaxis and hippocampal-sparing whole-brain radiotherapy (WBRT) techniques. These studies showed a relative reduction in CD four to six months after WBRT. However, the failure to achieve statistical significance in one study that tested memantine alone (RTOG 0614) led to widespread skepticism about this drug in the WBRT setting. Moreover, interest grew in the reasons for the strong patient dropout rates in the first few months after WBRT and for early CD onset. In fact, the latter can only partially be explained by subclinical tumor progression. An emerging interpretation of the (not only) cognitive impairment during and immediately after WBRT is the dysfunction of the limbic and hypothalamic system with its immune and hormonal consequences. This new understanding of WBRT-induced toxicity may represent the basis for further innovative trials. These studies should aim to: (i) evaluate in greater detail the cognitive effects and, more generally, the quality of life impairment during and immediately after WBRT; (ii) study the mechanisms producing these early effects; (iii) test in clinical studies, the modern and advanced WBRT techniques based on both hippocampal-sparing and hypothalamic-pituitary-sparing, currently evaluated only in planning studies; (iv) test new timings of antiglutamatergic drugs administration aimed at preventing not only late toxicity but also acute effects.

Neuroprotection in radiotherapy of brain metastases: A pattern-of-care analysis in Germany, Austria and Switzerland by the German Society for radiation Oncology − working group Neuro-Radio-Oncology (DEGRO AG-NRO)

“…Concerns about side effects appear to play a minor role for German-speaking ROs (3 %), compared to ROs in the US (22.4 %) [17] . Further increasing pre-clinical and clinical evidence regarding the mechanism of action of memantine may gradually alter current opinions [33] .…”

Actual, Personalized Approaches to Preserve Cognitive Functions in Brain Metastases Breast Cancer Patients

“…Memantine, an N-methyl-D-aspartate receptor antagonist, has been proved to reduce the neurocognitive dysfunctions after WBRT. Brain irradiation, especially neural stem cells of hippocampi, leads to cognitive deterioration as a result of the radiation-induced accelerated neurosclerosis, microangiopathy, and infarction [54,55]. Study of RTOG 0614 revealed that memantine as a pharmacological neuroprotector was well tolerated by patients and resulted in good neurocognitive function preservation in patients receiving WBRT with memantine compared to only WBRT at 24 weeks observation follow-up (p = 0.0041) [52].…”

The scheme, and regulative mechanism of pyroptosis, ferroptosis, and necroptosis in radiation injury

“…To mitigate radiation injury, various approaches are being explored. Radioprotective drugs like memantine 15 , vitamins 16 , amifostine 17 , 18 (NCT00040365), melatonin 19 , 20 (NCT03716583), evosk 21 , and trixiera 21 , 22 (NCT02334345) are explored. Advances in imaging and positioning techniques 23 provide a foundation for accurate RT.…”