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Memantine may help prevent cognitive decline after brain radiation
Lisa K. Lohr
Cognitive decline is one of the potential adverse effects of cranial radiation therapy in cancer patients.
It can be manifested by poor memory, psychomotor slowing, poor decision making and dementia.
Factors that influence cognitive decline include radiation-specific factors (total radiation dose, fractionation and volume of brain radiated), as well as tumor progression, comorbidities, chemotherapy and other medications.
Medications to reduce this cognitive decline, such as methylphenidate hydrochloride (Ritalin, Novartis) and donepezil (Aricept, Eisai), have been studied in small groups of patients.
Preservation of cognitive function
A recent abstract outlined a study of memantine hydrochloride (Namenda, Forest Labs) in the prevention of cognitive dysfunction in patients who receive whole-brain radiation treatment (WBRT).
In that study, Brown and colleagues conducted a randomized, double blind assessment of memantine vs. placebo in 508 patients who received WBRT for brain metastases. Radiation doses of 37.5 Gy were administered in 15 fractions. Memantine was administered at a dose of 20 mg orally daily, beginning within 3 days of that start of WBRT.
Investigators used standardized tests to assess cognitive function domains such as memory, processing speed, executive function, global function, self-report of cognitive function and quality of life at baseline, as well as at 8, 16, 24 and 52 weeks. Memory decline, assessed with the Hopkins Verbal Learning Test-Revised delayed recall evaluation (HVLT-R DR), served as the primary outcome.
This study revealed that patients treated with memantine showed a significantly longer time to cognitive decline. In addition, there was less cognitive decline in the memantine arm as measured by the HVLT-R DR. The relative risk of cognitive decline was reduced by 17%, and this was maintained even after memantine was discontinued.
In addition, fewer memantine-treated patients showed decline in other standardized tests of cognitive function, such as cognition, executive and global function and processing speed.
Researchers observed no difference in OS, PFS, or rates of grade 3 and 4 adverse effects between the two arms.
The investigators concluded that memantine helps to preserve cognitive function in patients treated with WBRT for brain metastases.
Mechanism of action
Memantine is approved for the treatment of Alzheimer’s dementia, and it also is used in patients with vascular dementia.
Memantine is thought to work by mitigating the neuronal loss caused by overstimulation of the N-methyl-D-aspartate (NMDA) receptor, which allows processes that lead to neuronal loss. Memantine is a NMDA receptor antagonist that has a longer binding time than magnesium, which does not bind well during states of pathologic overactivation of the receptor.
It is well absorbed orally and rapidly crosses the blood-brain barrier. It is eliminated partially by the liver and partially in the urine as unchanged drug. The terminal half-life is long at 60 to 80 hours, and it is somewhat longer in patients with severe renal impairment. Memantine is not metabolized by the hepatic CYP enzymes.
The target dose of memantine is 10 mg orally twice daily for the treatment of Alzheimer’s dementia. To reduce adverse effects, it is often started at a dose of 5 mg daily and increased by 5 mg every week to the target dose. The dose should be capped at 5 mg orally twice daily for patients with severe renal impairment (creatinine clearance, 5 mL/min-29 mL/min). It is available as tablets of 5 mg and 10 mg, as well as an oral solution.
Memantine is generally well tolerated. In studies of patients with Alzheimer’s disease, the most common adverse effects were dizziness, headache, constipation, somnolence, hypertension, vomiting and abnormal gait. The incidence of all of these reported adverse effects was less than 10%.
There are fewer potential drug interactions with memantine. Some agents may decrease the renal excretion of memantine. These include carbonic anhydrase inhibitors, sodium bicarbonate, trimethoprim, quinidine, ranitidine, hydrochlorothiazide, nicotine and cimetidine. The blood levels of both memantine and these other agents may be increased.
Conclusion
Cognitive decline from WBRT can have serious consequences for the quality of life for the patient. Memantine has been shown in this trial to reduce and delay this cognitive dysfunction.
Memantine has few serious adverse effects and generally is well tolerated, and it may have a role in preserving the quality of life for patients who receive WBRT for brain metastases.
References:
Brown PD. Abstract #1. Presented at: ASTRO Annual Meeting; Oct. 28-31, 2012; Boston.
Robinson DM. Drugs. 2006;66:1515-1534.
For more information:
Lisa K. Lohr, PharmD, BCPS, BCOP, is a clinical pharmacy specialist and oncology medication therapy management provider at the University of Minnesota Physicians Cancer Care at Fairview in Minneapolis. She also is a HemOnc Today Editorial Board member. She may be reached at the University of Minnesota Physicians Cancer Care at Fairview, 424 Harvard St. SE (MMC 114), Minneapolis, MN 55455.
Disclosure: Lohr reports no relevant financial disclosures.