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Wartena et al. J Cancer Metastasis Treat 2018;4:59 I http://dx.doi.org/10.20517/2394-4722.2018.66 Page 7 of 8

level of cognitive functioning. Also, neurocognitive decline may be due to tumour progression or based on
neurotoxicity caused by the irradiation.

Besides, the drug administration started at different points in time. Most of the identified studies
administered the study drugs after completion of the radiation therapy, but some studies administered
[17]
the drug during the irradiation. In the trial by Castellino et al. the median time from radiotherapy to
enrolment of the study was 4.7 years (range 1.9-11.9 years) making it hard to determine whether donepezil
would have any preventive effect on neurocognitive function. Another issue is the fact that a neuroprotective
drug could interfere with the cytotoxic tumour effect of the irradiation if given concurrently.

[19]
A previously published review in 2014 by Attia et al. analysed different treatment options for radiation-
[11]
induced cognitive decline. We included two more recent articles on donepezil; Rapp et al. (2015) and
[16]
[19]
Correa et al. (2016). Attia et al. reported a statistically significant improvement after administration
[15]
of donepezil in several cognitive domains as based on the trial by Shaw et al. . These domains include
verbal memory, working memory, visual-motor and psychomotor performance and executive functioning.
[15]
Importantly, in the trial by Shaw et al. (2006) no significant change was reported in global cognitive
function or executive function.
[11]
The article on donepezil by Rapp et al. is a randomized placebo-controlled clinical trial in 198 subjects.
This study did not show a global improvement in cognitive function, but differences in a few cognitive tests
were shown.

Several trials are ongoing at the time of this literature study. One of these trials (NCT03342443) is a large (n
= 240) randomized, double-blind, placebo-controlled trial carried out by the Sun Yat-Sen Memorial Hospital
of Sun Yat-Sen University. This trial aims to determine the effect of memantine on cognitive function in
patients with radiotherapy-related cognitive impairment due to head- and neck cancer. Another large (n =
510) ongoing trial is the randomized phase III trial by NRG Oncology (NCT02360215). This trial aims to
evaluate whether memantine and WBRT with or without hippocampal avoidance in patients with brain
metastases can reduce neurocognitive decline.

CONCLUSION
In conclusion, the results of this systematic review on neurocognitive preservation in patients undergoing
brain irradiation with memantine, methylphenidate or donepezil showed heterogeneity in the selected
patients, the neurocognitive test used and the radiation treatment. Valuable clinical placebo controlled
trials on neurocognitive preservation in patients undergoing brain irradiation are sparse. The results of this
systematic review showed some evidence for the use of memantine to delay cognitive decline in patients
undergoing brain irradiation. The results for methylphenidate remain inconclusive. Donepezil did show
benefit in some domains although the global cognition was not influenced. Results from two ongoing trials
on memantine (NCT03342443 and NCT02360215) are to be awaited.

DECLARATIONS
Acknowledgements
The authors acknowledge the important input of Sanne Schagen, Division of Psychosocial Research and
Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Authors’ contributions
Data collection and extraction, data analysis, writing: Wartena R
Data analysis: Brandsma D
Data analysis, writing, editing: Belderbos J