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Page 6 of 8 Wartena et al. J Cancer Metastasis Treat 2018;4:59 I http://dx.doi.org/10.20517/2394-4722.2018.66

well as the radiation treatment they have received and the neurocognitive tests varied which makes the
exact difference between the three agents hard to determine. Another difficulty is that disease regression
or progression interferes with neurocognitive improvement or deterioration. Our literature study identified
eight papers of three studied agents. For memantine the evidence for delaying neurocognitive decline found
in a single randomized trial that examined the effect of memantine on cognition in patients with brain
metastases treated with WBRT was not statistically significant, although there was a trend that approached
significance (P = 0.059; 35% statistical power). However, the secondary endpoints showed that memantine
deferred the time to cognitive decline and also reduced the rate of this decline significantly. So on the long
term, memantine could be beneficial for patients with brain tumours or brain metastases. Methylphenidate
showed positive results for cognitive preservation in a small group of brain tumour patients undergoing
brain irradiation. However, no advantage on MMSE was found in a double blind randomized trial between
patients receiving methylphenidate and patients receiving placebo. Methylphenidate was studied in two
[13]
[14]
clinical trials by Butler et al. and Meyers et al. . The results were conflicting and the endpoints of the
[14]
[13]
trials were different. Butler et al. used the MMSE whereas Meyers et al. used multiple, more sensitive
[13]
cognitive tests. Butler et al. found no advantage for prophylactic use of methylphenidate using the MMSE.
The study was prematurely closed because of slow accrual, a high dropout rate and an interim analysis which
[14]
did not show an effect for methylphenidate. Meyers et al. studied the use of methylphenidate on 30 brain
tumour patients and found a significant improvement in the following cognitive domains; psychomotor
speed, memory, visual-motor function, executive function, motor speed and dexterity. Besides the small
sample size an important limitation of this study is the lack of long-term follow up. As a result, the observed
[11]
differences could have been no more than just the result of chance findings. Rapp et al. conducted a
placebo-controlled clinical trial in 198 brain tumour patients on cognition after the use of donepezil at
24 weeks. The improvement in cognitive function using multiple well-validated cognitive test-batteries
occurred in both the donepezil-group and in the placebo-group. This means that there is an anti-tumour
effect due to the irradiation and therefore improvement in cognitive function in both treatment arms. This
trial emphasises the importance of a placebo-controlled trial to answer the question of neuroprotection.
Without a placebo control group, an effect of the anti-cancer treatment on neurocognition could not be
distinguished from an improvement due to the neuroprotective effects of the studied drug. Lastly, since the
study was carried out in two academic medical centres (Wake Forest University Baptist Medical Centre and
MD Anderson Cancer Centre), geographic diversity of the study population was achieved.

[15]
[11]
In accordance to the study by Rapp et al. , the study by Shaw et al. showed significant improvement
in attention/concentration, verbal memory and figural memory and a trend toward significance for verbal
[11]
fluency. However, their study population was small and only MMSE was used. Unlike Rapp et al. , the
[15]
study by Shaw et al. clearly lacked a control-group.
[17]
[16]
The pilot studies carried out by Correa et al. and Castellino et al. lacked a placebo-control group
and both included extremely small study populations of respectively 24 and 13 subjects. The study by
[18]
[17]
Castellino et al. included only childhood subjects, aged 8-17 years. Jatoi et al. reported on a prematurely
stopped trial after only nine patients were included and results are not available.
There are several limitations to our study. There has been heterogeneity in the selected patients: patients
with primary as well as secondary brain tumours have been included. Besides, the type of radiation
therapy differed: four out of eight studies included patients receiving partial and WBRT whereas one study
[16]
included patients receiving WBRT and one study included patients only treated with PCI. Correa et al.
[14]
even included patients receiving concurrent chemotherapy. Meyers et al. did not specify the type of
irradiation used. In addition, the delivered radiation dose was not specified in four trials. Furthermore,
there is no consensus on the optimal neurocognitive test battery to be used. In some trials only the MMSE
was used. The HVLT-test was most commonly used, but no standard test was applied to determine the