Page 10 - Read Online

Wartena et al. J Cancer Metastasis Treat 2018;4:59 I http://dx.doi.org/10.20517/2394-4722.2018.66 Page 5 of 8

cognition using an extensive test battery including memory recall and recognition and the trail making test
(TMT) after radiotherapy treatment. The delivered radiation dose was not specified and only 30 patients with
primary brain tumours were included. Each receiving 10-30 mg of methylphenidate twice daily for as long
[13]
as the duration of the study which was not specified. Unlike Butler et al. , this study indicated a significant
improved function in psychomotor speed, memory, visual-motor function, executive function, motor speed
and dexterity.

DONEPEZIL
[11]
Donepezil is an acetylcholinesterase inhibitor and is widely studied. Rapp et al. performed a phase III
placebo-controlled trial in 198 subjects to determine whether donepezil improves cognitive function in
primary brain tumour patients and patients with brain metastases treated with partial brain irradiation or
WBRT receiving ≥ 30 Gy. Patients received 5 mg of donepezil for six weeks and 10 mg of donepezil for 18
weeks after completing their course of radiation therapy (WBRT as well as partial brain irradiation). They
found no difference in global cognition at 24 weeks. However, significant differences favouring donepezil
were observed for recognition memory and motor speed and dexterity. The authors reported that the
[15]
benefit from donepezil increased as the pre-treatment level of cognitive impairment increased. Shaw et al.
performed a phase II clinical trial to evaluate cognitive functioning in partial or WBRT for patients with
[11]
brain tumour after a 24-week donepezil treatment. Like Rapp et al. doses of 5 and 10 mg daily were used.
This study showed significant improvement in the following cognitive domains; attention/concentration,
verbal memory and figural memory with a favourable trend for donepezil for verbal fluency. However, no
[16]
[11]
change in global cognitive function was found, which is in line with the findings of Rapp et al. , Correa et al.
performed a pilot study including only 24 patients with brain tumours. Fifteen of these 24 patients received
donepezil, after completion of therapy (80% RT with or without chemotherapy, 20% received chemotherapy
[11]
[15]
only), in the same quantities as Rapp et al. and Shaw et al. . This pilot study showed a significant post-
baseline improvement in some aspects of attention; longest digit span forward, graphomotor speed, digit
symbol subtest and Brief Visuospatial Memory Test - Revised for delayed recall. Improvements in other
[17]
measurements were not conclusive or significant. Another pilot study was carried out by Castellino et al.
to assess the toxicity and efficacy of donepezil in childhood brain tumour survivors. Thirteen children were
enrolled into the study receiving a daily dose of 5 to 10 mg of donepezil (depending on the child’s weight).
The median time from radiation therapy to study enrolment was extremely long: 4.7 years. This long interval
possibly influences the effect of the donepezil treatment on cognitive sparing after cranial irradiation.
This study showed improved as well as non-improved outcomes. Memory measured with the Wide Range
Assessment of Memory and Learning scale was improved and a small effect in number/letter memory was
found. Attention and concentration showed only non-significant effects. Other outcome measures like letter
[18]
fluency and sorting tasks did not show significant improvement. Lastly, Jatoi et al. conducted a double blind,
placebo-controlled trial to test how donepezil 5 mg/day (with dose escalation to 10 mg/day after one month),
and vitamin E, would affect the cognitive function of small-cell lung cancer patients after completing PCI.
However, this study only accrued nine out of the calculated 104 patients and no results were available.

DISCUSSION
In this literature search, the neuroprotective effect of memantine, methylphenidate and donepezil was
studied in patients with primary brain tumours, brain metastases or PCI treated with partial irradiation or
WBRT. Memantine appeared to benefit cognitive outcomes after partial or WBRT, however the benefit did
not reach significance at 24 weeks. Donepezil revealed significant differences in a few cognitive tests however
the global cognition was not influenced. Methylphenidate showed indistinct results in the performed
trials. Leaving the benefits of its use during brain irradiation unanswered. Overall, it is hard to conclude
whether a possible neuroprotective agent we studied is effective in preserving cognitive function in patients
receiving brain irradiation because of three reasons: in the reported studies, patient populations differ as