Discussion
Androgen deprivation therapy is commonly used in the treatment of
locally advanced disease with combination therapies and in metastatic
prostatic cancer patients. Androgen suppressing treatments cause side
effects such as anemia, flushing, fatigue, gynecomastia, osteoporosis,
erectile dysfunction, diabetes, and cardiovascular complications. The
present study was designed to evaluate the effect of ADT on cognitive
functions in metastatic prostate cancer patients. The study used 4
cognitive tests to interpret 4 main cognitive domains: information
processing speed, verbal memory, visuospatial memory, and executive
functions. In a large, prospective study about cognitive functions in
prostate cancer patients, it has been shown that ADT has no significant
effect on cognitive function [16]. However, some studies have
demonstrated that patients show greater impairment after ADT in
visuomotor functions, visuospatial abilities, and executive functions as
compared to healthy patients [8,17]. Furthermore, studies have shown
that higher free testosterone levels are positively associated with
visuospatial function, visual memory, visuomotor scanning, and episodic
memory [18]. Some systematic reviews and meta-analyses have been
conducted regarding ADT and cognition in prostate cancer patients
[8,17,19]. Nelson et al. show that patients who receive ADT have a
deterioration in 1 or more cognitive areas (usually visuospatial skills
or executive functions), at rates of 47–69%. Jamadar et al. conclude
that spatial memory in particular may be sensitive to ADT. The largest
and most up-to-date systematic review, conducted by McGinty et al.,
evaluates 14 studies (417 patients) and 7 cognitive domains. This review
concludes that cognitive functions other than visual skills remain
largely unchanged.
Although Gonzalez et al. have reported a significant risk of cognitive
impairment with ADT, in a prospective, controlled study conducted by
Alibhai et al. in 2010, cognitive impairment is not shown in elderly men
with prostate cancer after 12 months of ADT [ 16,20]. However, one
finding of the regression analysis is that the use of ADT is associated
with worse immediate memory, working memory, and visuospatial ability,
although this is not confirmed by other analytical approaches. Alibhai
et al. have followed one patient group for 36 months to evaluate the
long-term results, again showing that there is no relationship between
the use of ADT and cognitive impairment [21].
Preclinical studies have shown that ADT can increase the risk of
dementia or Alzheimer’s disease through various mechanisms, such as
beta-amyloid accumulation in the central nervous system [22,23].
Androgens have also been associated with neuron growth and axonal
regeneration, and low testosterone levels and ADT have been shown to
increase the risk of cardiovascular and metabolic diseases [6].
Anatomical studies have shown the wide distribution of androgen
receptors in areas related to memory, emotional processing, and libido,
mainly in the hippocampus and amygdala. Neurological changes associated
with androgen deprivation occur in the same regions affected by the
age-related decline and are consistent with our knowledge of the loci of
androgen receptor expression [24]. In the population of elderly
males without prostate cancer, low levels of free testosterone have been
associated with decreased visuospatial memory and abilities, as well as
verbal memory and processing speed [25].
Marzouk et al. have investigated the relationship between 12-month ADT
and cognitive changes using the functional assessment of cancer therapy
- cognitive function (FACT-Cog) assessment tool [7]. However, data
from patient-reported outcome (PRO) measurements should be carefully
evaluated, as PROs have not been validated as a tool to assess
cognition. This is because they are subjective, based on a personal
perception of cognitive function, and can be influenced by factors such
as mood and fatigue. Objective tests remain the gold standard for
measuring cognitive function, as they allow the identification of
treatment-related cognitive problems that can affect daily life.
However, it should be kept in mind that PROs provide a useful measure of
the effect of cognitive functions on the perception and quality of life
of the patient; thus, PROs should also be used in studies [26].
In a population-based analysis, 101,089 men (15,748 with PCa receiving
ADT, 34,865 with PCa not treated with ADT, and 50,476 without cancer)
were evaluated using Medicare data linked to surveillance, epidemiology,
and end results data to assess exposure to ADT. The cognition of PCa
patients not treated with ADT and men with PCa treated with ADT were
compared. In that study, ADT was shown not to be associated with an
increased risk of cognitive impairment (hazard ratio 0.99; 95% CI
0.94–1.04) [27]. The present study included 48 patients with
metastatic prostate cancer scheduled to undergo ADT and followed them
for 6 months, testing 4 main cognitive domains: visuospatial memory,
executive functions, information processing speed, and verbal memory. To
test cognitive functions, the SDMT, CVLT, TMT, and BVMT-R tests were
chosen due to their availablility in Turkish, easy application in daily
practice, and ability to measure cognitive functions in a short time
frame (i.e., 15 min to conduct all 4 tests). In some studies examining
cognitive functions in men who underwent ADT using objective cognitive
assessment tools, impairment in verbal memory, spatial abilities, and
attention has been shown [28,29]. However, in other studies, no
significant change in cognition is observed with ADT, consistent with
our study [21,30].
Some methodological differences exist among previous studies, such as
intermittent versus continuous ADT, various methods of creating androgen
deprivation (i.e., orchiectomy, gonadotropin-releasing hormone agonists,
and other treatments), varied timing of cognitive evaluation visits, the
presence of concurrent treatments, and the characteristics of the
control groups [8,17,19]. Furthermore, some meta-analyses report
that the relationship between ADT and cognitive impairment is not
reliably confirmed [8,9].
The neuropsychological tests used in the studies in which all cognitive
areas are evaluated take about 60 min. This time period is not
practicable in daily practice; thus, it is important to evaluate the
cognitive states of patients globally in a shorter time. By contrast,
the cognitive assessment tests used in this prospective study were short
(15 min.) and easy for both the patient and the physician, the reasoning
being that they are more viable for daily practice. Developing
standardized tools for assessing cognitive impairment and making them
applicable in daily practice is thought to be important for
comprehensive monitoring of patients.