Prostate cancer is the most common cancer in men after skin cancer.1 Circulating serum androgens, such as testosterone, promote the growth and development of prostate cancer cells. Thus, lowering levels of these hormones is a common and effective treatment strategy for many patients with this disease. It is estimated that ~50% of patients diagnosed with prostate cancer will receive androgen deprivation therapy (ADT) at some point following their initial diagnosis.2 Historically, ADT was reserved mostly for patients who had developed metastatic, incurable disease. However, it is now often utilized in earlier stages of prostate cancer, as there is a survival benefit when given in conjunction with radiation therapy.3,4
ADT is associated with a number of adverse effects including fatigue, erectile dysfunction, hot flashes, and osteoporosis.5,6 Some studies,7–9 but not others,10,11 suggest that ADT use is associated with cognitive impairment. Cognitive impairment among patients with any type of cancer may be because of a combination of biological, psychosocial, and treatment factors. Biological processes in cancer such as DNA damage, oxidative stress, and immunologic alterations share a role with the natural aging process, and may contribute to cognitive impairment seen in cancer patients. Men with prostate cancer who receive ADT have lowered testosterone levels, serving as an added factor that may precipitate them to cognitive impairment. Cancer-related cognitive impairment has a significant impact on the ability of patients to make informed choices about their treatment, and on activities of daily living and quality of life.12 The main objectives of this study were to determine, among men enrolled in the Mayo Clinic Study of Aging (MCSA): (1) the association of prostate cancer and the odds of mild cognitive impairment (MCI), and (2) whether ADT use among the prostate cancer patients was associated with odds of MCI.
This was a case-control study which included all men at their visit of enrollment into the MCSA, a prospective population-based study that began in 2004 in Olmsted County, MN.13 The study initially recruited Olmsted County residents between the ages of 70 and 89 using an age-stratified and sex-stratified random sampling design within the context of the Rochester Epidemiology Project (REP) medical records-linkage system. Since 2004, the population has been re-enumerated several times and extended to cover the ages of 50 to 90+ years following the same sampling strategy. Olmsted County residents were randomly selected from the population and were invited to participate in the MCSA. The baseline MCSA visits occurred between 2004 and 2018.
The baseline MCSA visit included a physician examination, an interview by a study coordinator, and neuropsychological testing administered by a psychometrist.14 The physician examination included a neurological examination and administration of the Short Test of Mental Status.14 Study coordinator interviews included participant demographic information, assessments of depression and anxiety, and the participant and informant Clinical Dementia Rating scale.15
The neuropsychological battery included 9 tests covering 4 domains: (1) memory (Auditory Verbal Learning Test Delayed Recall Trial,16 Wechsler Memory Scale-Revised Logical Memory II and Visual Reproduction II17); (2) language (Boston Naming Test18 and Category Fluency19); (3) executive function (Trail Making Test B20 and WAIS-R Digit Symbol subtest21); and (4) visuospatial (WAIS-R Picture Completion and Block Design subtests).21 Using the mean and SD from all participants included in this study, test scores were converted to z scores. Global cognition was calculated using the z transformed averages of the 4 cognitive domains.
For each participant, performance in a cognitive domain was compared with the age-adjusted scores of cognitively unimpaired (CU) individuals previously obtained using Mayo’s Older American Normative Studies.22 This approach relies on prior normative work and extensive experience with the measurement of cognitive abilities in an independent sample of volunteers from the same population. Participants with scores around 1.0 SD below the age-specific mean in the general population were considered for possible cognitive impairment. A final decision was made after considering education, occupation, visual or hearing deficits, and reviewing all other participant information. The diagnosis of MCI was made by a consensus agreement between the study coordinator, examining physician, and neuropsychologist using published criteria.23 The diagnosis of dementia and Alzheimer disease24 was based on published criteria. Participants who performed in the normal range and did not meet criteria for MCI or dementia were deemed CU.
A diagnosis of prostate cancer, use of ADT, and other therapies were abstracted using the REP medical records-linkage system. Nurse abstractors looked through the medical records of all MCSA participants and confirmed all cancer diagnoses. The variables collected for prostate cancer included: date of diagnosis (including recurrence, staging, and treatment type), surgery, radiation, chemotherapy, and hormonal treatment. Methods of ADT were also identified (gonadotropin-releasing hormone agonists, antiandrogens, orchiectomy, other) and length of exposure to these interventions were recorded along with time from initial ADT exposure to inclusion in MCSA.
Assessment of Covariate
Demographic variables (eg, age and education) were collected by self-report during the in-clinic examination. Medical conditions (eg, hypertension, diabetes) and the Charlson comorbidity index25 were determined for each participant by REP medical record abstraction. Participants’ blood samples were used to determine APOE genotypes.
Logistic regression was used to examine the association between prostate cancer, with and without ADT use, and odds of MCI at the baseline visit.
Multivariable models adjusted for age, education, APOE genotype, Charlson comorbidity index, anxiety, and depression. All analyses were conducted using JMP Pro 13 software.
Among the 2513 men included in this study, the mean age was 73.1 years and the mean years of education was 14.5 (Table 1). Of the 349 prostate cancer patients, 99 (28.3%) used ADT before or at their first MCSA visit. There were 382 (15.2%) participants with a diagnosis of MCI. A further description specific to participants with a history of prostate cancers and their treatment modalities is included in Table 2. Of note, the mean survival for patients with metastatic disease was 71 months with a median of 46.5. A history of prostate cancer was associated with increased odds of MCI in univariate models [odds ratio, 1.50; 95% confidence interval (CI), 1.12-2.00; Table 3]. Further, there was a modest dose response relationship with prostate cancer and ADT use in univariate analyses such that compared with men without prostate cancer, those with prostate cancer who did not have a history of ADT use had a 1.32 increased odds of MCI (95% CI, 0.94-1.86), and those with a history of ADT use had a 1.57 increased odds (95% CI, 0.96-2.58). However, the difference between these 2 groups was not significant.
All associations were greatly attenuated in multivariable models, specifically after adjusting for age (P-value for prostate cancer and ADT use >0.70; Table 4). We conducted a sensitivity analysis stratifying ADT exposure by ≤12 months or >12 months, but we still found no association with MCI in multivariable analyses.
Survival rates for prostate cancers continue to improve, resulting in an older population of men at risk of cognitive impairment. In the present study, we examined the relationship between prostate cancer and odds of MCI in the population-based MCSA, and the use of ADT. Using a case-control study design, we did not find an association between a history of prostate cancer and odds of MCI among men aged 70 and older. We also did not find an association between a history of ADT use, including the length of exposure, and odds of MCI.
The association between cancer and dementia has been controversial, with some studies showing that a history of cancer is associated with a reduced risk of dementia, whereas other studies show an increased risk or no association.26–29 Many of these studies did not examine specific cancer subtypes nor did they examine cancer in relation to MCI, a prodromal stage of dementia. In the current study, we did not find an association between a history of prostate cancer and odds of MCI among men aged 70 and older after adjusting for covariates.
Low levels of testosterone may have a negative impact on neuronal connectivity and neurotransmitter modulation, eventually leading to impairment in the executive and visuospatial functions.30 This has led to the hypothesis that prostate cancer patients using ADT medications might be at risk of cognitive impairment. However, studies examining the association between ADT use among prostate cancer patients and cognitive impairment or dementia have been equivocal, with some studies showing increased risk and others not finding an association.7–11,31–33 The conflicting results at least partly reflect the heterogeneity of study designs and cognitive endpoint definitions. The majority of studies utilized diagnostic codes and did not have objective clinical assessments that included a neuropsychological battery. In the current study, the cognitive outcome was well-defined. MCI was diagnosed after an extensive clinical evaluation, including neuropsychological testing performed as part of the MCSA. Using this protocol, we did not observe an association between ADT use among participants with a history of prostate cancer and odds of MCI. Transient changes may be possible during ADT medication use, which are subsequently improved after return of circulating testosterone. Thus, it is possible that many of the participants’ cognition improved after stopping ADT. It is also possible that the effect of ADT use on cognition is more subtle, and therefore we did not observe a difference when comparing MCI and CU participants.
Strengths of the study include the large sample size, the population-based sampling frame, and the confirmation of prostate cancer and ADT use through medical record abstraction as compared with self-report. However, limitations also warrant consideration. First, is the concern of survival bias such that those with a history of prostate cancer might have disproportionately not participated or may have died before having a chance to be included in the MCSA. Because prostate cancer often has a more indolent course than other cancers, the effect of survival bias may be less, but it is still present. Second, the MCSA originally focused on the prevalence and incidence of MCI, and therefore excluded those with a diagnosis of dementia at baseline. This eliminates the inclusion of potential participants who had a history of prostate cancer already carried a diagnosis of dementia at the time of invitation to the study, and would underestimate the true association. Future prospective studies would better alleviate survival bias by performing a prospective study beginning at the time of initial ADT exposure with regular follow-up to assess cognition. Lastly, the proposed study may not be generalizable to other, more racially and ethnically diverse, populations. However, participants enrolled in the MCSA are representative of residents of Olmsted County and of the upper Midwest.
In the current study, we did not find an association between a history of a diagnosis of prostate cancer, or use and length of ADT, and odds of MCI. However, given the limitations of this study and the conflicting evidence in the existing literature, it is important for physicians to discuss the risk and benefits of ADT with prostate cancer patients when proposing use of the effective therapy.
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