Cognitive effects of androgen deprivation therapy in an older cohort of men with prostate cancer

Abstract

Objective

To determine the baseline prevalence of cognitive impairment in older men treated with ADT and to assess changes in cognitive performance over time.

Methods and results

Thirty-two patients (median age of 71 years, range 51–87) were administrated an extensive neuropsychological testing battery prior to ADT initiation, with 21 (65%) completing post-treatment evaluations 6 months later. At baseline, 45% scored >1.5 standard deviations below the mean on ≥2 neuropsychological measures. Using standardized inferential statistics, no change in cognition was documented following treatment. The Reliable Change Index revealed that, on a case-by-case basis, 38% demonstrated a decline in measures of executive functioning and 48% showed improvement on measures of visuospatial abilities. Within exploratory analyses, patients who scored below expectation at baseline displayed no change in cognition, while patients with average or better scores at baseline displayed improvements in visuospatial planning and timed tests of phonemic fluency.

Conclusions

We found a high prevalence of lower than expected cognitive performance among a sample of patients just starting ADT for prostate cancer. Assessment of baseline cognitive function should be taken into account for future research and to inform clinical management.

Introduction

Prostate cancer is currently the leading cancer diagnosis of men in the United States and is the second leading cause of male cancer-related death. The incidence of prostate cancer rapidly increases with age. Data from autopsy studies reveal that prostate cancer incidence rises from >30% in men over 50 years to 80% by age 80 [1]. With increasing life expectancy, prostate cancer will become even more prevalent over the next few decades [1].

Androgen deprivation therapy (ADT) by medical or surgical castration (i.e., LHRH agonists or orchiectomy) is commonly combined with surgery or radiation options for locally advanced or high-risk prostate cancer. In addition, androgen ablation, with or without the concurrent use of peripheral anti-androgen therapies, is the mainstay of treatment for men with systemic disease, evident either by a rising prostate specific antigen (PSA) or overt metastatic disease. ADT has an initial response rate on the order of 85% and many men sustain long-term responses on therapy. For example, in a recent cooperative group trial, 43% of patients with metastatic bone disease achieved a PSA ≤.2 ng/ml with ADT and their median survival was 75 months. These numbers are expected to be even higher in the larger group of patients in whom ADT is employed for biochemical recurrence only on the basis of controversial survival benefits [2], [3], [4].

As a result increasing attention is being paid to ADT toxicities, which include not only the highly discussed sexual dysfunction (e.g., decline in libido, difficulty initiating and maintaining erections), but also decreased bone mineral density, lean body mass and muscle strength and overall lower quality of life scores [5], [6]. More recently, the effects of ADT on cognition have been evaluated. The reported studies have used a variety of methodologies and the results have been inconsistent. Nevertheless, a review by Nelson et al. of the published literature showed that between 47% and 69% of men on ADT declined in at least 1 cognitive domain [7]. The deficits were primarily noted within visuospatial abilities and executive functioning. However, none of the reviewed studies evaluated baseline cognitive performance before attributing poor performance on cognitive tests to ADT.

Like prostate cancer, the prevalence of cognitive impairment also increases with age. It is estimated that 6–10% of people 65 years or older suffer from some form of clinically significant dementia. The prevalence increases to 25–48% in samples of community-living populations over 80 years of age [8]. The prevalence of early or mild cognitive impairment (MCI) is estimated to be even higher. In one large longitudinal study, the prevalence of dementia was 13.9%, while the prevalence of cognitive impairment without a defined dementia diagnosis was 22.2% in persons aged 71 years and over [8], [9]. It is estimated that mild cognitive impairment is associated with an increased risk for progression to dementia, with progression rates of 10–15% per year as compared with 1–2.5% in persons who are cognitively intact at initial testing [9], [10], [11], [12], [13]. Of importance to note, the definition of mild cognitive impairment remains controversial but generally includes evaluation of performance on standard neuropsychological tests, but subjective memory loss symptoms, functional status, and imaging studies [13]. The high prevalence of MCI or dementia in community-dwelling older adult population suggests that elderly patients who are initiated on ADT may have a high prevalence of baseline cognitive dysfunction and may be at risk for further deterioration with such treatment.

In the current study, we examined the neuropsychological functioning of a cohort of men diagnosed with prostrate cancer before and 6 months following ADT initiation to assess potential changes in cognitive abilities. Furthermore, we examined separately the impact of ADT on those who performed below expectation at baseline to determine if they are uniquely susceptible to ADT effects and thus may explain, in part, disparate findings in the literature.