Cognitive effects of androgen deprivation therapy in an older cohort of men with prostate cancer☆
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.
Section snippets
Methods
This investigation reports an analysis of a longitudinal pilot study evaluating the potential neurocognitive effects of ADT in an older prostate cancer population. The study, conducted at the University of Chicago Hospitals, was approved by the Institutional Review Board and all patients provided written informed consent.
Results
A total of 32 subjects were recruited with a median age of 71.0 and a median of 15 years of education (Table 1). Twenty-one patients completed the second 6-month evaluation. The most common reason for not completing the second assessment was unwillingness to participate due to long time commitment (60%), loss to follow-up (20%), and funding or administrative issues (15%). One patient died due to a comorbid illness prior to the second assessment.
Seventy-five percent of patients were over the age
Discussion
Prostate cancer is highly prevalent in older men. ADT is commonly utilized for these men in combination with other therapies for localized disease and long-term for systemic disease. In the present study, we examined the cognitive functioning of patients with recently diagnosed prostate cancer prior to ADT and again 6 months later. At baseline, prior to initiation of treatment, over half of our sample displayed memory impairment (e.g., >1.5 standard deviations below the normative mean on the
Reviewers
Shabbir M.H. Alibhai, MD, MSc, Staff Physician, University Health Network, Medicine, Room EN 14-214, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
Heather J. Green, Ph.D., Lecturer in Clinical Psychology, Griffith University, School of Psychology, Griffith University Gold Coast Campus, Gold Coast, QLD 4222, Australia.
Conflict of interest statement
The authors report no conflict of interests in the writing of this manuscript.
Acknowledgments
The authors did not have any writing assistance. Funding sources include the American Society of Clinical Oncology Young Investigator Award and the Hartford Geriatrics Health Outcomes Scholar Award to Supriya Mohile. Study sponsors had no role in the writing of the manuscript and in the decision to submit the manuscript for publication.
Supriya Gupta Mohile, M.D., M.S. is a geriatric oncologist whose research focuses on the quality of life and health outcomes of vulnerable and frail older adults with cancer. She is an Assistant Professor at the University of Rochester's James Wilmost Cancer Center and was the recipient of an American Society of Clinical Oncology Young Investigator Award and a Hartford Geriatrics Health Outcomes Research Award. Her clinical expertise focuses on the care of older patients with genitourinary and
References (35)
- et al.
Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy
Lancet Oncol
(2006) - et al.
Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study
J Urol
(1998) - et al.
Alzheimer's disease and mild cognitive impairment
Neurol Clin
(2007) - et al.
Reliable change scores and their relation to perceived change in memory: implications for the diagnosis of mild cognitive impairment
Arch Clin Neuropsychol
(2006) - et al.
Chemotherapy in advanced prostate cancer
Semin Oncol
(1996) - et al.
Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin
N Engl J Med
(1997) - et al.
Risks versus benefits of testosterone therapy in elderly men
Drugs Aging
(1999) - et al.
Long-term effects of androgen deprivation therapy in prostate cancer patients
Clin Endocrinol (Oxf)
(2002) - et al.
Cognitive effects of hormone therapy in men with prostate cancer: a review
Cancer
(2008) - et al.
Prevalence of dementia in the United States: the aging, demographics, and memory study
Neuroepidemiology
(2007)
Prevalence of cognitive impairment without dementia in the United States
Ann Intern Med
Mild cognitive impairment as a diagnostic entity
J Intern Med
Mild cognitive impairment: current research and clinical implications
Semin Neurol
Current concepts in mild cognitive impairment
Arch Neurol
The relation of the trail making test to organic brain damage
J Consult Psychol
Practice effect and test–retest reliability of attentional and executive tests in middle-aged to elderly subjects
Clin Neuropsychol
Rey Complex Figure Test and Recognition Trial
Professional Manual
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Supriya Gupta Mohile, M.D., M.S. is a geriatric oncologist whose research focuses on the quality of life and health outcomes of vulnerable and frail older adults with cancer. She is an Assistant Professor at the University of Rochester's James Wilmost Cancer Center and was the recipient of an American Society of Clinical Oncology Young Investigator Award and a Hartford Geriatrics Health Outcomes Research Award. Her clinical expertise focuses on the care of older patients with genitourinary and gastrointestinal malignancies.
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This article was originally published in the Journal of Geriatric Oncology 2010;1:13–9. This article is republished with kind permission from the Journal of Geriatric Oncology.