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1.  Management of complications of androgen deprivation therapy in the older man☆ 
Prostate cancer is the most common malignancy in older men. With the aging of the population, the number of older men with prostate cancer will grow rapidly. Androgen deprivation therapy (ADT) is the mainstay of treatment for men with systemic disease and is increasingly utilized as primary therapy or in combination with other therapies for localized disease. Side effects of therapy are multifold and include hot flashes, osteoporosis, and adverse psychological and metabolic effects. Recent research has illustrated that ADT can negatively impact the functional, cognitive, and physical performance of older men. Patients with prostate cancer, despite recurrence of the disease, have a long life expectancy and may be subjected to the side effects of ADT for many years. This review highlights the complications of ADT and approaches to management. We also provide recommendations for assessment and management of ADT complications among the most vulnerable and frail older male patients.
doi:10.1016/j.critrevonc.2008.09.004
PMCID: PMC3074615  PMID: 18952456
Disability; Geriatric assessment; Prostate cancer; Vulnerable elders; Functional impairment; Androgen deprivation; Quality of life; Complications
2.  Obese frailty, physical performance deficits, and falls in older men with biochemical recurrence of prostate cancer on androgen deprivation therapy: a case-control study 
Urology  2011;77(4):934-940.
Objectives
Early androgen deprivation therapy (ADT) has no proven survival advantage in older men with biochemical recurrence (BCR) of prostate cancer (PCa), and it may contribute to geriatric frailty; we tested this hypothesis.
Methods
We conducted a case-control study of men aged 60+ with BCR on ADT (n=63) versus PCa survivors without recurrence (n=71). Frailty prevalence, “obese” frailty, Short Physical Performance Battery (SPPB) scores and falls were compared. An exploratory analysis of frailty biomarkers (CRP, ESR, hemoglobin, albumin, and total cholesterol) was performed. Summary statistics, univariate and multivariate regression analyses were conducted.
Results
More patients on ADT were obese (BMI >30; 46.2% vs. 20.6%; p=0.03). There were no statistical differences in SPPB (p=0.41) or frailty (p=0.20). Using a proposed “obese” frailty criteria, 8.7% in ADT group were frail and 56.5% were “prefrail”, compared with 2.9% and 48.8% of controls (p=0.02). Falls in the last year were higher in ADT group (14.3% vs. 2.8%; p=0.02). In analyses controlling for age, clinical characteristics, and comorbidities, the ADT group trended toward significance for “obese” frailty (p = 0.14) and falls (OR = 4.74, p = 0.11). Comorbidity significantly increased the likelihood of “obese” frailty (p=0.01) and falls (OR 2.02, p = 0.01).
Conclusions
Men with BCR on ADT are frailer using proposed modified “obese” frailty criteria. They may have lower performance status and more falls. A larger, prospective trial is necessary to establish a causal link between ADT use and progression of frailty and disability.
doi:10.1016/j.urology.2010.11.024
PMCID: PMC3074039  PMID: 21269665
prostate cancer; biochemical recurrence; androgen deprivation therapy; frailty; older adults
3.  Muscle function, physical performance and body composition changes in men with prostate cancer undergoing androgen deprivation therapy 
Asian Journal of Andrology  2012;14(2):204-221.
Prostate cancer (PCa) is the most common visceral malignancy in men with androgen deprivation therapy (ADT) the preferred therapy to suppress testosterone production and hence tumor growth. Despite its effectiveness in lowering testosterone, ADT is associated with side effects including loss of muscle mass, diminished muscle strength, decrements in physical performance, earlier fatigue and declining quality of life. This review reports a survey of the literature with a focus on changes in muscle strength, physical function and body composition, due to short-term and long-term ADT. Studies in these areas are sparse, especially well-controlled, prospective randomized trials. Cross-sectional and longitudinal data (up to 2 years) for men with PCa treated with ADT as well as patients with PCa not receiving ADT and age-matched healthy men are presented when available. Based on limited longitudinal data, the adverse effects of ADT on muscle function, physical performance and body composition occur shortly after the onset of ADT and tend to persist and worsen over time. Exercise training is a safe and effective intervention for mitigating these changes and initial guidelines for exercise program design for men with PCa have been published by the American College of Sports Medicine. Disparities in study duration, types of studies and other patient-specific variables such as time since diagnosis, cancer stage and comorbidities may all affect an understanding of the influence of ADT on health, physical performance and mortality.
doi:10.1038/aja.2011.104
PMCID: PMC3735097  PMID: 22367184
androgen deprivation therapy; androgen suppression; exercise prescription; exercise training; functional assessment; lean body mass; older men; prostate cancer
4.  Changes in neuronal activation patterns in response to androgen deprivation therapy: a pilot study 
BMC Cancer  2010;10:1.
Background
A common treatment option for men with prostate cancer is androgen deprivation therapy (ADT). However, men undergoing ADT may experience physical side effects, changes in quality of life and sometimes psychiatric and cognitive side effects.
Methods
In this study, hormone naïve patients without evidence of metastases with a rising PSA were treated with nine months of ADT. Functional magnetic resonance imaging (fMRI) of the brain during three visuospatial tasks was performed at baseline prior to treatment and after nine months of ADT in five subjects. Seven healthy control patients, underwent neuroimaging at the same time intervals.
Results
ADT patients showed reduced, task-related BOLD-fMRI activation during treatment that was not observed in control subjects. Reduction in activation in right parietal-occipital regions from baseline was observed during recall of the spatial location of objects and mental rotation.
Conclusions
Findings, while preliminary, suggest that ADT reduces task-related neural activation in brain regions that are involved in mental rotation and accurate recall of spatial information.
doi:10.1186/1471-2407-10-1
PMCID: PMC2824708  PMID: 20047689
5.  Functional Correlates of Lower Cognitive Test Scores in Essential Tremor 
Background
Although motor features have been the defining element of essential tremor (ET), lower neurocognitive test scores are increasingly being recognized. However, the clinical correlates, if any, of these lower test scores remain largely unexplored.
Objective
To determine whether cognitive test scores in ET have any functional correlates.
Methods
The Modified Mini Mental Status Examination (MMSE), Katz Activities of Daily Living (ADL) scale and Lawton Instrumental (I) ADL scale were administered to 95 cases.
Results
The Katz ADL score (rho = 0.26, p = 0.01) and Lawton IADL score (rho = 0.32, p = 0.001) were correlated with MMSE scores, such that poorer cognitive performance indicated greater dysfunction. Furthermore, cognitive test scores were a better predictor of functional disability than was tremor severity.
Conclusions
Poorer cognitive performance in ET was associated with greater functional deficit. Cognition should enter the clinical dialogue with ET patients as an issue of clinical significance.
doi:10.1002/mds.22920
PMCID: PMC2847294  PMID: 20108374
essential tremor; cognition; dementia; mini mental status; functional disability; epidemiology; Alzheimer’s disease
6.  Effects of recreational soccer in men with prostate cancer undergoing androgen deprivation therapy: study protocol for the ‘FC Prostate’ randomized controlled trial 
BMC Cancer  2013;13:595.
Background
Androgen deprivation therapy (ADT) is a cornerstone in the treatment of advanced prostate cancer. Adverse musculoskeletal and cardiovascular effects of ADT are widely reported and investigations into the potential of exercise to ameliorate the effects of treatment are warranted. The ‘Football Club (FC) Prostate’ study is a randomized trial comparing the effects of soccer training with standard treatment approaches on body composition, cardiovascular function, physical function parameters, glucose tolerance, bone health, and patient-reported outcomes in men undergoing ADT for prostate cancer.
Methods/Design
Using a single-center randomized controlled design, 80 men with histologically confirmed locally advanced or disseminated prostate cancer undergoing ADT for 6 months or more at The Copenhagen University Hospital will be enrolled on this trial. After baseline assessments eligible participants will be randomly assigned to a soccer training group or a control group receiving usual care. The soccer intervention will consist of 12 weeks of training 2–3 times/week for 45–60 min after which the assessment protocol will be repeated. Soccer training will then continue bi-weekly for an additional 20 weeks at the end of which all measures will be repeated to allow for additional analyses of long-term effects. The primary endpoint is changes in lean body mass from baseline to 12 weeks assessed by dual X-ray absorptiometry scan. Secondary endpoints include changes of cardiovascular, metabolic, and physical function parameters, as well as markers of bone metabolism and patient-reported outcomes.
Discussion
The FC Prostate trial will assess the safety and efficacy of a novel soccer-training approach to cancer rehabilitation on a number of clinically important health outcomes in men with advanced prostate cancer during ADT. The results may pave the way for innovative, community-based interventions in the approach to treating prostate cancer.
Trial registration
ClinicalTrials.gov: NCT01711892
doi:10.1186/1471-2407-13-595
PMCID: PMC3867428  PMID: 24330570
Prostate cancer; Androgen deprivation therapy; Physical exercise; Soccer training; Rehabilitation; Body composition; Cardiovascular function
7.  Predictors of mortality and short-term physical and cognitive dependence in critically ill persons 75 years and older: a prospective cohort study 
Background
The purpose of this study was to identify predictors of 3-month mortality in critically ill older persons under medical care and to assess the clinical impact of an ICU stay on physical and cognitive dependence and subjective health status in survivors.
Methods
We conducted a prospective observational cohort study including all older persons 75 years and older consecutively admitted into ICU during a one-year period, except those admitted after cardiac arrest, All patients were followed for 3 months or until death. Comorbidities were assessed using the Charlson index and physical dependence was evaluated using the Katz index of Activity of Daily Living (ADL). Cognitive dependence was determined by a score based on the individual components of the Lawton index of Daily Living and subjective health status was evaluated using the Nottingham Health Profile (NHP) score.
Results
One hundred patients were included in the analysis. The mean age was 79.3 ± 3.4 years. The median Charlson index was 6 [IQR, 4 to 7] and the mean ADL and cognitive scores were 5.4 ± 1.1 and 1.2 ± 1.4, respectively, corresponding to a population with a high level of comorbidities but low physical and cognitive dependence. Mortality was 61/100 (61%) at 3 months. In multivariate analysis only comorbidities assessed by the Charlson index [Adjusted Odds Ratio, 1.6; 95% CI, 1.2-2.2; p < 0.003] and the number of organ failures assessed by the SOFA score [Adjusted Odds Ratio, 2.5; 95% CI, 1.1-5.2; p < 0.02] were independently associated with 3-month mortality. All 22 patients needing renal support after Day 3 died. Compared with pre-admission, physical (p = 0.04), and cognitive (p = 0.62) dependence in survivors had changed very little at 3 months. In addition, the mean NHP score was 213.1 ± 132.8 at 3 months, suggesting an acceptable perception of their quality of life.
Conclusions
In a selected population of non surgical patients 75 years and older, admission into the ICU is associated with a 3-month survival rate of 38% with little impact on physical and cognitive dependence and subjective health status. Nevertheless, a high comorbidity level (ie, Charlson index), multi-organ failure, and the need for extra-renal support at the early phase of intensive care could be considered as predictors of death.
doi:10.1186/1477-7525-9-35
PMCID: PMC3112374  PMID: 21575208
older persons; intensive care unit; mortality; functional autonomy; quality of life
8.  Kinetics of testosterone recovery in clinically localized prostate cancer patients treated with radical prostatectomy and subsequent short-term adjuvant androgen deprivation therapy 
Asian Journal of Andrology  2013;15(4):466-470.
Androgen deprivation therapy (ADT) is a standard treatment for metastatic, recurrent and locally advanced prostate cancer (PCa). The aim of this study is to investigate the timing and extent of testosterone recovery in clinically localized PCa patients treated with radical prostatectomy (RP) and subsequent short-term adjuvant ADT. A total of 95 localized PCa patients underwent RP and 9-month adjuvant ADT were included in this prospective study. Serum testosterone level was measured before adjuvant ADT, at ADT cessation, and at 1, 3, 6, 9 and 12 months after cessation of ADT. A Cox proportional hazards model was used to assess variables associated with the time of testosterone normalization. The results showed that median patient age was 67 years and median testosterone level before adjuvant ADT was 361 (230–905) ng dl−1. All patients finished 9-month adjuvant ADT and achieved castrate testosterone level. At 3 months after ADT cessation, testosterone recovered to supracastrate level in 97.9% patients and to normal level in 36.9% patients. The percentage of patients who recovered to normal testosterone level increased to 66.3%, 86.3% and 92.6% at 6, 9 and 12 months, respectively. Cox regression model found that higher baseline testosterone level (≥300 ng dl−1) was the only variable associated with a shorter time to testosterone normalization (hazard ratio: 1.98; P = 0.012). In conclusion, in most patients, testosterone recovered to supracastrate level at 3 months and to normal level at 12 months after 9-month adjuvant ADT cessation. Patients with higher baseline testosterone level need shorter time of testosterone normalization.
doi:10.1038/aja.2012.169
PMCID: PMC3739223  PMID: 23708460
androgen deprivation therapy (ADT); luteinizing hormone-releasing hormone; prostatic neoplasms; recovery of function; testosterone
9.  Effects of androgen deprivation on brain function in prostate cancer patients – a prospective observational cohort analysis 
BMC Cancer  2012;12:371.
Background
Despite a lack of consensus regarding effectiveness, androgen deprivation therapy (ADT) is a common treatment for non-metastatic, low-risk prostate cancer. To examine a particular clinical concern regarding the possible impact of ADT on cognition, the current study combined neuropsychological testing with functional magnetic resonance imaging (fMRI) to assess both brain activation during cognitive performance as well as the integrity of brain connectivity.
Methods
In a prospective observational cohort analysis of men with non-metastatic prostate cancer at a Veterans Affairs medical center, patients receiving ADT were compared with patients not receiving ADT at baseline and at 6 months. Assessments included fMRI, the N-back task (for working memory), the stop-signal task (for cognitive control), and a quality of life questionnaire.
Results
Among 36 patients enrolled (18 in each group), 30 completed study evaluations (15 in each group); 5 withdrew participation and 1 died. Results for the N-back task, stop-signal task, and quality of life were similar at 6 months vs. baseline in each group. In contrast, statistically significant associations were found between ADT use (vs. non use) and decreased medial prefrontal cortical activation during cognitive control, as well as decreased connectivity between the medial prefrontal cortex and other regions involved with cognitive control.
Conclusions
Although ADT for 6 months did not affect selected tests of cognitive function, brain activations during cognitive control and functional brain connectivity were impaired on fMRI. The long-term clinical implications of these changes are not known and warrant future study.
doi:10.1186/1471-2407-12-371
PMCID: PMC3502584  PMID: 22925152
Androgen deprivation; Prostate cancer; Brain function; Cognitive function
10.  A randomised controlled trial to evaluate the efficacy of a 6 month dietary and physical activity intervention for prostate cancer patients receiving androgen deprivation therapy 
Trials  2010;11:86.
Background
Treatment with Androgen Deprivation Therapy (ADT) for prostate cancer is associated with changes in body composition including increased fat and decreased lean mass; increased fatigue, and a reduction in quality of life. No study to date has evaluated the effect of dietary and physical activity modification on the side-effects related to ADT. The aim of this study is to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer survivors receiving ADT to minimise the changes in body composition, fatigue and quality of life, typically associated with ADT.
Methods
Men are recruited to this study if their treatment plan is to receive ADT for at least 6 months. Men who are randomised to the intervention arm receive a home-based tailored intervention to meet the following guidelines a) ≥ 5 servings vegetables and fruits/day; b) 30%-35% of total energy from fat, and < 10% energy from saturated fat/day; c) 10% of energy from polyunsaturated fat/day; d) limited consumption of processed meats; e) 25-35 gm of fibre/day; f) alcoholic drinks ≤ 28 units/week; g) limited intake of foods high in salt and/or sugar. They are also encouraged to include at least 30 minutes of brisk walking, 5 or more days per week. The primary outcomes are change in body composition, fatigue and quality of life scores. Secondary outcomes include dietary intake, physical activity and perceived stress. Baseline information collected includes: socio-economic status, treatment duration, perceived social support and health status, family history of cancer, co-morbidities, medication and supplement use, barriers to change, and readiness to change their health behaviour. Data for the primary and secondary outcomes will be collected at baseline, 3 and 6 months from 47 intervention and 47 control patients.
Discussion
The results of this study will provide detailed information on diet and physical activity levels in prostate cancer patients treated with ADT and will test the feasibility and efficacy of a diet and physical activity intervention which could provide essential information to develop guidelines for prostate cancer patients to minimise the side effects related to ADT.
Trial registration
ISRCTN trial number ISCRTN75282423
doi:10.1186/1745-6215-11-86
PMCID: PMC2925820  PMID: 20704726
11.  The relation between age and androgen deprivation therapy use among men in the Medicare population receiving radiation therapy for prostate cancer 
Objectives
Neoadjuvant and concurrent androgen deprivation therapy (ncADT) is recommended for men with high-risk prostate cancer, but not low-risk cancer or short life expectancy. It is unclear whether the use of ncADT among older men in the community setting is aligned with the potential for clinical benefit.
Materials and methods
We used the Surveillance, Epidemiology, and End Results-Medicare database to assess patterns of ncADT use among men diagnosed with prostate cancer during 2004–2007 who received radiation therapy. Men were stratified according to tumor risk groups and life expectancy. We used logistic regression to identify factors associated with ncADT use within each risk group.
Results
There were 10,686 men in the sample (mean age 74.2 years; 83.4% white). The use of ncADT was 80.7%, 54.1%, and 27.8% in the high-, intermediate-, and low-risk groups, respectively. Men with life expectancy <5 years had higher rates of ncADT use than men with life expectancy ≥10 years in all risk groups. Within each risk group, advancing age was associated with higher likelihood of receiving of ncADT (odds ratio for men aged 80–84 compared to 67–69 = 1.93 (95% CI 1.37–2.70); 1.51 (95% CI 1.22–1.87); and 1.71 (95% CI 1.14–2.57) for high-, intermediate-, and low-risk groups, respectively).
Conclusion
ncADT use is not consistent with guideline recommendations and is more frequent among men who are older, have shorter life expectancy, and are less likely to benefit from therapy.
doi:10.1016/j.jgo.2012.08.007
PMCID: PMC3591488  PMID: 23482846
Prostate cancer; androgen deprivation therapy; elderly; life expectancy; guidelines
12.  Body composition changes during androgen deprivation therapy for prostate cancer: A 2-year prospective study 
Background
Little is known about the long-term impact of androgen deprivation therapy (ADT) on body composition in men with prostate cancer. We compared body composition parameters in men with non-metastatic prostate cancer on or not on therapy with healthy, age-matched controls at baseline and monitored changes over a 2-year period.
Methods
We measured body fat mass and lean body mass in 81 men with prostate cancer on no ADT, 43 men on acute ADT (less than 6 months), 67 men on chronic ADT (more than 6 months) and 53 age-matched healthy controls. Measurements were performed every 6 months for 2 years.
Results
Men with prostate cancer on acute ADT (mean 3 months) had significant gains in body fat mass [1499.56 ± 322.28 g (mean ± S.E.) after 12 months, 2167.15 ± 676.45 g after 24 months, p < 0.01 for both] and losses in lean body mass (929.74 ± 296.36 g after 12 months, 1785.81 ± 501.31 g after 24 months, p < 0.01 for both) over 2 years. Men on chronic ADT (mean 31 months) had smaller but still significant body composition changes over 24 months. Changes in body composition in men on no ADT were small and healthy controls had no significant changes.
Conclusions
Men with prostate cancer on ADT have significant gains in body fat mass and losses lean body mass over 2 years. These changes are most pronounced with initiation of ADT.
doi:10.1016/j.critrevonc.2008.06.006
PMCID: PMC2826163  PMID: 18706829
Prostate cancer; Androgen deprivation therapy; Body composition; Dual-energy X-ray absorptiometry
13.  Evaluating the Utility of Existing Patient-Reported Outcome Scales in Novel Patient Populations with Pancreatic Cancer, Lung Cancer, and Myeloproliferative Neoplasms Using Medicare Current Beneficiary Survey Data 
The Patient  2013;6:189-200.
Background
While there are validated patient-reported outcomes (PRO) instruments for use in specific cancer populations, no validated general instruments exist for use in conditions common to multiple cancers, such as muscle wasting and consequent physical disability. The Medicare Current Beneficiary Survey (MCBS), a survey in a nationally representative sample of Medicare beneficiaries, includes items from three well known scales with general applicability to cancer patients: Katz activities of daily living (ADL), Rosow–Breslau instrumental ADL (IADL), and a subset of physical performance items from the Nagi scale.
Objective
This study evaluated properties of the Katz ADL, Rosow–Breslau IADL, and a subset of the Nagi scale in patients with pancreatic cancer, lung cancer, and myeloproliferative neoplasms (MPN) using data from MCBS linked with Medicare claims in order to understand the potential utility of the three scales in these populations; understanding patient-perceived significance was not in scope.
Methods
The study cohorts included Medicare beneficiaries aged ≥65 years as of 1 January of the year of their first cancer diagnosis with one or more health assessments in a community setting in the MCBS Access to Care data from 1991 to 2009. Beneficiaries had at least two diagnoses in de-identified Medicare claims data linked to the MCBS for one of the following cancers: pancreatic, lung, or MPN. The Katz ADL, Rosow–Breslau IADL, and Nagi scales were calculated to assess physical functioning over time from cancer diagnosis. Psychometric properties for each scale in each cohort were evaluated by testing for internal consistency, test–retest reliability, and responsiveness by comparing differences in mean scale scores over time as cancer progresses, and differences in mean scale scores before and after hospitalization (for lung cancer cohort).
Results
The study cohorts included 90 patients with pancreatic cancer, 863 with lung cancer, and 135 with MPN. Among each cancer cohort, the Katz ADL, Rosow–Breslau IADL, and Nagi scales had acceptable internal consistency (Cronbach’s alpha generally between 0.70 and 0.90) and test–retest reliability for consecutive surveys before diagnosis and consecutive surveys after diagnosis (when patients’ functioning was more stable). Compared with mean scale scores at the survey 1–2 years before cancer diagnosis (baseline), mean scale scores at the first survey after cancer diagnosis were significantly higher (P < 0.05), indicating worsening, for Katz ADL, Rosow–Breslau IADL, and Nagi scales (items scored 0–1) (0.54 vs. 1.45, 1.15 vs. 2.20, and 2.29 vs. 3.08, respectively, for pancreatic cancer; 0.73 vs. 1.24, 1.29 vs. 2.01, and 2.41 vs. 2.85 for lung cancer; and 0.44 vs. 0.86, 0.87 vs. 1.36, and 1.87 vs. 2.32 for MPN). Among lung cancer patients, scale scores increased significantly following a hospitalization, suggesting a worsening of functional status.
Conclusions
The Katz ADL, Rosow–Breslau IADL, and Nagi scales collected in the MCBS demonstrate acceptable internal consistency and test–retest reliability among patients with pancreatic cancer, lung cancer, and MPN, and are consistent with clinical worsening following diagnosis or hospitalization. These results suggest that using retrospective data may allow researchers to conduct preliminary assessments of existing PRO instruments in new populations of interest and generate useful exploratory disease information before embarking on de novo PRO development.
doi:10.1007/s40271-013-0018-z
PMCID: PMC3751268  PMID: 23828691
14.  Strength Training Induces Muscle Hypertrophy and Functional Gains in Black Prostate Cancer Patients Despite Androgen Deprivation Therapy 
Background.
Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with weakness, fatigue, sarcopenia, and reduced quality of life (QoL). Black men have a higher incidence and mortality from PCa than Caucasians. We hypothesized that despite ADT, strength training (ST) would increase muscle power and size, thereby improving body composition, physical function, fatigue levels, and QoL in older black men with PCa.
Methods.
Muscle mass, power, strength, endurance, physical function, fatigue perception, and QoL were measured in 17 black men with PCa on ADT before and after 12 weeks of ST. Within-group differences were determined using t tests and regression models.
Results.
ST significantly increased total body muscle mass (2.7%), thigh muscle volume (6.4%), power (17%), and strength (28%). There were significant increases in functional performance (20%), muscle endurance (110%), and QoL scores (7%) and decreases in fatigue perception (38%). Improved muscle function was associated with higher functional performance (R 2 = 0.54) and lower fatigue perception (R 2 = 0.37), and both were associated with improved QoL (R 2 = 0.45), whereas fatigue perception tended to be associated with muscle endurance (R 2 = 0.37).
Conclusions.
ST elicits muscle hypertrophy even in the absence of testosterone and is effective in counteracting the adverse functional consequences of ADT in older black men with PCa. These improvements are associated with reduced fatigue perception, enhanced physical performance, and improved QoL. Thus, ST may be a safe and well-tolerated therapy to prevent the loss of muscle mass, strength, and power commonly observed during ADT.
doi:10.1093/gerona/gls206
PMCID: PMC3593619  PMID: 23089339
15.  Sarcopenia During Androgen-Deprivation Therapy for Prostate Cancer 
Journal of Clinical Oncology  2012;30(26):3271-3276.
Purpose
To characterize changes in lean body mass (LBM) in men with prostate cancer receiving androgen-deprivation therapy (ADT).
Patients and Methods
We prospectively evaluated LBM in a prespecified substudy of a randomized controlled trial of denosumab to prevent fractures in men receiving ADT for nonmetastatic prostate cancer. LBM was measured by total-body dual-energy x-ray absorptiometry at study baseline and at 12, 24, and 36 months. The analyses included 252 patients (132, denosumab; 120, placebo) with a baseline and at least one on-study LBM assessment. Patients were stratified by age (< 70 v ≥ 70 years) and by ADT duration (≤ 6 v > 6 months).
Results
Median ADT duration was 20.4 months at study baseline. Mean LBM decreased significantly from baseline, by 1.0% at month 12 (95% CI, 0.4% to 1.5%; P < .001; n = 248), by 2.1% at month 24 (95% CI, 1.5% to 2.7%; P < .001; n = 205), and by 2.4% at month 36 (95% CI, 1.6% to 3.2%; P < .001; n = 168). Men age ≥ 70 years (n = 127) had significantly greater changes in LBM at all measured time points than younger men. At 36 months, LBM decreased by 2.8% in men age ≥ 70 years and by 0.9% in younger men (P = .035). Men with ≤ 6 months of ADT at study entry (n = 36) had a greater rate of decrease in LBM compared with men who had received more than 6 months of ADT at study entry (3.7% v 2.0%; P = .0645).
Conclusion
In men receiving ADT, LBM decreased significantly after 12, 24, and 36 months.
doi:10.1200/JCO.2011.38.8850
PMCID: PMC3434987  PMID: 22649143
16.  Activity Restriction Induced by Fear of Falling and Objective and Subjective Measures of Physical Function: A Prospective Cohort Study 
Objectives
To examine whether activity restriction specifically induced by fear of falling (FF) contributes to greater risk of disability and decline in physical function.
Design
Prospective cohort study.
Setting
Population-based older cohort.
Participants
Six hundred seventy-three community-living elderly (≥65) participants in the Invecchiare in Chianti Study who reported FF.
Measurements
FF, fear-induced activity restriction, cognition, depressive symptoms, comorbidities, smoking history, and demographic factors were assessed at baseline. Disability in activities of daily living (ADLs) and instrumental activities of daily living (IADLs) and performance on the Short Performance Physical Battery (SPPB) were evaluated at baseline and at the 3-year follow-up.
Results
One-quarter (25.5%) of participants did not report any activity restriction, 59.6% reported moderate activity restriction (restriction or avoidance of <3 activities), and 14.9% reported severe activity restriction (restriction or avoidance of ≥3 activities). The severe restriction group reported significantly higher IADL disability and worse SPPB scores than the no restriction and moderate restriction groups. Severe activity restriction was a significant independent predictor of worsening ADL disability and accelerated decline in lower extremity performance on SPPB over the 3-year follow-up. Severe and moderate activity restriction were independent predictors of worsening IADL disability. Results were consistent even after adjusting for multiple potential confounders.
Conclusion
In an elderly population, activity restriction associated with FF is an independent predictor of decline in physical function. Future intervention studies in geriatric preventive care should directly address risk factors associated with FF and activity restriction to substantiate long-term effects on physical abilities and autonomy of older persons.
doi:10.1111/j.1532-5415.2007.01639.x
PMCID: PMC2645621  PMID: 18312314
fear of falling; activity restriction; aging; disability; physical function
17.  Patient Anxiety About Prostate Cancer Independently Predicts Early Initiation of Androgen Deprivation Therapy for Biochemical Cancer Recurrence in Older Men: A Prospective Cohort Study 
Journal of Clinical Oncology  2009;27(10):1557-1563.
Purpose
Androgen deprivation therapy (ADT) is first-line therapy for patients with prostate cancer (PCA) who experience biochemical recurrence (BCR). However, the optimal timing of ADT initiation is uncertain, and earlier ADT initiation can cause toxicities that lower quality of life (QOL). We tested the hypothesis that elevated cancer anxiety leads to earlier ADT initiation for BCR in older men.
Patients and Methods
We conducted a prospective cohort study of older patients with BCR of PCA (n = 67). Patients completed questionnaires at presentation and each follow-up visit until initiation of ADT. PCA-specific anxiety was measured with the Memorial Anxiety Scale for Prostate Cancer (MAX-PC). Other collected data included demographics, clinical information, and general anxiety information. Treating oncologists were surveyed about their recommendations for ADT initiation. The primary outcome was the time to ADT initiation. Univariate, multivariate logistic regression, and time-to-event analyses were conducted to evaluate whether cancer anxiety was a predictor of earlier initiation of ADT.
Results
Thirty-three percent of patients initiated ADT at the first or second clinic visit. Elevated PCA anxiety (MAX-PC > 16) was the most robust predictor in multivariate analyses of early initiation (odds ratio [OR], 9.19; P = .01). PSA also independently correlated with early initiation (OR, 1.31; P = .01). PSA did not correlate with MAX-PC.
Conclusion
Cancer anxiety independently and robustly predicts earlier ADT initiation in older men with BCR. For older patients with PCA, earlier ADT initiation may not change life expectancy and can negatively impact QOL. PCA-specific anxiety is a potential target for a decision-making intervention in this setting.
doi:10.1200/JCO.2008.18.5850
PMCID: PMC2738613  PMID: 19255325
18.  Cognitive and Mood Changes in Men Undergoing Intermittent Combined Androgen Blockade for Non-Metastatic Prostate Cancer 
Psycho-oncology  2009;18(3):237-247.
Purpose
Men with PSA-only relapse of prostate cancer after primary therapy are generally fully functional and asymptomatic with a life expectancy of up to ten or more years. Androgen deprivation therapy (ADT) is a common treatment option. This study examined mood and cognitive changes in otherwise healthy men with prostate cancer prior to, during and after ADT.
Experimental Design
Twenty hormone naïve, eugonadal prostate cancer patients without evidence of metastases and with a rising PSA were treated with intermittent ADT consisting of nine months of complete androgen blockade achieved with combined leuprolide and flutamide followed by an “off treatment” period. Cognitive function tests and mood measures were administered at baseline, after three and nine months of ADT and after three months of no treatment. Twenty healthy control patients without prostate cancer range matched for age and education were tested at the same time intervals.
Results
ADT patients evidenced a significant decline in spatial reasoning, spatial abilities and working memory during treatment compared to baseline. No changes were noted for measures of verbal or spatial memory, selective attention or language. Significant changes in self-rated mood such as increased depression, tension, anxiety, fatigue and irritability were evident during treatment compared to baseline for ADT patients. No significant changes in either cognitive tests or mood measures were noted for the healthy control group.
Conclusions
These findings, suggest that nine months of combined androgen blockade may result in some adverse changes in cognition and mood. However, many but not all of these changes can return to baseline after cessation of ADT.
doi:10.1002/pon.1401
PMCID: PMC2853938  PMID: 18636420
Cancer; Oncology; Complete Androgen Blockade (CAB); Mood; Cognition; Memory; Prostate Cancer; Testosterone; Flutamide; Intermittent Androgen Ablation Therapy (ADT)
19.  Prostate Cancer Survivorship: Prevention and Treatment of the Adverse Effects of Androgen Deprivation Therapy 
Journal of General Internal Medicine  2009;24(Suppl 2):389-394.
ABSTRACT
BACKGROUND
More than one-third of the estimated 2 million prostate cancer survivors in the United States receive androgen deprivation therapy (ADT). This population of mostly older men is medically vulnerable to a variety of treatment-associated adverse effects.
MEASUREMENTS AND RESULTS
Androgen-deprivation therapy (ADT) causes loss of libido, vasomotor flushing, anemia, and fatigue. More recently, ADT has been shown to accelerate bone loss, increase fat mass, increase cholesterol and triglycerides, and decrease insulin sensitivity. Consistent with these adverse metabolic effects, ADT has also recently been associated with greater risks for fractures, diabetes and cardiovascular disease.
CONCLUSION
Primary care clinicians and patients should be aware of the potential benefits and harms of ADT. Screening and intervention to prevent treatment-related morbidity should be incorporated into the routine care of prostate cancer survivors. Evidence-based guidelines to prevent fractures, diabetes, and cardiovascular disease in prostate cancer survivors represent an important unmet need. We recommend the adapted use of established practice guidelines designed for the general population.
doi:10.1007/s11606-009-0968-y
PMCID: PMC2763167  PMID: 19838837
prostate cancer; survivorship; GnRH agonists; osteoporosis; bisphosphonates; diabetes; obesity; cardiovascular disease
20.  Sex Differences in Stroke Recovery 
Preventing Chronic Disease  2005;2(3):A13.
Introduction
This study examined differences between men and women in the ability to perform basic activities of daily living, instrumental activities of daily living, and higher physical functioning after stroke. The objective of the study was to determine whether sex differences in stroke recovery can be explained by depressive status beyond older age, stroke severity, prestroke physical functioning, and other medical comorbidities.
Methods
A total of 459 stroke patients were recruited from acute and subacute facilities in an urban midwestern community. These patients were followed prospectively from stroke onset until 6 months poststroke. All study participants were assessed using standardized stroke outcome measures, including the National Institutes of Health Stroke Scale, the Barthel Activities of Daily Living Index, the Lawton Instrumental Activities of Daily Living scale, and the SF-36 Health Survey physical functioning scale. The Geriatric Depression Scale was used to assess depressive status. Each outcome was measured at baseline (within 2 weeks of stroke onset), as well as 1, 3, and 6 months poststroke. Prestroke physical functioning, stroke characteristics, and comorbidities were also assessed at baseline.
Results
Female patients in the study were older than male patients, with a mean age of 71 years for women vs 69 years for men. Female patients reported lower prestroke physical functioning than their male counterparts. Six months after stroke, women in the study were less likely than the men to achieve a score of ?95 on the Barthel Activities of Daily Living Index (hazards ratio [HR] = 0.68; 95% confidence interval [CI], 0.52–0.90), carry out eight of nine instrumental activities of daily living without assistance (HR = 0.46; 95% CI, 0.30–0.68), and score ?90 on the SF-36 Health Survey physical functioning scale (HR = 0.54; 95% CI, 0.28–1.01). When age, prestroke physical functioning, stroke severity, and depressive status at baseline were controlled in the analysis, women in the study continued to be less likely (HR = 0.51; 95% CI, 0.32–0.79) than men in the study to be able to carry out eight of nine instrumental activities of daily living completely without assistance, but there were no observed sex differences in achievement of independence in basic activities of daily living or higher physical functioning.
Conclusion
Prestroke physical functioning and depressive symptoms are important factors in the investigation of sex differences in stroke recovery. Lower recovery of activities of daily living and physical functioning in women after stroke may be due to multifactorial effects of older age, poor physical function prior to stroke onset, and depressive status after stroke.
PMCID: PMC1364522  PMID: 15963315
21.  Role of Androgen Deprivation Therapy for Node-Positive Prostate Cancer 
Journal of Clinical Oncology  2008;27(1):100-105.
Purpose
To determine the impact of adjuvant androgen deprivation therapy (ADT) for patients who have node-positive prostate cancer in the prostate-specific antigen (PSA) era.
Patients and Methods
We used linked Surveillance, Epidemiology and End Results-Medicare data to construct a cohort of men who underwent radical prostatectomy (RP) between 1991 and 1999 and who had positive regional lymph nodes. We classified men as receiving adjuvant ADT if they received ADT within 120 days of RP, and we compared them to the men who had not received adjuvant ADT. We used propensity scores to balance potential confounders of receiving adjuvant ADT (ie, tumor characteristics, extent of nodal disease, demographics, receipt of radiation therapy) and Cox proportional hazard methods to measure the impact of adjuvant ADT on overall survival (OS), stratified by propensity score quintile. We conducted a sensitivity analysis that used 90, 150, 180, and 365 days as the definition for adjuvant ADT.
Results
A total of 731 men were identified, 209 of whom received ADT within 120 days of RP. There was no statistically significant difference in OS between the adjuvant ADT and non-ADT group (HR, 0.97; 95% CI, 0.71 to 1.27). There was no statistically significant survival difference with 90, 150, 180, and 365 days as the adjuvant ADT definition.
Conclusion
Deferring immediate ADT in men with positive lymph nodes after RP may not significantly compromise survival. Because observational studies should be considered hypothesis-generating studies, these results should be validated in a prospective fashion in a similar patient population.
doi:10.1200/JCO.2007.14.2042
PMCID: PMC2645095  PMID: 19047295
22.  A pilot study of exercise in men with prostate cancer receiving androgen deprivation therapy 
BMC Cancer  2012;12:103.
Background
Androgen deprivation therapy (ADT) is the mainstay therapy for men with prostate cancer. However, there are musculoskeletal side effects from ADT that increase the risk for osteoporosis and fracture, and can compromise the quality of life of these individuals. The objectives of this study are to determine the efficacy of a home-based walking exercise program in promoting bone health, physical function and quality of life in men with prostate cancer receiving ADT.
Methods/Design
A 12-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Sixty men with prostate cancer who will be starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 12-month home-based walking exercise program, while the Control Group will receive standard medical advice from the attending physician. A number of outcome measures will be used to assess bone health, physical function, and health-related quality of life. At baseline and 12 months, bone health will be assessed using dual-energy X-ray absorptiometry. At baseline and every 3 months up to 12 months, physical function will be evaluated using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale, Activities-specific Balance Confidence Scale, Short Physical Performance Battery, and Six-Minute Walk Test; and health-related quality of life will be assessed using the Functional Assessment of Cancer Therapy Prostate Module and the Medical Outcomes Study 12-item Short Form Health Survey Version 2. A mixed multiple analysis of variance will be used to analyze the data.
Discussion
Musculoskeletal health management remains a challenge in men with prostate cancer receiving ADT. This study addresses this issue by designing a simple and accessible home-based walking exercise program that will potentially have significant impact on reducing the risk of fracture, promoting physical function, and ultimately improving the health-related quality of life in men with prostate cancer receiving ADT.
Trial registration
ClinicalTrials.gov: NCT00834392.
doi:10.1186/1471-2407-12-103
PMCID: PMC3352294  PMID: 22436542
Prostate cancer; Androgen deprivation therapy; Walking; Home-based exercise; Bone health; Physical function; Quality of life
23.  The Use of Androgen Deprivation Therapy (ADT) and Chemotherapeutic Agents in New Zealand Men with Prostate Cancer 
Journal of Cancer  2014;5(3):214-220.
Purpose: To assess the patterns of use of androgen deprivation therapy (ADT) and chemotherapeutic agents in New Zealand men with prostate cancer.
Methods: Men diagnosed with prostate cancer between 2006 and 2011 were identified from the New Zealand Cancer Registry. Through data linkage with the Pharmaceutical Collection and the National Minimum Dataset information on subsidised anti-androgens, luteinising hormone-releasing hormone (LHRH) analogues, chemotherapeutic agents, and orchidectomy was retrieved. The frequency of ADT and chemotherapy use in the first year post-diagnosis was assessed by patients' age, ethnicity, and extent of disease at diagnosis.
Results: The study population included 15,947 men diagnosed with prostate cancer, of whom 4978 (31%) were prescribed ADT or chemotherapeutic agents. ADT was dispensed for 72% of men with metastatic disease. Only 24 (0.2%) men received chemotherapeutic agents. Men with advanced (regional or metastatic) disease older than 70 were more likely to receive anti-androgens only and to be treated with orchidectomy compared with younger men. Māori and Pacific men (compared with non-Māori/non-Pacific men) were more likely to receive pharmacologic ADT, and Māori men were also more likely to be treated with orchidectomy.
Conclusions: It was expected that all men diagnosed with metastatic prostate cancer should be using ADT in the first year post-diagnosis. However, for more than one-fourth of men neither anti-androgens nor LHRH analogues were dispensed within this period. Chemotherapeutic agents were used very rarely, so it seems that both pharmacologic ADT and chemotherapy is under-utilised in New Zealand patients with advanced prostate cancer.
doi:10.7150/jca.8152
PMCID: PMC3931269  PMID: 24563676
anti-androgens; LHRH analogues; chemotherapy; orchidectomy; prostate cancer
24.  DOSE-ESCALATED RADIOTHERAPY FOR HIGH-RISK PROSTATE CANCER: OUTCOMES IN MODERN ERA WITH SHORT-TERM ANDROGEN DEPRIVATION THERAPY 
Purpose
Randomized data have supported the use of long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) for men with high-risk prostate cancer. The present study reviewed the outcomes of intermediate- and high-risk men treated with RT and short-term ADT.
Materials and Methods
A total of 184 men with any single risk factor of prostate-specific antigen ≥10 ng/mL, clinical Stage T2b or greater, or Gleason score ≥7 were treated with primary external beam RT for nonmetastatic adenocarcinoma of the prostate. The median radiation dose was 74 Gy; 55% were treated with intensity-modulated RT. All patients received ADT for 1 to 6 months (median, 4), consisting of a gonadotropin-releasing hormone analog. Univariate and multivariable analyses were performed for risk factors, including T stage, Gleason score, radiation dose, and prostate-specific antigen level.
Results
With a median follow-up of 51 months, the 4-year freedom from biochemical failure (FFBF) using the nadir plus 2 ng/mL definition was 83% for all patients. Clinical Stage T3 disease was the only variable tested associated with FFBF on univariate (4-year FFBF rate, 46% vs. 87% for Stage T1-T2c disease; p = .0303) and multivariable analysis (hazard ratio, 3.9; p = .0016). On a subset analysis of high-risk patients (National Comprehensive Cancer Network criteria), those with clinical Stage T3 disease (4-year FFBF rate, 46% vs. 80%; p = .0303) and a radiation dose <74 Gy (4-year FFBF rate, 64% vs. 80%) had a poorer outcome on univariate analysis. However, clinical Stage T3 disease and radiation dose were not significant on multivariable analysis, although a statistical multivariable trend was seen for both (p = .0650 and p = .0597, respectively).
Conclusion
Short-term ADT and RT might be acceptable for men with intermediate- and high-risk prostate cancer, especially for clinically localized disease treated with doses of ≥74 Gy.
doi:10.1016/j.ijrobp.2009.04.074
PMCID: PMC3049990  PMID: 19695789
Prostate cancer; radiotherapy; hormonal therapy
25.  Characterization of Activities of Daily Living in Individuals With Mild Cognitive Impairment 
Objective
To determine whether participants with mild cognitive impairment (MCI) differ from cognitively normal (NC) older adults on traditional and novel informant-based measures of activities of daily living (ADL) and to identify cognitive correlates of ADLs among participants with MCI.
Design
Cross-sectional.
Setting
University medical setting.
Participants
Seventy-seven participants (NC: N = 39; MCI: N = 38), 60 to 90 years old (73.5 ± 6.6 years; 53% female).
Measurements
Neuropsychological and ADL measures.
Methods
Neuropsychological tests were administered to NC and MCI participants. Informants completed the Lawton and Brody Instrumental Activities of Daily Living and Physical Self-Maintenance Scale, including instrumental (IADL) and basic ADL (BADL) scales, as well as the Functional Capacities for Activities of Daily Living (FC-ADL), an error-based ADL measure.
Results
No statistically or clinically significant between-group differences emerged for the BADL or IADL subscales. However, a robust difference was noted for the FC-ADL scale (MCI errors > NC errors; F(1,75) = 13.6, p <0.001; d = 0.84). Among MCI participants, correlations revealed that a measure of verbal learning was the only neuropsychological correlate of FC-ADL total score (r =-0.39, df = 36, p = 0.007). No neuropsychological measures were significantly associated with the IADL or BADL subscale score.
Conclusion
Traditional measures assessing global ADLs may not be sensitive to early functional changes related to MCI; however, error-based measures may capture the subtle evolving functional decline associated with MCI. Among MCI participants, early functional difficulties are associated with verbal learning performance, possibly secondary to the hallmark cognitive impairment associated with this cohort.
doi:10.1097/JGP.0b013e318162f197
PMCID: PMC2682324  PMID: 18332397
Instrumental activities of daily living; MCI; memory; functional errors; neuropsychology

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