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PHYS THER
Vol. 87, No. 10, October 2007, pp. 1325-1333
DOI: 10.2522/ptj.20060302
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Research Reports

Physical Function in Men With Prostate Cancer on Androgen Deprivation Therapy

Cheryl A Clay, Subashan Perera, Julie M Wagner, Megan E Miller, Joel B Nelson and Susan L Greenspan

CA Clay, MD, is Co-Investigator, Akron Children's Hospital, Akron, Ohio
S Perera, PhD, is Statistician, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa
JM Wagner, PA-C, is Study Coordinator, Department of Medicine, University of Pittsburgh
ME Miller, BS, is Study Coordinator, Department of Medicine, University of Pittsburgh
JB Nelson, MD, is Co-Investigator, Department of Urology, University of Pittsburgh
SL Greenspan, MD, is Principal Investigator and Professor, Department of Medicine, University of Pittsburgh, 3471 Fifth Ave, Suite 1110, Pittsburgh, PA 15213-3221 (USA)

Address all correspondence to Dr Greenspan at: greenspans{at}dom.pitt.edu


Submitted October 3, 2006; Accepted May 23, 2007


   Abstract
 
Background and Purpose: Androgen deprivation therapy (ADT) has become an increasingly standard intervention for both early and advanced stages of prostate cancer; however, decreased physical function and hypogonadism have been reported in men receiving ADT. The objectives of this study were: (1) to determine whether ADT (and hypogonadism) resulted in decreased strength and mobility and (2) to examine the effect of ADT on an associated test of cognitive and motor function by assessing visuomotor performance.

Subjects and Methods: Physical function, walking speed, visuomotor performance, gonadal status, body composition, and Comorbidity Disease Index (CMDI) scores were assessed in a cohort of 100 participants that included: (1) men with prostate cancer who were not on ADT, (2) men with prostate cancer who were on short-term ADT (<6 months), (3) men with prostate cancer who were on long-term ADT (≥6 months), and (4) control subjects who did not have prostate cancer.

Results: Walking speed varied significantly across the 4 groups, even after adjusting for age, CMDI, and percentage of body fat. Age and CMDI were significantly associated with measurements of physical performance. Adjusted for covariates, men on long-term ADT walked 0.18 m/s slower than the control subjects. Physical function also varied significantly across the 4 groups. Androgen deprivation therapy did not have a significant effect on visuomotor performance.

Discussion and Conclusion: The results suggest that ADT has a significant effect on walking speed and physical performance in men with prostate cancer.


   Introduction
Top
 Abstract
 Introduction
Materials and Method
 Results
 Discussion
 Conclusion
 References
 
Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in men.1 Androgen deprivation therapy (ADT) has become an increasingly standard intervention for both early and advanced stages of prostate cancer.2,3 Studies have shown that ADT is similar to orchiectomy in its ability to suppress plasma levels of testosterone, and both interventions share the adverse effects of hot flashes and loss of libido.4

Stoch et al5 and Maillefert et al6 have previously demonstrated that men on ADT have poor skeletal integrity, as shown by low bone mineral density and high levels of biochemical markers of bone turnover. These men also have a higher percentage of total body fat and a lower percentage of lean body mass compared with men who are eugonadal.5 Androgen deprivation therapy is known to affect quality of life adversely, leading to increased fatigue, erectile difficulties, and decline in sexual function.3,7,8 Dacal et al9 demonstrated that men on short- and long-term ADT have poorer quality of life in the dimensions of physical function and general health, as reflected by a lower physical health component summary score from a questionnaire. Physical function and gait, however, were not measured. This is clinically relevant because poor gait speed has been associated with greater disability and risk of major health-related outcomes in community-dwelling populations.10,11

Although decreased physical function has been reported in men receiving ADT,12,13 limited studies have measured physical performance.3,14 Because of the hypogonadism induced by the ADT15 and the association of testosterone with muscle strength (force-generating capacity), our objective was to determine whether ADT (and hypogonadism) resulted in decreased strength and mobility. Furthermore, because lower testosterone levels have been associated with impairment in cognitive function, we examined the effect of ADT on an associated test of cognitive and motor function by assessing visuomotor performance. These findings could provide the rationale for health care providers to help maintain or improve physical and visuomotor function.

We postulated that men who were hypogonadal because of ADT would be more likely to have deficits in physical function and visuomotor performance than men who were eugonadal. We also postulated that a longer duration of ADT would be associated with a greater reduction in function.


   Materials and Method
Top
 Abstract
 Introduction
 Materials and Method
Results
 Discussion
 Conclusion
 References
 
Subjects

Men with prostate cancer and control subjects who were healthy were recruited from the private practices of the University of Pittsburgh physicians, local newspaper advertisements, and cancer support groups as described previously.9,16 All participants were community-dwelling men 50 years of age and older. We enrolled men with prostate cancer, but without evidence of metastatic disease, who were or were not treated with ADT, in addition to a group of men of similar ages but without prostate cancer. The participants were part of a longitudinal study to examine the effect of ADT on skeletal health.16

Men were excluded if they had any disease or were taking any medication known to affect bone and mineral metabolism. We included men willing to participate in this substudy to examine physical function. Additional exclusion criteria based on musculoskeletal impairments were not included; however, control subjects who were hypogonadal were excluded. Androgen deprivation therapy was defined as orchiectomy, gonadotrophin-releasing hormone agonists, anti-androgens, or a combination of these interventions. Participants were categorized into 4 groups: (1) men with prostate cancer who were not taking ADT (no ADT), (2) men with prostate cancer who were on short-term ADT (<6 months) (short-term ADT), (3) men with prostate cancer who were on long-term ADT (≥6 months) (long-term ADT), or (4) older men without prostate cancer (control subjects)

All patient visits were performed at the General Clinical Research Center, Montefiore University Hospital, University of Pittsburgh, Pittsburgh, Pa. All tests were completed at one visit, with the exception of body composition measurements; 10% of participants had this performed within 1 month of the other tests. Although the study coordinator was aware of subject group assignment, the investigator who assessed physical function was not. Written informed consent was obtained from all subjects prior to their enrollment.

Outcome Measures

Measures of body composition.
Measures of body composition included height (in centimeters), weight (in kilograms), and body mass index (BMI) (in kilograms per square meter). Height was measured to the nearest centimeter using a Harpenden stadiometer,* and weight was measured with a standard balance beam scale. Percentage of body fat and lean body mass were measured with dual-energy X-ray absorptiometry (DXA) using a QDR-4500A bone densitometer.17,{dagger} Assessment of body composition by DXA is based on the attenuation of the alternation of an x-ray beam, from a source with 2 energies, passing through the body. The attenuation ratio of these 2 energies is used to distinguish soft tissue from bone and to distinguish fat soft tissue from lean soft tissue.18 This method accurately predicts skeletal muscle assessed by magnetic resonance imaging.19

Testosterone and prostate-specific antigen (PSA) levels.
Total testosterone was measured by competitive immunoassay (Bayer Centaur{ddagger}) (in nanograms per deciliter; normal range=260–1,000 ng/dL; intra-assay coefficient of variation [CV]=2.4%–8.3%). Free testosterone was measured by tracer equilibrium dialysis{ddagger} (in picograms per milliliter; normal range=50–210 pg/mL; intra-assay CV=4.2%–11.6%). Prostate-specific antigen was measured by competitive immunoassay (in nanograms per milliliter; normal range=0–4 ng/mL; intra-assay CV=4.0%–4.4%).

Comorbidity Disease Index (CMDI).
The CMDI is a patient self-report that includes 18 common conditions that affect performance on physical function tasks.20 Scores range from 18 to 36, with a score of 18 representing having all conditions and a score of 36 representing having no conditions. The 18 medical conditions correspond to 8 domains: cardiac, respiratory, diabetic, neurological, cancer, vision, musculoskeletal, and generalized medical conditions (eg, depression, emotional problems, sleep problems, chronic pain). The agreement between self-reported disease and chart diagnosis ranged from 84% to 94% (kappa statistic=.56–.67).20

Digit Symbol Substitution Test (DSST).
The DSST from the Wechsler Adult Intelligence Scale–Revised21 was administered to all participants. The DSST measures visuomotor performance; it requires response speed, sustained attention, visual spatial skills, and set shifting. We presented the participants with a coding key pairing 9 numbers (1–9) with 9 symbols. Participants were first given a practice sample of 10 items. Then, they were given 90 seconds to transcribe as many symbols as possible into the empty boxes, based on the digit-symbol associations specified in the coding key.

Nine-Hole Peg Test (9HP).
The 9HP is a quantitative measure of upper-extremity (arm and hand) function.22 Participants were given a 9-hole pegboard and a dish of 9 pegs. Each individual was asked to remove all 9 pegs from the dish, place them in the holes, and then return them to the dish with one hand. The test began with a practice run and then continued with a timed measure of the dominant hand and the nondominant hand in the order the participant preferred.

Short Physical Performance Battery (SPPB).
The SPPB was based on the Established Population for Epidemiologic Studies of the Elderly (EPESE) lower-extremity performance battery.23 Lower-extremity function was assessed by measures of standing balance, gait speed, and ability to rise from a chair. A 5-level categorical score was created for each test, with 0 representing inability to complete the test and 4 representing the highest level of performance.23

For tests of standing balance, participants attempted to maintain the side-by-side, semi-tandem, and tandem positions for 10 seconds. The participants then were asked to walk a 4-m length at their usual pace from a standing start. The time of the faster of 2 walks was used for scoring. Finally, participants were asked to fold their arms across their chest and to stand up from a sitting position once. If they successfully rose from the chair, they were asked to stand up and sit down 5 times as quickly as possible. Participants were instructed to come to a full standing position and sit so their backs were touching the back of the chair. A summary performance score was created by summation of the scores for each test (score range=0–12).

Data Analysis

All data analyses were performed using SAS software, version 9.1.§ Descriptive statistics were used to characterize the 3 groups of subjects with prostate cancer in the study sample. Analysis of variance was used to compare characteristics among the 4 groups (including the control group). Correlations between various subject characteristics and physical and visuomotor function were examined using Pearson correlation coefficients. General linear models were used to make: (1) unadjusted comparisons of physical function across the 4 groups and (2) adjusted comparisons across the 4 groups controlling for covariates identified as being important in the bivariate correlation analyses. Graphical analysis of residuals from regression models was performed to identify any violations of the standard distributional assumptions.


   Results
Top
 Abstract
 Introduction
 Materials and Method
 Results
Discussion
 Conclusion
 References
 
Clinical Characteristics

Of the 152 participants in the original longitudinal study,16 102 men agreed to participate in this study. Two control subjects were found to be hypogonadal and were excluded from the analyses. The final cohort of 100 men included 25 men with prostate cancer who were not treated with ADT, 13 men with prostate cancer who were on short-term ADT, 42 men with prostate cancer who were on long-term ADT, and 20 men without prostate cancer (Tab. 1). Men who were on long-term ADT were receiving treatment for an average (±SD) of 31±29 months.


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  		Table 1. Participant Characteristicsa

 
There were significant differences in age across the 4 groups; men who were on short-term or long-term ADT were older than men who were not on ADT or the control subjects. There were no significant between-group differences in BMI. However, men who were receiving long-term ADT had the highest total body fat and lowest lean body mass compared with the other 3 groups (P<.01, Tab. 1). As expected, levels of total and free testosterone were significantly lower in men who were receiving ADT than in those who were not on ADT or the control subjects (Tab. 1). Prostate-specific antigen levels were higher in men who were on short-term ADT compared with men who were on long-term ADT. The overall CMDI score was lower in the men with prostate cancer compared with the control subjects. The prevalence of comorbid conditions (Tab. 1) for the cohort was similar among groups for cardiovascular disease (5%–24%), pulmonary disease (12%–17%), musculoskeletal disease (50%–74%), diabetes mellitus (0%–7%), vision problems (16%–40%), neurological disease (20%–31%), and generalized symptoms (eg, depression, sleep problems, chronic pain) (0%–15%).

Functional Performance

The control subjects, on average, walked at 1.17 m/s, whereas men who were on long-term ADT walked at 0.99 m/s (P<.001) (Tab. 2). This difference persisted after controlling for subject characteristics found to be important in the bivariate correlation analyses. After adjusting for age, CMDI, and percentage of body fat, men who were on long-term ADT walked 0.18 m/s slower than men who did not have prostate cancer (P<.001). Among men with cancer, there was no significant difference in gait speed between those who were on short- or long-term ADT and those who were not on ADT (P=.44 and P=.38, respectively) after adjusting for the covariates.


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  		Table 2. Functional and Visuomotor Performancea

 
Scores on the SPPB were significantly different across the 4 groups after adjusting for the same covariates (P=.02). Men with prostate cancer who were not on ADT or who were on short-term ADT had SPPB scores 0.8 and 1.1 points greater than men who were on long-term ADT (P=.04 and P=.01, respectively) (Tab. 2). Visuomotor performance assessed by the DSST was significantly different across the 4 groups (P=.02). Other measures of physical function were similar across the 4 groups (Tab. 2).

Associations Between Predictor Variables and Function

Although statistically significant, there were only marginal to moderate associations between subject characteristics and function (Tab. 3). The greatest unadjusted associations were between CMDI and DSST (r=.36, P<.001), CMDI and speed on the 9HP with the nondominant hand (r=–.23, P=.02), age and walking speed (r=–.23, P=.02), CMDI and time to rise from a chair (r=–.20, P=.05), and CMDI and SPPB (r=.26, P<.01).


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  		Table 3. Pearson Correlationsa

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Method
 Results
 Discussion
Conclusion
 References
 
In our study of mobility and physical function in older men with and without prostate cancer, we observed that gait speed varied across the 4 groups and that men who were on long-term ADT had a significantly slower gait speed than the control subjects (Figure). Function, as measured by the SPPB, also varied significantly across the groups, with men who were not on ADT or men who were on short-term ADT performing significantly better than men who were on long-term ADT. Finally, although visuomotor performance varied across the 4 groups, it was not significantly lower in any single group, suggesting that ADT had a minimal effect on this parameter.


Figure 1
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  		Figure. Four-meter gait speed, mean±SEM (m/s). P<.05 for overall 4-group comparison adjusted for covariates age, Comorbidity Disease Index, and percentage of body fat. *P<.01 pair-wise comparison of men who were receiving chronic androgen deprivation therapy (ADT) versus control subjects adjusted for age, Comorbidity Disease Index, and percentage of body fat.

 
Several investigators have examined mobility in men with prostate cancer who were on ADT. Joly and colleagues14 examined physical function using a limited walk test, grip strength, and the Timed "Up & Go" Test in men who were on ADT versus control subjects and reported no significant differences. In the present study, we assessed gait speed using the 4-m walk test and found that men with prostate cancer who were on long-term ADT had slower gait speed than the control subjects. Potential reasons for differences in the findings include a different test of gait (a 6-minute walk test by Joly and colleagues compared with a 4-m walk test in the present study) and differences in the duration of ADT (up to 7.4 years in the study by Joly et al and up to 11 years in our study).

Perera et al24 previously showed that small meaningful differences in gait speed are near 0.05 m/s, which was observed between our patient groups. Furthermore, in a population of more than 3,000 older people who were well functioning, Cesari and colleagues11 reported that a gait speed of less than 1 m/s identifies people who are at higher risk for health-related outcomes. Data from the 1999–2002 National Health and Nutrition Examination Survey also showed that walking speed was inversely related to disability.25 Other investigators10 have developed models using gait speed that predict disability in elderly people. Therefore, clinicians should monitor for a decrease in gait speed or mobility in men with prostate cancer who are on long-term ADT.

Forrest et al26 demonstrated that gait speed decreases with age. We also observed that gait speed decreased with age in our cohort. Furthermore, in elderly people, a higher fat mass or lower lean body mass has been associated with a slower walking speed and greater likelihood of functional limitation.27 We did not find a relationship between gait speed and body composition, either fat or lean mass. The difference between our study and the report by Sternfeld et al27 may be due to methods used for determining gait speed (4-m walk versus distance walked in 60 seconds). However, a more likely reason for the difference in associations between body composition and gait speed in the 2 studies may be the degree of debilitation of the subjects. In the study by Sternfeld et al,27 the average group gait speed was 0.69 m/s, whereas gait speed averaged between 0.99 and 1.17 m/s in our study. The slower gait speed may indicate more debilitation and perhaps greater changes in body composition and lean muscle mass.

In the present study, we observed small meaningful differences24 in SPPB scores of 0.8 point between men with prostate cancer who were on long-term ADT and men with prostate cancer who were not on ADT and 1.1 points between men who were on short-term ADT and men who were on long-term ADT (both P<.05). In a study that examined upper-extremity strength by handgrip, Stone and colleagues28 found no difference in strength after 3 months of ADT. In a cross-sectional study by Basaria et al,29 however, men on ADT for a mean of 45 months had reduced upper-body strength (by bench press) but not lower-body strength (by leg press) compared with control subjects. Because we did not assess strength by these measures, it is difficult to know whether the differences in the SPPB scores were due to decreased muscle strength or other factors.

Men who were on long-term ADT had approximately 4.5% less lean body mass than the control subjects, men who were not on ADT, or men who were on short-term ADT. Stoch and colleagues5 described a higher percentage of body fat and lower lean body mass in men with prostate cancer who were on ADT versus men with prostate cancer who were not receiving ADT. Greenspan et al16 recently reported a loss of muscle mass and bone with an increase in body fat in men receiving short-term ADT who were followed over 12 months. Because the current cross-sectional study included men in the short-term group with a mean duration of ADT of 3.7 months, this may not have been a long enough duration to see a difference in lean body mass. Smith and colleagues30 also discovered an association between decreased muscle size and ADT, which may have contributed to frailty and increased risk of falls in the men in their study.

We expected men who were hypogonadal, with low levels of testosterone, to have deficits in measures of physical function. Although testosterone levels were lower in men on ADT, total and free testosterone levels were not associated with scores on the SPPB measure of physical function in the present study. Serum testosterone levels decline gradually and progressively with aging in men. Many manifestations associated with aging, including muscle atrophy and weakness, increased fat body mass, and decreased lean body mass, are similar to changes associated with testosterone deficiency in young men.31 It is controversial whether giving testosterone to older men who are hypogonadal improves muscle strength, body composition, or even cognitive function.32–34

Several investigators have examined the effect of exercise in men with prostate cancer who were on ADT. Segal et al35 reported that resistance training reduced fatigue and improved muscular fitness in men with prostate cancer who were on ADT. Galvão et al36 reported that a 20-week program of progressive resistance training improved muscle strength, functional performance, and balance in older men who were on ADT. Exercise also may improve gait speed in older adults.37 Therefore, clinicians may consider physical therapy intervention for strength and gait interventions in these patients.

Little is known about the effect of ADT on visuomotor performance. There have been suggestions that lowered testosterone levels in older men who are healthy are associated with impairment of cognitive function38 and that testosterone replacement therapy may improve some cognitive domains, specifically visuospatial and working-memory function.32 The present study showed that visuomotor performance, as measured by DSST, varied across the groups but was not significantly lower in any one group.

Salminen et al39 demonstrated that men who were on ADT for 12 months had preserved cognitive function, as assessed by a battery of cognitive performance tests that included verbal visuomotor and memory tests. Similarly, Green et al12 found that, after 6 months of ADT, one half (n=50) of men receiving treatment had a clinically significant decrease on at least one cognitive task; however, no change was noted on DSST performance. Data from all of these studies suggest that ADT in men with prostate cancer may not have a significant effect on visuomotor performance. Future studies may need to do more sophisticated testing to find subtle declines in cognitive performance.

There are several limitations of this study. First, the men with prostate cancer who were not on ADT and the control subjects were younger than the men who were on ADT. However, when we adjusted for age, the between-group differences prevailed. Second, this is a relatively small, cross-sectional, secondary analysis of an observational study, which may have limited the statistical power and does not allow us to draw conclusions about the longitudinal patterns of cause and effect. Third, maximum participant effort for each task may not have been optimal, although participants were routinely given a practice run for these assessments.

This study also had several strengths. First, all men were seen at the same facility with the same coordinators administering the tests, reducing variability from nuisance factors. Second, a control group of older men without prostate cancer was included. Third, in addition to ADT, testosterone levels were assessed to determine whether the therapy or the hypogonadal state had the most significant effect. Finally, comorbidity was adjusted for, which has not been done in many studies.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Method
 Results
 Discussion
 Conclusion
References
 
The men with prostate cancer who were on long-term ADT (for more than 6 months) had a reduced gait speed compared with control subjects. Physical performance was decreased in men who were on long-term ADT compared with men who were not on ADT or who were on short-term ADT. Androgen deprivation therapy did not have a significant effect on visuomotor function. Because a reduced gait speed and a decrease in physical function are critical components for activities of daily living, this finding warrants further investigation. These findings have important clinical ramifications and suggest that long-term ADT can contribute to a decline in mobility and function in older men with prostate cancer.


   Footnotes
 
Dr Clay and Dr Greenspan provided concept/idea/research design and project management. Dr Clay, Dr Perera, and Dr Greenspan provided writing. Dr Clay, Ms Wagner, and Ms Miller provided data collection. Dr Clay, Dr Perera, and Dr Greenspan provided data analysis. Dr Greenspan provided fund procurement and facilities/equipment. Dr Nelson provided subjects. Ms Miller provided clerical/secretarial support. Dr Perera and Dr Nelson provided consultation (including review of manuscript before submission).

The study protocol was approved by the Institutional Review Board of the University of Pittsburgh.

The project was supported by a Mentored Medical Student in Clinical Research Fellowship Award through the General Clinical Research Center at the University of Pittsburgh to Dr Clay; a K24 Patient-Oriented Mid-Career Award from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (K24 DK062895) to Dr Greenspan; a grant to the General Clinical Research Center, University of Pittsburgh, from the National Institutes of Health/National Center for Research Resources (MO1 RR000056); and a grant to the Claude D Pepper Older Americans Independence Center, University of Pittsburgh, from the National Institutes of Health/National Institute on Aging (P30 AG024827). None of the funding sources played a role in the design or execution of the study, the analysis and interpretation of data, or the writing of the manuscript.

* Holtain Ltd, Crosswell, Crymych, Dyfed, United Kingdom SA41 3UF. Back

{dagger} Hologic Inc, 35 Crosby Dr, Bedford, MA 01730. Back

{ddagger} Nichols Institute, 1311 Calle Batido, San Juan Capistrano, CA 92673. Back

§ SAS Institute Inc, PO Box 8000, Cary, NC 27511. Back


   References
Top
 Abstract
 Introduction
 Materials and Method
 Results
 Discussion
 Conclusion
 References
 

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