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Increased Fall Risk in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer
Oncology Increased Fall Risk in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer Fang-Jen Wu, Shiow-Yunn Sheu, Herng-Ching Lin, and Shiu-Dong Chung OBJECTIVE
METHODS
RESULTS
CONCLUSION
To examine the relationship between the use of androgen deprivation therapy (ADT) and the subsequent risk of falls in men with prostate cancer (PC) by employing a population-based dataset. We retrieved the study sample from the Taiwan Longitudinal Health Insurance Database 2005. We included 886 patients with PC who had received ADT as the study group, whereas 862 patients with PC who had not received ADT served as the comparison group. We then individually tracked each study patient for a 3-year period to identify those who subsequently received a diagnosis of a fall. We performed Cox proportional hazard regressions to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI) for a fall during the 3-year follow-up period between these 2 groups. The incidence rates of falls per 1000 person-years were 13.37 (95% CI: 9.15~18.88) and 6.44 (95% CI: 3.61~10.63), respectively, for patients with PC who received ADT and those who did not receive ADT. Furthermore, the hazard ratio for a fall during the 3-year follow-up period for patients with PC who had received ADT was 1.95 (95% CI: 1.04~3.66, P = .037) compared to those who had not received ADT after censoring sampled patients who died during the 3-year follow-up period and adjusting for age, geographical location, monthly income, urbanization level, hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, stroke, and mental illness. The present findings suggest that patients with PC who had received ADT had an increased risk of falls. UROLOGY 95: 145–150, 2016. © 2016 Published by Elsevier Inc.
P
rostate cancer (PC) is the second most common diagnosed malignancy in men worldwide, with an estimated 1.1 million cases reported in 2012.1 Androgen deprivation therapy (ADT) is the standard treatment for aggressive and advanced PC.2 ADT includes an orchiectomy, estrogens, antiandrogens, luteinizing hormonereleasing hormone (LHRH) agonists and antagonists.3,4 Plenty of studies have demonstrated that ADT can improve disease-free and overall survival when used in combination with radiation for patients with locally advanced PC.5,6 However, androgens are an important part Shiow-Yunn Sheu, Herng-Ching Lin, and Shiu-Dong Chung contributed equally to this study. Financial Disclosure: The authors declare that they have no relevant financial interests. From the School of Pharmacy, Taipei Medical University, Taipei, Taiwan; the School of Medical Laboratory Sciences and Biotechnology, Taipei Medical University, Taipei, Taiwan; the Sleep Research Center, Taipei Medical University Hospital, Taipei, Taiwan; and the Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, Ban Ciao, Taipei, Taiwan Address correspondence to: Shiu-Dong Chung, M.D., Ph.D., Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, Ban Ciao, Taipei 110, Taiwan. E-mail: [email protected] Submitted: March 15, 2016, accepted (with revisions): May 12, 2016
© 2016 Published by Elsevier Inc.
of the body composition in males as they support lean body mass over fat mass.7 One study indicated that LHRH agonist therapy increased fat mass by 10% and decreased lean body mass by 3% and also the associated sarcopenic obesity.8 The reduced muscle mass may be related to the risk of falls.9 Globally, falls are the major cause of accidental or unintentional injury and deaths.10 However, previous findings rarely examined the association between ADT and the risk of falls. To fill in this gap in the literature, the present study aimed to examine the relationship between the use of ADT and the subsequent risk of falls in men with PC by employing a population-based dataset in Taiwan.
METHODS Database We retrieved the study sample for this population-based retrospective cohort study from the Taiwan Longitudinal Health Insurance Database 2005 (LHID2005). The LHID2005 includes beneficiary registration files and medical claims data for reimbursement for 1 million individuals randomly selected from all enrollees in the Taiwan National http://dx.doi.org/10.1016/j.urology.2016.05.058 0090-4295
145
Health Insurance program in 2005 (n = 25.68 million). The LHID2005 was created by the Taiwan National Health Research Institute and is provided to researchers in Taiwan for academic purposes. Numerous studies that employed this dataset have been published.11,12 Study Sample This study features a study group and a comparison group. The study sample first included 1932 patients who received a first-time diagnosis of PC (ICD-9-CM code 185, malignant neoplasm of the prostate) in ambulatory care centers or hospitalization between January 1, 2001 and December 31, 2010. We then limited the study sample to patients aged ≥40 years (n = 1897) because of the very low prevalence of PC in the age group of <40 years. We further designated the date of their first ambulatory care visit for receiving ADT, including LHRH agonists, antiandrogens, and estrogens, as the index date for these PC patients who received ADT. On the other hand, for PC patients who did not receive ADT, we designated the first ambulatory care visit in which they received a PC diagnosis as the index date. Thereafter, we further excluded 149 patients who received an orchiectomy (ICD-9-CM procedure codes 623 or 624) during the 3-year follow-up period following their index date. Finally, a total of 1748 PC patients were selected for the study. We defined 886 PC patients who received ADT as the study group, whereas 862 PC patients who did not receive ADT served as the comparison group. We then individually tracked each study patient for a 3-year period to identify those who subsequently received a diagnosis of a fall (ICD-9-CM External Cause of Injury Codes E880~E888) following the index date. Statistical Analysis We conducted statistical analyses in this study using the SAS system (SAS System for Windows, vers. 9.2, SAS Institute). Chi-squared tests were used to investigate differences in sociodemographic characteristics (monthly income and the urbanization level and geographic location of the patient’s residence) between PC patients who received and those who did not receive ADT. Many medications may increase the risk of a fall. However, we were incapable of taking all types of different medications into consideration in the study, but instead we adjusted for relevant medical comorbidities in the regression models. These comorbidities included hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, stroke, and mental illness (ICD-9-CM codes 290~299). We further performed Cox proportional hazard regressions to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI) for a fall during the 3-year follow-up period between these two groups. Adjustments were made for patients’ age, geographic location, monthly income, urbanization level, hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, stroke, and mental illness in regression models. In this study, we found that the proportional hazards assumption was satisfied since the survival curves 146
for both strata (patients who received and those who did not receive ADT) had hazard functions that were proportional over time. We also censored those patients who died during the 3-year follow-up period (448 study sample died, including 247 patients who received ADT [27.9%] and 201 patients who did not receive ADT [23.3%]) (P = .455). We used the conventional two-sided P value of .05 to indicate statistical significance in this study.
RESULTS Table 1 shows the distribution of demographic characteristics of PC patients according to the use of ADT. We found that PC patients who had received ADT were more likely to be older than those who had not received ADT (74.2 years vs 70.5 years, P < .001). In addition, there were significant differences in geographic region and monthly income between PC patients who had received ADT and those who had not (both P < .001). However, there was no significant difference in the prevalence of comorbidities of hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, and mental illness between these 2 groups. In addition, the mean length of ADT therapy for PC patients who had received ADT was 524 (±439) days during the 3-year follow-up period. Table 2 presents the incidence of falls among the sampled patients. Among the total sampled patients, the incidence rate of falls per 1000 person-years was 9.99 (95% CI: 7.32~13.24). The incidence rates of falls per 1000 person-years were 13.37 (95% CI: 9.15~18.88) and 6.44 (95% CI: 3.61~10.63), respectively, for PC patients who had received ADT and those who had not received ADT. The log-rank test suggested that PC patients who had received ADT were more likely to have a fall incidence than those who had not received ADT (P = .016). Furthermore, Table 2 reveals that after censoring sampled patients who died during the 3-year follow-up period, the HR for a fall in PC patients who had received ADT was 2.12 (95% CI: 1.14~3.94) compared to those who had not received ADT. Furthermore, Table 3 shows the adjusted HR for a fall during the 3-year follow-up period between the 2 groups. Cox proportional hazard regressions suggested that the HR for a fall during the 3-year follow-up period for PC patients who had received ADT was 1.95 (95% CI: 1.04~3.66, P = .037) compared to those who had not received ADT after censoring sampled patients who died during the 3-year follow-up period and adjusting for age, geographical location, monthly income, urbanization level, hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, stroke, and mental illness.
DISCUSSION Prior studies have reported that ADT may lead to a hypogonadal condition,2 reduce the quality of life,13 cause or exacerbate anemia,2,14 increase risk for diabetes,8,15 and UROLOGY 95, 2016
Table 1. Demographic characteristics of patients with prostate cancer stratified by the use of androgen deprivation therapy (ADT) (n = 1748) Patients Who Received ADT (n = 886) Variable Age (years), mean (SD) Urbanization level 1 (most urbanized) 2 3 4 5 (least urbanized) Geographic region Northern Central Southern Eastern Monthly income NT$0~15,840 NT$15,841~25,000 ≥NT$25,001 Hypertension Diabetes Hyperlipidemia Coronary heart disease Mental illness Epilepsy Parkinson’s disease Stroke
Total No.
Patients Who Did Not Receive ADT (n = 862)
Column %
Total No.
74.2 (8.4)
Column %
P Value <.001 .258
70.5 (10.8)
273 244 135 123 111
30.8 27.5 15.2 13.9 12.5
282 263 112 116 89
32.7 30.5 13.0 13.5 10.2
412 199 253 22
46.5 22.5 28.5 2.5
498 180 171 13
57.8 20.9 19.8 1.5
569 240 77 627 257 341 330 123 7 41 294
64.2 27.1 8.7 70.8 29.0 38.5 37.3 13.9 0.8 4.6 33.2
505 209 148 582 244 343 317 101 9 34 247
58.6 24.2 17.2 67.5 28.3 39.8 36.8 11.7 1.0 3.9 28.7
<.001
<.001
.141 .746 .577 .838 .176 .577 .481 .041
The average exchange rate in 2015 was US$1.00 ≈ New Taiwan (NT)$32.
Table 2. Crude and adjusted hazard ratios (HRs) for falls among patients with prostate cancer during a 3-year follow-up period, stratified by the use of androgen deprivation therapy (ADT)
Presence of a Fall Three-year follow-up period Incidence rate per 1000 person-years (95% CI) Crude HR (95% CI)†
Total Sample (n = 1748)
Patients Who Received ADT (n = 886)
Patients Who Did Not Receive ADT (n = 862)
9.99 (7.32~13.24) —
13.37 (9.15~18.88) 2.12* (1.14~3.94)
6.44 (3.61~10.63) 1.00
CI, confidence interval. * P ≤ .05. † Using a Cox proportional regression with cases censored if individuals died during the 3-year follow-up period.
cognitive alterations.16,17 The present findings suggest that PC patients who had received ADT had an increased risk of falls. This study found that that the adjusted HR for a fall during the 3-year follow-up period for PC patients who had received ADT was 1.95 (95% CI: 1.04~3.66) compared to those who had not received ADT. The mechanisms of the relationship between the use of ADT and the risk of falls remain unclear. One possible explanation for this relationship is that ADT may drastically reduce androgen activity and lead to a hypogonadal condition that has detrimental effects on cognitive health.2 Green et al reported that men receiving androgensuppression monotherapy had a clinically significant decline in cognitive function.16 One systematic review study by Muir et al concluded that cognitive impairment was an important risk factor for a fall.18 A second explanation could be the decreased insulin sensitivity after receiving ADT. Using the US-based Surveillance, Epidemiology, and End Results Medicare database, UROLOGY 95, 2016
Keating et al found that men with PC who were receiving ADT with an LHRH agonist had a 44% increased risk of incident diabetes.15 Some studies indicated that diabetes is associated with an increased incidence of falls.19,20 Therefore, the decreased insulin sensitivity caused by ADT may increase the risk of a fall. Another possible explanation is the decreased level of hemoglobin in patients receiving ADT. Prior studies reported that men receiving ADT had a median decrease in hemoglobin.2,21 A study by Dharmarajan et al also found that mild anemia was related to an increased risk of falls among patients.22 In addition, another study by Penninx et al suggested that anemia could help identify patients at higher risk for subsequent falls.23 Furthermore, androgens are an important determinant of the body’s composition in males. A bilateral orchiectomy or pharmacological methods with LHRH receptor agonists can induce significant alterations in the chemical composition of cell membranes.8 For example, Smith 147
Table 3. Adjusted HR for a fall during the 3-year followup period among patients with prostate cancer (n = 1748) Fall Occurrence Variable ADT receiver Age Geographic region Northern Central Southern Eastern Monthly income NT$0~15,840 NT$15,841~25,000 ≥NT$25,001 Urbanization level 1 (most urbanized) 2 3 4 5 (least urbanized) Hypertension Diabetes Hyperlipidemia Coronary heart disease Mental illness Parkinson’s disease Stroke Epilepsy
HR
95% CI
P Value
1.95 1.06
1.04~3.66 1.02~1.10
.037 .004
1.00 1.37 1.04 2.72
0.63~2.97 0.47~2.31 0.69~10.65
.431 .927 .152
1.00 0.88 0.68
0.42~1.85 0.15~3.08
.741 .614
1.00 0.57 1.17 2.00 1.68 1.87 0.95 0.89 1.01 2.00 2.42 1.81 1.79
0.22~1.47 0.44~3.16 0.78~5.17 0.58~4.90 0.83~4.21 0.48~1.88 0.46~1.70 0.54~1.89 0.99~4.04 0.96~6.10 0.97~3.40 0.23~14.67
.243 .751 .151 .342 .131 .888 .720 .965 .054 .062 .065 .589
Abbreviations as in Table 1. All hazard ratios were derived from the same Cox regression model and adjusted for all other variables. The average exchange rate in 2015 was US$1.00 ≈ New Taiwan (NT)$32.
et al conducted a prospective study of 32 men initiating ADT for PC and found that the lean body mass in this group of patients decreased by 2.7%, whereas there was a 9.4% increase in the body fat percentage.24 In addition, a study by Grossmann et al reported that body composition changes lead to sarcopenia, which may result in an increased risk of falls.9 Recently, Scott et al also identified an association between sarcopenia and a risk of falls in community-dwelling middle-aged and older adults.25 Consequently, changes in the body’s composition after the use of ADT may increase the risk of falls in patients with PC. Using the LHID2005, the strength of our study is the representative large sample from this population-based dataset that represents the national distribution of PC patients receiving ADT. This avoids problems of a selfselection bias inherent in voluntary registries or hospitalbased studies in which many PC patients may have been overlooked and results in lower levels of control for such patients. Additionally, the longitudinal data and completed reimbursement claims provide precise estimates of drug expenditures and consumption. Furthermore, potential confounders and important medical comorbidities that may contribute to the risk of falls, including hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, stroke, and mental illness, were taken into consideration in the Cox regression models. 148
However, the findings from our study must be interpreted while bearing several caveats in mind. Firstly, selection bias is prone to occur in a retrospective study. However, our study represented a large sample from a population-based dataset. This avoided the problem of selfselection bias. Secondly, the retrospective study did not record some important patients’ characteristics that included patients’ body mass index, alcohol and tobacco consumption, physical activity, substance use, and patient’s environmental risk factors. In addition, information on patients’ adherence to medication was unavailable when the claims data were used. Therefore, considerable differences regarding patient characteristics may exist between ADT and non-ADT group that could not be considered in this study. Thirdly, according to the National Comprehensive Cancer Network clinical practice guidelines in PC, ADT is usually advised to treat those PC patients with nodepositive or metastatic PC. Therefore, those PC patients who received ADT had a greater tendency to have severe and advanced PC. However, the LHID2005 lacked clinical information on the severity of PC. 12 Furthermore, the LHID2005 did not allow us to determine that patients on ADT were mostly primary ADT, adjuvant ADT, or treatment for advanced PC from the LHID2005 database. Finally, it may be difficult to generalize our findings to Western societies because of differences in dietary habits, lifestyle, nutritional status, and smoking prevalence. In spite of our study limitations, we were able to present a relationship between ADT and the increased fall risks, whereas little is known about the optimal strategy that mitigated the risk of falls among PC patients who received ADT. Therefore, altered cognitive function could be 1 of the multifactorial mechanisms that contributed to the increased risk of falls among PC patients who received ADT. Guo et al demonstrated that exercise interventions significantly decreased the numbers of falls among older adults with cognitive impairment.26 Muscle loss may be associated with fall risk as well; a combination of resistance and aerobic exercise programs has shown continual benefits to muscle loss in men who underwent ADT for PC patients,2 and may be an appropriate and costless fall prevention strategy.
CONCLUSION The present findings suggest that PC patients who had received ADT had an increased risk of falls. Medical professionals should be aware that the medication used for ADT, when administered to patients, may act as a trigger of falls. Clinicians, especially urologists, and pharmacists may consider alerting their PC patients who take ADT of the potential risk of a fall, and need to do a better job preventing falls, with PC patients utilizing multidisciplinary care pathways and fall prevention therapies. References 1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87-108.
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2. Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol. 2015;67:825-836. 3. Schroder F, Crawford ED, Axcrona K, et al. Androgen deprivation therapy: past, present and future. BJU Int. 2012;109:1-12. 4. Oh WK, Landrum MB, Lamont EB, et al. Does oral antiandrogen use before luteinizing hormone-releasing hormone therapy in patients with metastatic prostate cancer prevent clinical consequences of a testosterone flare? Urology. 2010;75:642-647. 5. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002;360:103-106. 6. D’Amico AV, Manola J, Loffredo M, et al. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA. 2004;292:821-827. 7. Smith MR. Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology. 2004;63:742-745. 8. Morote J, Go˘ mez-Caamanˇ o A, Alvarez-Ossorio JL, et al. The metabolic syndrome and its components in patients with prostate cancer on androgen deprivation therapy. J Urol. 2015;193:19631969. 9. Grossmann M, Hamilton EJ, Gilfillan C, et al. Bone and metabolic health in patients with non-metastatic prostate cancer who are receiving androgen deprivation therapy. Med J Aust. 2011;194:301306. 10. WHO MCo. WHO Factsheets Falls. 2012. Available at: http://www.who.int/mediacentre/factsheets/fs344/en/. Accessed January 10, 2016. 11. Chung SD, Chen YK, Wu FJ, et al. Hormone therapy for prostate cancer and the risk of stroke: a 5-year follow-up study. BJU Int. 2012;109:1001-1005. 12. Wang LH, Liu CK, Chen CH, et al. No increased risk of coronary heart disease for patients receiving androgen deprivation therapy for prostate cancer in Chinese/Taiwanese men. Andrology. 2016;4:128132. 13. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009;360:2516-2527. 14. Choo R, Chander S, Danjoux C, et al. How are haemoglobin levels affected by androgen deprivation in nonmetastatic prostate cancer patients? Can J Urol. 2005;12:2547-2552. 15. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448-4456. 16. Green HJ, Pakenham KI, Headley BC, et al. Altered cognitive function in men treated for prostate cancer with luteinizing hormonereleasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJU Int. 2002;90:427-432. 17. Levy ME. Physical function changes in prostate cancer patients on androgen deprivation therapy: a 2-year prospective study. Urology. 2008;71:735-739. 18. Muir SW, Gopaul K, Montero Odasso MM. The role of cognitive impairment in fall risk among older adults: a systematic review and meta-analysis. Age Ageing. 2012;41:299-308. 19. Lu CL, Hsu PC, Shen HN, et al. Association between history of severe hypoglycemia and risk of falls in younger and older patients with diabetes. Medicine (Baltimore). 2015;94:e1339. 20. Tilling LM, Darawil K, Britton M. Falls as a complication of diabetes mellitus in older people. J Diabetes Complications. 2006;20:158162. 21. Fonseca R, Rajkumar SV, White WL, et al. Anemia after orchiectomy. Am J Hematol. 1998;59:230-233. 22. Dharmarajan TS, Avula S, Norkus EP. Anemia increases risk for falls in hospitalized older adults: an evaluation of falls in 362 hospitalized, ambulatory, long-term care, and community patients. J Am Med Dir Assoc. 2006;7:287-293.
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23. Penninx BW, Pluijm SM, Lips P, et al. Late-life anemia is associated with increased risk of recurrent falls. J Am Geriatr Soc. 2005;53:21062111. 24. Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87:599-603. 25. Scott D, Hayes A, Sanders KM, et al. Operational definitions of sarcopenia and their associations with 5-year changes in falls risk in community-dwelling middle-aged and older adults. Osteoporos Int. 2014;25:187-193. 26. Guo JL, Tsai YY, Liao JY, et al. Interventions to reduce the number of falls among older adults with/without cognitive impairment: an exploratory meta-analysis. Int J Geriatr Psychiatry. 2014;29:661669.
EDITORIAL COMMENT Androgen deprivation therapy (ADT) has been the cornerstone treatment of metastatic prostate cancer for the past half century.1 A significant rise in the use of hormonal manipulation has been seen over the past decade. Cetin et al recently reported that in the United States, 190,000 men aged ≥45 years were actively receiving continuous ADT for ≥6 months in the nonmetastatic setting.2 It is well known that ADT is linked to significant adverse effects, such as metabolic syndrome,3 cardiovascular diseases,4 and bone loss.5 In this study, the authors provide data on increased fall risk in 886 patients receiving ADT for prostate cancer.6 This is a retrospective study and thus, there is an inherent selection bias. However, it should be emphasized that it is the first study in the literature examining fall risk as it is accurately retrieved from a country’s’ population-based dataset using an ICD-9 diagnosis. The authors have shown that patients receiving ADT have doubled risk of falls and this risk was not altered after adjusting for other risk factors such as metabolic syndrome and other mental illnesses. Similarly, Bylow et al reported a 22% risk of fall in a sample of 50 patients receiving ADT for systemic prostate cancer.7 The combination of low bone density and increased falls could contribute to the increased risk of fractures noted in this population. In a large retrospective cohort study, men treated with ADT for at least 6 months experienced more fractures than matched controls (9.0% vs 5.9%).8 Shao et al reported that if a fracture occurred, it was associated with an overall 40% higher relative risk of mortality compared to if no fracture occurred.9 Therefore, the risk of ADT use must be balanced carefully with the potential for benefit to the patient. Preventative strategies should be developed to reduce adverse events related with increased morbidity, mortality, and costs. When making treatment decisions about ADT, physicians should be aware of the existing guidelines for the indications of ADT in prostate cancer so as to avoid overtreatment, and patients should be informed of the increased risk of adverse effects such as osteoporosis, fracture risks, obesity, alteration in lipids, diabetes, and cardiovascular disease. Intermittent ADT is another option to reduce exposure to ADT. A recent study of more than 1500 men with metastatic prostate cancer reported that intermittent treatment improved the quality of life.10 Physicians caring for this patient population should consider routinely screening for abnormal physical performance and falls, and patients receiving ADT should be counseled to recognize, prevent, and manage side effects. A healthy lifestyle including
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a heart-healthy diet and manageable regular exercise program should be recommended for these patients. Additional controlled studies are necessary to determine the effect of ADT on physical disability and the effect of interventions on preventing falls and physical dysfunction. Nikolaos Grivas, M.D., Ph.D., F.E.B.U., Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; Department of Urology, G. Hatzikosta General Hospital, Ioannina, Greece
References 1. Shahinian VB, Kuo YF, Gilbert SM. Reimbursement policy and androgen-deprivation therapy for prostate cancer. N Engl J Med. 2010;363:1822-1832. 2. Cetin K, Li S, Blaes AH, et al. Prevalence of patients with nonmetastatic prostate cancer on androgen deprivation therapy in the United States. Urology. 2013;81:1184-1189. 3. Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol. 2006;24:39793983.
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4. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448-4456. 5. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352:154-164. 6. Wu F-J, Sheu S-Y, Lin H-C, Chung S-D. Increased fall risk in patients receiving androgen deprivation therapy for prostate cancer. Urology. 2016. doi: 10.1016/j.urology.2016.05.058. 7. Bylow K, Dale W, Mustian K, et al. Falls and physical performance deficits in older patients with prostate cancer undergoing androgen deprivation therapy. Urology. 2008;72:422-427. 8. Alibhai SM, Duong-Hua M, Cheung AM, et al. Fracture types and risk factors in men with prostate cancer on androgen deprivation therapy: a matched cohort study of 19,079 men. J Urol. 2010;184:918923. 9. Shao YH, Moore DF, Shih W, et al. Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications. BJU Int. 2013;111:745-752. 10. Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368:1314-1325.
http://dx.doi.org/10.1016/j.urology.2016.05.059 UROLOGY 95: 149–150, 2016. © 2016 Published by Elsevier
Inc.
UROLOGY 95, 2016
METHODS
RESULTS
CONCLUSION
To examine the relationship between the use of androgen deprivation therapy (ADT) and the subsequent risk of falls in men with prostate cancer (PC) by employing a population-based dataset. We retrieved the study sample from the Taiwan Longitudinal Health Insurance Database 2005. We included 886 patients with PC who had received ADT as the study group, whereas 862 patients with PC who had not received ADT served as the comparison group. We then individually tracked each study patient for a 3-year period to identify those who subsequently received a diagnosis of a fall. We performed Cox proportional hazard regressions to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI) for a fall during the 3-year follow-up period between these 2 groups. The incidence rates of falls per 1000 person-years were 13.37 (95% CI: 9.15~18.88) and 6.44 (95% CI: 3.61~10.63), respectively, for patients with PC who received ADT and those who did not receive ADT. Furthermore, the hazard ratio for a fall during the 3-year follow-up period for patients with PC who had received ADT was 1.95 (95% CI: 1.04~3.66, P = .037) compared to those who had not received ADT after censoring sampled patients who died during the 3-year follow-up period and adjusting for age, geographical location, monthly income, urbanization level, hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, stroke, and mental illness. The present findings suggest that patients with PC who had received ADT had an increased risk of falls. UROLOGY 95: 145–150, 2016. © 2016 Published by Elsevier Inc.
P
rostate cancer (PC) is the second most common diagnosed malignancy in men worldwide, with an estimated 1.1 million cases reported in 2012.1 Androgen deprivation therapy (ADT) is the standard treatment for aggressive and advanced PC.2 ADT includes an orchiectomy, estrogens, antiandrogens, luteinizing hormonereleasing hormone (LHRH) agonists and antagonists.3,4 Plenty of studies have demonstrated that ADT can improve disease-free and overall survival when used in combination with radiation for patients with locally advanced PC.5,6 However, androgens are an important part Shiow-Yunn Sheu, Herng-Ching Lin, and Shiu-Dong Chung contributed equally to this study. Financial Disclosure: The authors declare that they have no relevant financial interests. From the School of Pharmacy, Taipei Medical University, Taipei, Taiwan; the School of Medical Laboratory Sciences and Biotechnology, Taipei Medical University, Taipei, Taiwan; the Sleep Research Center, Taipei Medical University Hospital, Taipei, Taiwan; and the Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, Ban Ciao, Taipei, Taiwan Address correspondence to: Shiu-Dong Chung, M.D., Ph.D., Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, Ban Ciao, Taipei 110, Taiwan. E-mail: [email protected] Submitted: March 15, 2016, accepted (with revisions): May 12, 2016
© 2016 Published by Elsevier Inc.
of the body composition in males as they support lean body mass over fat mass.7 One study indicated that LHRH agonist therapy increased fat mass by 10% and decreased lean body mass by 3% and also the associated sarcopenic obesity.8 The reduced muscle mass may be related to the risk of falls.9 Globally, falls are the major cause of accidental or unintentional injury and deaths.10 However, previous findings rarely examined the association between ADT and the risk of falls. To fill in this gap in the literature, the present study aimed to examine the relationship between the use of ADT and the subsequent risk of falls in men with PC by employing a population-based dataset in Taiwan.
METHODS Database We retrieved the study sample for this population-based retrospective cohort study from the Taiwan Longitudinal Health Insurance Database 2005 (LHID2005). The LHID2005 includes beneficiary registration files and medical claims data for reimbursement for 1 million individuals randomly selected from all enrollees in the Taiwan National http://dx.doi.org/10.1016/j.urology.2016.05.058 0090-4295
145
Health Insurance program in 2005 (n = 25.68 million). The LHID2005 was created by the Taiwan National Health Research Institute and is provided to researchers in Taiwan for academic purposes. Numerous studies that employed this dataset have been published.11,12 Study Sample This study features a study group and a comparison group. The study sample first included 1932 patients who received a first-time diagnosis of PC (ICD-9-CM code 185, malignant neoplasm of the prostate) in ambulatory care centers or hospitalization between January 1, 2001 and December 31, 2010. We then limited the study sample to patients aged ≥40 years (n = 1897) because of the very low prevalence of PC in the age group of <40 years. We further designated the date of their first ambulatory care visit for receiving ADT, including LHRH agonists, antiandrogens, and estrogens, as the index date for these PC patients who received ADT. On the other hand, for PC patients who did not receive ADT, we designated the first ambulatory care visit in which they received a PC diagnosis as the index date. Thereafter, we further excluded 149 patients who received an orchiectomy (ICD-9-CM procedure codes 623 or 624) during the 3-year follow-up period following their index date. Finally, a total of 1748 PC patients were selected for the study. We defined 886 PC patients who received ADT as the study group, whereas 862 PC patients who did not receive ADT served as the comparison group. We then individually tracked each study patient for a 3-year period to identify those who subsequently received a diagnosis of a fall (ICD-9-CM External Cause of Injury Codes E880~E888) following the index date. Statistical Analysis We conducted statistical analyses in this study using the SAS system (SAS System for Windows, vers. 9.2, SAS Institute). Chi-squared tests were used to investigate differences in sociodemographic characteristics (monthly income and the urbanization level and geographic location of the patient’s residence) between PC patients who received and those who did not receive ADT. Many medications may increase the risk of a fall. However, we were incapable of taking all types of different medications into consideration in the study, but instead we adjusted for relevant medical comorbidities in the regression models. These comorbidities included hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, stroke, and mental illness (ICD-9-CM codes 290~299). We further performed Cox proportional hazard regressions to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI) for a fall during the 3-year follow-up period between these two groups. Adjustments were made for patients’ age, geographic location, monthly income, urbanization level, hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, stroke, and mental illness in regression models. In this study, we found that the proportional hazards assumption was satisfied since the survival curves 146
for both strata (patients who received and those who did not receive ADT) had hazard functions that were proportional over time. We also censored those patients who died during the 3-year follow-up period (448 study sample died, including 247 patients who received ADT [27.9%] and 201 patients who did not receive ADT [23.3%]) (P = .455). We used the conventional two-sided P value of .05 to indicate statistical significance in this study.
RESULTS Table 1 shows the distribution of demographic characteristics of PC patients according to the use of ADT. We found that PC patients who had received ADT were more likely to be older than those who had not received ADT (74.2 years vs 70.5 years, P < .001). In addition, there were significant differences in geographic region and monthly income between PC patients who had received ADT and those who had not (both P < .001). However, there was no significant difference in the prevalence of comorbidities of hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, and mental illness between these 2 groups. In addition, the mean length of ADT therapy for PC patients who had received ADT was 524 (±439) days during the 3-year follow-up period. Table 2 presents the incidence of falls among the sampled patients. Among the total sampled patients, the incidence rate of falls per 1000 person-years was 9.99 (95% CI: 7.32~13.24). The incidence rates of falls per 1000 person-years were 13.37 (95% CI: 9.15~18.88) and 6.44 (95% CI: 3.61~10.63), respectively, for PC patients who had received ADT and those who had not received ADT. The log-rank test suggested that PC patients who had received ADT were more likely to have a fall incidence than those who had not received ADT (P = .016). Furthermore, Table 2 reveals that after censoring sampled patients who died during the 3-year follow-up period, the HR for a fall in PC patients who had received ADT was 2.12 (95% CI: 1.14~3.94) compared to those who had not received ADT. Furthermore, Table 3 shows the adjusted HR for a fall during the 3-year follow-up period between the 2 groups. Cox proportional hazard regressions suggested that the HR for a fall during the 3-year follow-up period for PC patients who had received ADT was 1.95 (95% CI: 1.04~3.66, P = .037) compared to those who had not received ADT after censoring sampled patients who died during the 3-year follow-up period and adjusting for age, geographical location, monthly income, urbanization level, hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, stroke, and mental illness.
DISCUSSION Prior studies have reported that ADT may lead to a hypogonadal condition,2 reduce the quality of life,13 cause or exacerbate anemia,2,14 increase risk for diabetes,8,15 and UROLOGY 95, 2016
Table 1. Demographic characteristics of patients with prostate cancer stratified by the use of androgen deprivation therapy (ADT) (n = 1748) Patients Who Received ADT (n = 886) Variable Age (years), mean (SD) Urbanization level 1 (most urbanized) 2 3 4 5 (least urbanized) Geographic region Northern Central Southern Eastern Monthly income NT$0~15,840 NT$15,841~25,000 ≥NT$25,001 Hypertension Diabetes Hyperlipidemia Coronary heart disease Mental illness Epilepsy Parkinson’s disease Stroke
Total No.
Patients Who Did Not Receive ADT (n = 862)
Column %
Total No.
74.2 (8.4)
Column %
P Value <.001 .258
70.5 (10.8)
273 244 135 123 111
30.8 27.5 15.2 13.9 12.5
282 263 112 116 89
32.7 30.5 13.0 13.5 10.2
412 199 253 22
46.5 22.5 28.5 2.5
498 180 171 13
57.8 20.9 19.8 1.5
569 240 77 627 257 341 330 123 7 41 294
64.2 27.1 8.7 70.8 29.0 38.5 37.3 13.9 0.8 4.6 33.2
505 209 148 582 244 343 317 101 9 34 247
58.6 24.2 17.2 67.5 28.3 39.8 36.8 11.7 1.0 3.9 28.7
<.001
<.001
.141 .746 .577 .838 .176 .577 .481 .041
The average exchange rate in 2015 was US$1.00 ≈ New Taiwan (NT)$32.
Table 2. Crude and adjusted hazard ratios (HRs) for falls among patients with prostate cancer during a 3-year follow-up period, stratified by the use of androgen deprivation therapy (ADT)
Presence of a Fall Three-year follow-up period Incidence rate per 1000 person-years (95% CI) Crude HR (95% CI)†
Total Sample (n = 1748)
Patients Who Received ADT (n = 886)
Patients Who Did Not Receive ADT (n = 862)
9.99 (7.32~13.24) —
13.37 (9.15~18.88) 2.12* (1.14~3.94)
6.44 (3.61~10.63) 1.00
CI, confidence interval. * P ≤ .05. † Using a Cox proportional regression with cases censored if individuals died during the 3-year follow-up period.
cognitive alterations.16,17 The present findings suggest that PC patients who had received ADT had an increased risk of falls. This study found that that the adjusted HR for a fall during the 3-year follow-up period for PC patients who had received ADT was 1.95 (95% CI: 1.04~3.66) compared to those who had not received ADT. The mechanisms of the relationship between the use of ADT and the risk of falls remain unclear. One possible explanation for this relationship is that ADT may drastically reduce androgen activity and lead to a hypogonadal condition that has detrimental effects on cognitive health.2 Green et al reported that men receiving androgensuppression monotherapy had a clinically significant decline in cognitive function.16 One systematic review study by Muir et al concluded that cognitive impairment was an important risk factor for a fall.18 A second explanation could be the decreased insulin sensitivity after receiving ADT. Using the US-based Surveillance, Epidemiology, and End Results Medicare database, UROLOGY 95, 2016
Keating et al found that men with PC who were receiving ADT with an LHRH agonist had a 44% increased risk of incident diabetes.15 Some studies indicated that diabetes is associated with an increased incidence of falls.19,20 Therefore, the decreased insulin sensitivity caused by ADT may increase the risk of a fall. Another possible explanation is the decreased level of hemoglobin in patients receiving ADT. Prior studies reported that men receiving ADT had a median decrease in hemoglobin.2,21 A study by Dharmarajan et al also found that mild anemia was related to an increased risk of falls among patients.22 In addition, another study by Penninx et al suggested that anemia could help identify patients at higher risk for subsequent falls.23 Furthermore, androgens are an important determinant of the body’s composition in males. A bilateral orchiectomy or pharmacological methods with LHRH receptor agonists can induce significant alterations in the chemical composition of cell membranes.8 For example, Smith 147
Table 3. Adjusted HR for a fall during the 3-year followup period among patients with prostate cancer (n = 1748) Fall Occurrence Variable ADT receiver Age Geographic region Northern Central Southern Eastern Monthly income NT$0~15,840 NT$15,841~25,000 ≥NT$25,001 Urbanization level 1 (most urbanized) 2 3 4 5 (least urbanized) Hypertension Diabetes Hyperlipidemia Coronary heart disease Mental illness Parkinson’s disease Stroke Epilepsy
HR
95% CI
P Value
1.95 1.06
1.04~3.66 1.02~1.10
.037 .004
1.00 1.37 1.04 2.72
0.63~2.97 0.47~2.31 0.69~10.65
.431 .927 .152
1.00 0.88 0.68
0.42~1.85 0.15~3.08
.741 .614
1.00 0.57 1.17 2.00 1.68 1.87 0.95 0.89 1.01 2.00 2.42 1.81 1.79
0.22~1.47 0.44~3.16 0.78~5.17 0.58~4.90 0.83~4.21 0.48~1.88 0.46~1.70 0.54~1.89 0.99~4.04 0.96~6.10 0.97~3.40 0.23~14.67
.243 .751 .151 .342 .131 .888 .720 .965 .054 .062 .065 .589
Abbreviations as in Table 1. All hazard ratios were derived from the same Cox regression model and adjusted for all other variables. The average exchange rate in 2015 was US$1.00 ≈ New Taiwan (NT)$32.
et al conducted a prospective study of 32 men initiating ADT for PC and found that the lean body mass in this group of patients decreased by 2.7%, whereas there was a 9.4% increase in the body fat percentage.24 In addition, a study by Grossmann et al reported that body composition changes lead to sarcopenia, which may result in an increased risk of falls.9 Recently, Scott et al also identified an association between sarcopenia and a risk of falls in community-dwelling middle-aged and older adults.25 Consequently, changes in the body’s composition after the use of ADT may increase the risk of falls in patients with PC. Using the LHID2005, the strength of our study is the representative large sample from this population-based dataset that represents the national distribution of PC patients receiving ADT. This avoids problems of a selfselection bias inherent in voluntary registries or hospitalbased studies in which many PC patients may have been overlooked and results in lower levels of control for such patients. Additionally, the longitudinal data and completed reimbursement claims provide precise estimates of drug expenditures and consumption. Furthermore, potential confounders and important medical comorbidities that may contribute to the risk of falls, including hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson’s disease, epilepsy, stroke, and mental illness, were taken into consideration in the Cox regression models. 148
However, the findings from our study must be interpreted while bearing several caveats in mind. Firstly, selection bias is prone to occur in a retrospective study. However, our study represented a large sample from a population-based dataset. This avoided the problem of selfselection bias. Secondly, the retrospective study did not record some important patients’ characteristics that included patients’ body mass index, alcohol and tobacco consumption, physical activity, substance use, and patient’s environmental risk factors. In addition, information on patients’ adherence to medication was unavailable when the claims data were used. Therefore, considerable differences regarding patient characteristics may exist between ADT and non-ADT group that could not be considered in this study. Thirdly, according to the National Comprehensive Cancer Network clinical practice guidelines in PC, ADT is usually advised to treat those PC patients with nodepositive or metastatic PC. Therefore, those PC patients who received ADT had a greater tendency to have severe and advanced PC. However, the LHID2005 lacked clinical information on the severity of PC. 12 Furthermore, the LHID2005 did not allow us to determine that patients on ADT were mostly primary ADT, adjuvant ADT, or treatment for advanced PC from the LHID2005 database. Finally, it may be difficult to generalize our findings to Western societies because of differences in dietary habits, lifestyle, nutritional status, and smoking prevalence. In spite of our study limitations, we were able to present a relationship between ADT and the increased fall risks, whereas little is known about the optimal strategy that mitigated the risk of falls among PC patients who received ADT. Therefore, altered cognitive function could be 1 of the multifactorial mechanisms that contributed to the increased risk of falls among PC patients who received ADT. Guo et al demonstrated that exercise interventions significantly decreased the numbers of falls among older adults with cognitive impairment.26 Muscle loss may be associated with fall risk as well; a combination of resistance and aerobic exercise programs has shown continual benefits to muscle loss in men who underwent ADT for PC patients,2 and may be an appropriate and costless fall prevention strategy.
CONCLUSION The present findings suggest that PC patients who had received ADT had an increased risk of falls. Medical professionals should be aware that the medication used for ADT, when administered to patients, may act as a trigger of falls. Clinicians, especially urologists, and pharmacists may consider alerting their PC patients who take ADT of the potential risk of a fall, and need to do a better job preventing falls, with PC patients utilizing multidisciplinary care pathways and fall prevention therapies. References 1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87-108.
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2. Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol. 2015;67:825-836. 3. Schroder F, Crawford ED, Axcrona K, et al. Androgen deprivation therapy: past, present and future. BJU Int. 2012;109:1-12. 4. Oh WK, Landrum MB, Lamont EB, et al. Does oral antiandrogen use before luteinizing hormone-releasing hormone therapy in patients with metastatic prostate cancer prevent clinical consequences of a testosterone flare? Urology. 2010;75:642-647. 5. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002;360:103-106. 6. D’Amico AV, Manola J, Loffredo M, et al. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA. 2004;292:821-827. 7. Smith MR. Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology. 2004;63:742-745. 8. Morote J, Go˘ mez-Caamanˇ o A, Alvarez-Ossorio JL, et al. The metabolic syndrome and its components in patients with prostate cancer on androgen deprivation therapy. J Urol. 2015;193:19631969. 9. Grossmann M, Hamilton EJ, Gilfillan C, et al. Bone and metabolic health in patients with non-metastatic prostate cancer who are receiving androgen deprivation therapy. Med J Aust. 2011;194:301306. 10. WHO MCo. WHO Factsheets Falls. 2012. Available at: http://www.who.int/mediacentre/factsheets/fs344/en/. Accessed January 10, 2016. 11. Chung SD, Chen YK, Wu FJ, et al. Hormone therapy for prostate cancer and the risk of stroke: a 5-year follow-up study. BJU Int. 2012;109:1001-1005. 12. Wang LH, Liu CK, Chen CH, et al. No increased risk of coronary heart disease for patients receiving androgen deprivation therapy for prostate cancer in Chinese/Taiwanese men. Andrology. 2016;4:128132. 13. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009;360:2516-2527. 14. Choo R, Chander S, Danjoux C, et al. How are haemoglobin levels affected by androgen deprivation in nonmetastatic prostate cancer patients? Can J Urol. 2005;12:2547-2552. 15. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448-4456. 16. Green HJ, Pakenham KI, Headley BC, et al. Altered cognitive function in men treated for prostate cancer with luteinizing hormonereleasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJU Int. 2002;90:427-432. 17. Levy ME. Physical function changes in prostate cancer patients on androgen deprivation therapy: a 2-year prospective study. Urology. 2008;71:735-739. 18. Muir SW, Gopaul K, Montero Odasso MM. The role of cognitive impairment in fall risk among older adults: a systematic review and meta-analysis. Age Ageing. 2012;41:299-308. 19. Lu CL, Hsu PC, Shen HN, et al. Association between history of severe hypoglycemia and risk of falls in younger and older patients with diabetes. Medicine (Baltimore). 2015;94:e1339. 20. Tilling LM, Darawil K, Britton M. Falls as a complication of diabetes mellitus in older people. J Diabetes Complications. 2006;20:158162. 21. Fonseca R, Rajkumar SV, White WL, et al. Anemia after orchiectomy. Am J Hematol. 1998;59:230-233. 22. Dharmarajan TS, Avula S, Norkus EP. Anemia increases risk for falls in hospitalized older adults: an evaluation of falls in 362 hospitalized, ambulatory, long-term care, and community patients. J Am Med Dir Assoc. 2006;7:287-293.
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23. Penninx BW, Pluijm SM, Lips P, et al. Late-life anemia is associated with increased risk of recurrent falls. J Am Geriatr Soc. 2005;53:21062111. 24. Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87:599-603. 25. Scott D, Hayes A, Sanders KM, et al. Operational definitions of sarcopenia and their associations with 5-year changes in falls risk in community-dwelling middle-aged and older adults. Osteoporos Int. 2014;25:187-193. 26. Guo JL, Tsai YY, Liao JY, et al. Interventions to reduce the number of falls among older adults with/without cognitive impairment: an exploratory meta-analysis. Int J Geriatr Psychiatry. 2014;29:661669.
EDITORIAL COMMENT Androgen deprivation therapy (ADT) has been the cornerstone treatment of metastatic prostate cancer for the past half century.1 A significant rise in the use of hormonal manipulation has been seen over the past decade. Cetin et al recently reported that in the United States, 190,000 men aged ≥45 years were actively receiving continuous ADT for ≥6 months in the nonmetastatic setting.2 It is well known that ADT is linked to significant adverse effects, such as metabolic syndrome,3 cardiovascular diseases,4 and bone loss.5 In this study, the authors provide data on increased fall risk in 886 patients receiving ADT for prostate cancer.6 This is a retrospective study and thus, there is an inherent selection bias. However, it should be emphasized that it is the first study in the literature examining fall risk as it is accurately retrieved from a country’s’ population-based dataset using an ICD-9 diagnosis. The authors have shown that patients receiving ADT have doubled risk of falls and this risk was not altered after adjusting for other risk factors such as metabolic syndrome and other mental illnesses. Similarly, Bylow et al reported a 22% risk of fall in a sample of 50 patients receiving ADT for systemic prostate cancer.7 The combination of low bone density and increased falls could contribute to the increased risk of fractures noted in this population. In a large retrospective cohort study, men treated with ADT for at least 6 months experienced more fractures than matched controls (9.0% vs 5.9%).8 Shao et al reported that if a fracture occurred, it was associated with an overall 40% higher relative risk of mortality compared to if no fracture occurred.9 Therefore, the risk of ADT use must be balanced carefully with the potential for benefit to the patient. Preventative strategies should be developed to reduce adverse events related with increased morbidity, mortality, and costs. When making treatment decisions about ADT, physicians should be aware of the existing guidelines for the indications of ADT in prostate cancer so as to avoid overtreatment, and patients should be informed of the increased risk of adverse effects such as osteoporosis, fracture risks, obesity, alteration in lipids, diabetes, and cardiovascular disease. Intermittent ADT is another option to reduce exposure to ADT. A recent study of more than 1500 men with metastatic prostate cancer reported that intermittent treatment improved the quality of life.10 Physicians caring for this patient population should consider routinely screening for abnormal physical performance and falls, and patients receiving ADT should be counseled to recognize, prevent, and manage side effects. A healthy lifestyle including
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a heart-healthy diet and manageable regular exercise program should be recommended for these patients. Additional controlled studies are necessary to determine the effect of ADT on physical disability and the effect of interventions on preventing falls and physical dysfunction. Nikolaos Grivas, M.D., Ph.D., F.E.B.U., Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; Department of Urology, G. Hatzikosta General Hospital, Ioannina, Greece
References 1. Shahinian VB, Kuo YF, Gilbert SM. Reimbursement policy and androgen-deprivation therapy for prostate cancer. N Engl J Med. 2010;363:1822-1832. 2. Cetin K, Li S, Blaes AH, et al. Prevalence of patients with nonmetastatic prostate cancer on androgen deprivation therapy in the United States. Urology. 2013;81:1184-1189. 3. Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol. 2006;24:39793983.
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4. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448-4456. 5. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352:154-164. 6. Wu F-J, Sheu S-Y, Lin H-C, Chung S-D. Increased fall risk in patients receiving androgen deprivation therapy for prostate cancer. Urology. 2016. doi: 10.1016/j.urology.2016.05.058. 7. Bylow K, Dale W, Mustian K, et al. Falls and physical performance deficits in older patients with prostate cancer undergoing androgen deprivation therapy. Urology. 2008;72:422-427. 8. Alibhai SM, Duong-Hua M, Cheung AM, et al. Fracture types and risk factors in men with prostate cancer on androgen deprivation therapy: a matched cohort study of 19,079 men. J Urol. 2010;184:918923. 9. Shao YH, Moore DF, Shih W, et al. Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications. BJU Int. 2013;111:745-752. 10. Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368:1314-1325.
http://dx.doi.org/10.1016/j.urology.2016.05.059 UROLOGY 95: 149–150, 2016. © 2016 Published by Elsevier
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