Androgen Deprivation Therapy Impact on Quality of Life and Cardiovascular Health, Monitoring Therapeutic Replacement

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Androgen Deprivation Therapy Impact on Quality of Life and Cardiovascular Health, Monitoring Therapeutic Replacement Landon W. Trost, MD,* Ege Serefoglu, MD,† Ahmet Gokce, MD,† Brian J. Linder, MD,* Alton O. Sartor, MD,† and Wayne J.G. Hellstrom, MD† *Mayo Clinic, Rochester, MN, USA; †Tulane University, Urology, New Orleans, LA, USA DOI: 10.1111/jsm.12036

ABSTRACT

Introduction. Androgen deprivation therapy (ADT) is commonly utilized in the management of both localized and advanced adenocarcinoma of the prostate. The use of ADT is associated with several adverse events, physical changes, and development of medical comorbidities/mortality. Aim. The current article reviews known adverse events associated with ADT as well as treatment options, where available. Current recommendations and guidelines are cited for ongoing monitoring of patients receiving ADT. Methods. A PubMed search of topics relating to ADT and adverse outcomes was performed, with select articles highlighted and reviewed based on level of evidence and overall contribution. Main Outcome Measures. Reported outcomes of studies detailing adverse effects of ADT were reviewed and discussed. Where available, randomized trials and meta-analyses were reported. Results. ADT may result in several adverse events including decreased libido, erectile dysfunction, vasomotor symptoms, cognitive, psychological and quality of life impairments, weight gain, sarcopenia, increased adiposity, gynecomastia, reduced penile/testicular size, hair changes, periodontal disease, osteoporosis, increased fracture risk, diabetes and insulin resistance, hyperlipidemia, and anemia. The definitive impact of ADT on lipid profiles, cardiovascular morbidity/mortality, and all-cause mortality is currently unknown with available data. Treatment options to reduce ADT-related adverse events include changing to an intermittent treatment schedule, biophysical therapy, counseling, and pharmacotherapy. Conclusions. Patients treated with ADT are at increased risk of several adverse events and should be routinely monitored for the development of potentially significant morbidity/mortality. Where appropriate, physicians should reduce known risk factors and counsel patients as to known risks and benefits of therapy. Trost LW, Serefoglu E, Gokce A, Linder BJ, Sartor AO, and Hellstrom WJG. Androgen deprivation therapy impact on quality of life and cardiovascular health, monitoring therapeutic replacement. J Sex Med 2013;10(suppl 1):84–101. Key Words. Adverse Events; LHRH; GnRH; Antiandrogen; Morbidity

Introduction

A

denocarcinoma of the prostate is the most common visceral malignancy among U.S. males with 241,740 new cases and 28,170 deaths estimated in 2012 [1]. Several management options are available for the treatment of prostate cancer including surgical extirpation, radiation/ proton therapy, high intensity focused ultrasound, and cryotherapy, among others. Androgen deprivation therapy (ADT) is commonly utilized in cases of lymph node involvement, J Sex Med 2013;10(suppl 1):84–101

metastatic disease, for adjunctive use with radiation, with biochemical recurrences following initial primary treatment, and is also employed as primary therapy for localized prostate cancer [2–6]. Treatment with ADT has increased in the prostatespecific antigen (PSA) era with utilization rates in nonmetastatic prostate cancer increasing from 3.7% of patients in 1991 to 31% in 1999 among North American men and from 16,000 in 2003–04 to 23,500 in 2008–09 among Australian men [7–9]. ADT includes various treatment modalities, which reduce circulating androgen levels or block © 2013 International Society for Sexual Medicine

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Androgen Deprivation Therapy

Figure 1 Summary of mechanism of action for current drug classes of androgen deprivation therapy

their effect on prostate cancer cells. Common methods of administering ADT include surgical or pharmacologic castration (administered intermittently or continuously) with both therapies demonstrating equivalent overall survival, time to treatment failure, and progression-free survival [10]. Although several medical therapies exist to reduce androgen levels, the most commonly employed agents are luteinizing hormonereleasing hormone (LHRH) or gonadotropinreleasing hormone agonists, including leuprolide, goserelin, triptorelin, and histrelin, among others. Additional categories used alone or in conjunction with LHRH agonists include LHRH antagonists (abarelix, degarelix), antiandrogens (flutamide, bicalutamide, nilutamide), adrenal androgen inhibitors (ketoconazole), estrogens (diethylstilbestrol [DES], estradiol, polyestradiol phosphate, premarin), and abiraterone (Figure 1). Given the prevalence of ADT, treating physicians should recognize the known adverse and long-term untoward effects and provide monitoring of patients undergoing treatment. This communication is outlined to review adverse effects of ADT as well as management options, where applicable. Discussion of the effects of testosterone therapy on the prostate and prostate cancer, including supplementation in the setting of previ-

ously treated prostate cancer, is beyond the scope of the current article, and the interested reader is referred to a recent article of this topic [11]. Adverse Effects of ADT

ADT is associated with side effects including decreased libido, erectile dysfunction (ED), vasomotor symptoms, fatigue, decreased energy, depressed mood and cognition, emotional lability, reduced quality of life (QOL), weight gain, gynecomastia, alterations in muscle mass/body fat distribution, reduction in penile/testicular size, development of osteoporosis, increased fractures, anemia, insulin resistance, diabetes mellitus (DM), and possible cardiovascular (CV) disease, among others.

Subjective Symptoms Decreased Libido/ED Patients treated with ADT experience diminished libido with only 13–20% maintaining sexual activity [12,13]. Compared with prostate cancer controls, patients treated with intermittent ADT (IADT) experienced reductions in libido (28% with moderate/high libido off therapy vs. 10% on therapy), masculinity (50% vs. 26%), and erectile function (46% vs. 13%), with effects beginning at 3 months and peaking at 9 months [13]. During J Sex Med 2013;10(suppl 1):84–101

86 off-phase treatment periods, 52% of previously sexually active men resumed sexual activity with erectile function returning to pretreatment levels. Although libido, masculinity, and sexual activity improved off of therapy, they failed to return to pretreatment levels. These findings are consistent with similar reports demonstrating decreased libido and ED with ADT [14–17]. Following discontinuation of ADT, recovery of testosterone levels is dependent upon several factors including patient age, duration of treatment, and pretreatment testosterone. In patients treated with one or two 6-month ADT cycles, testosterone normalization occurred at a median of 15.4 and 18.3 weeks, respectively [18]. Among patients treated with 2 years of ADT, 73% achieved baseline and/or normal testosterone levels at a median time of 22.3 months [19]. Impaired erectile function with ADT is likely multifactorial in nature and may be associated with a reduction in neurogenic signaling from decreased central stimulus and elimination of androgen dependent nitric oxide production and alternative pathways [20]. These findings may additionally explain the observed poor response to phosphodiesterase type 5 inhibitor therapies in this patient population [21].

Vasomotor Symptoms Vasomotor symptoms occur as brief and sudden onset of heat occurring over the face and upper torso with occasional perspiration and flushing. Symptoms occur in 50–80% of men undergoing ADT and are considered the most bothersome symptom among 27% of patients [22,23]. Although the exact etiology for vasomotor symptoms with ADT remains unclear, it may be related to the absence of negative feedback from sexual hormones on the hypothalamus, resulting in thermoregulatory dysfunction and neurogenicmediated vascular dilation [24]. Among patients undergoing combined androgen deprivation, the selection of antiandrogen may influence the degree of hot flashes experienced [25]. Compared with partial blockage, complete androgen ablation is associated with more severe symptoms and decreased likelihood for spontaneous resolution [22]. Cognitive and Psychological Impairment The impact of ADT on cognitive functioning is unclear [26,27]. Patients undergoing ADT have reported reductions in spatial rotation, preserved executive functions, language, verbal and spatial J Sex Med 2013;10(suppl 1):84–101

Trost et al. memory, and improvements identified in verbal memory [28]. Salminen and colleagues noted reduced visual memory of figures, recognition speed of numbers, and demonstrated improvements in verbal fluency, object recall, and semantic memory [29,30]. Further studies have found declines in spatial reasoning, spatial ability, and working memory compared with baseline [26]. These studies highlight the variability and selective nature of cognitive impairments experienced with ADT. ADT is further associated with symptoms of fatigue, decreased energy, and perceived loss of initiative. Stone and colleagues reported a 14% (8/58) rate of severe fatigue (defined as >95th percentile of elderly volunteers without cancer) at baseline with 66% (38/58) experiencing increased fatigue during treatment [31]. Among patients undergoing long-term ADT, 43% (69/140) reported clinically relevant fatigue, which is associated with depression and pain and is independent of associated psychological issues and anemia [32,33]. Additional psychological symptoms associated with ADT include depression, anxiety, worsened body image, impaired sleep quality, irritability, and reduced QOL, some of which improve following discontinuation of therapy [26,34,35]. A retrospective analysis of 395 ADT patients demonstrated a 27.9% rate of de novo diagnoses of psychiatric illness including depression (56.4%), dementia (13.9%), and anxiety (8.9%) [36]. These findings should be taken in the context of confounding variables of underlying cancer diagnosis, aging, and physician consultations, among others. Depression associated with ADT is inversely correlated with QOL scores and remains associated on multivariate analysis after controlling for age, stage and Gleason scores, demographic, and social variables [34]. Psychological symptoms may further be exacerbated by the presence of other ADT-associated adverse effects and the physiologic impact of hypogonadism. Sharpley and colleagues noted that 18% of patients receiving ADT experienced side effects, the presence of which correlated with increased anxiety and depression scores [37]. Fatigue, pain, and discomfort, in particular, were found to be associated with increased anxiety and depression, while the frequency of side effects most greatly correlated with underlying anxiety. In contrast to the above studies, a subset analysis of patients with nonmetastatic prostate cancer receiving ADT, stratified by the presence or

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Androgen Deprivation Therapy Table 1

Summary of subjective symptoms with androgen deprivation therapy

Adverse effect

Summary of effects

Treatment*

Decreased libido/ erectile dysfunction

13–20% with preserved sexual activity Libido reduced in 28% Erectile dysfunction 87% Reduced masculinity 74%

Phosphodiesterase type 5 inhibitors 52% return to baseline after minimally effective ADT discontinued Sexual rehabilitation/counseling Effects peak at 9 months

Notes

Vasomotor symptoms

50–80%

If combined androgen blockade, consider changing antiandrogen Hormonal agents (progesterones/ estrogens) Nonhormonal agents (SSRIs, gabapentin, clonidine) Dietary supplements (soy, black cohosh, crushed flaxseed)

Cognitive impairment

Decreased spatial rotation, visual memory of figures, recognition speed of numbers, spatial reasoning/ability, working memory Improvements in verbal fluency, object recall, semantic memory

Physical aerobic/resistance exercise

Psychological impairment

Fatigue 14–43%, increases by 66% Decreased energy Loss of initiative De novo psychiatric illness 27.9% Depression 56.4% Anxiety 8.9% Dementia 13.9% Impaired sleep, irritability, impaired body image

Physical aerobic/resistance exercise

Psychological symptoms related to presence of ADT side effects Contrasting studies with unclear direct association of ADT with worsening depressive symptoms

Quality of life

Reduced scores in physical, general, and mental Physical aerobic/resistance health, impact of cancer, body image, activity, exercise energy, worries about cancer and dying Increased emotional distress Cognitive impairment Sexual dysfunction impaired

No differences noted between <6 months and ⱖ6 months of ADT ADT may not be predictor of QOL outcomes when controlling for comorbidities

Most bothersome symptom in 27%

*All symptoms are improved with ADT discontinuation or changing to intermittent schedule. ADT = androgen deprivation therapy; QOL = quality of life; SSRI = selective serotonin reuptake inhibitor

absence of depression at baseline, demonstrated no increase in depressive symptoms at 3, 6, and 12 months [38].

QOL Multiple studies have identified reduced QOL in patients undergoing ADT [15,39–45]. A prospective, population-based study of 1,642 men with localized prostate cancer treated with ADT at 3 years of follow-up demonstrated reduced general physical and mental health scores on questionnaires compared with other therapies and controls [40]. A similar questionnaire-based study of postprostatectomy men undergoing adjuvant/salvage ADT identified reductions in seven QOL measures including impact of cancer and treatment, concern regarding body image, mental health, general health, activity, energy, and worries about cancer and dying [41]. Two randomized trials further demonstrated increases in emotional distress, cognitive impairment, and sexual dysfunction in those receiving ADT [15,42]. In reviewing the effect of ADT duration on QOL, Dacal and colleagues found no significant

differences between men treated with short-term (<6 months) vs. long-term (ⱖ6 months) therapy, with both groups experiencing poorer overall physical function, general health, and physical health compared with controls [43]. When controlled for comorbidities and total testosterone, ADT was no longer found to be a significant predictor of QOL outcomes, highlighting a counterargument that comorbidities may account for many of the QOL differences observed in studies rather than from the effects of ADT itself [44,45]. See Table 1 for summary of subjective symptoms with ADT and available treatments.

Physical Changes Weight Gain/Body Composition Changes Men undergoing ADT experience significant body composition changes including increased body fat and decreased lean muscle mass (sarcopenia) [39,46–50]. The duration of therapy is associated with increasing body fat percentage, with a 4.3% and 9.4–14% increase in body fat reported after 12 and 48–52 weeks of therapy, respectively [47–50]. Further body changes identified after 48–52 weeks J Sex Med 2013;10(suppl 1):84–101

88 of therapy include increased overall body weight (1.8–2.4%), subcutaneous abdominal fat (11.1– 13%), and visceral fat (22%), with concomitantly reduced lean body mass (2.7–3.8%) [47,48,50]. A systematic review and meta-analysis of 16 studies, including 14 cohorts and two randomized controlled trials demonstrated average increases in body fat (7.7%), body weight (2.1%), body mass index (BMI; 2.2%), and decreased lean body mass (2.8%), with more extensive changes associated with longer duration of treatment [51]. These physical changes are further reflected in functional performance and fitness. Compared with age-matched controls, patients undergoing ADT experience 20–27% decreased functional performance in chair rise and walking tests, 7% decline in aerobic fitness, and 24% loss of muscular strength [45,52–54]. These findings are equivalent to a 10- to 20-year difference in age-related abilities, further highlighting the impact of prostate cancer and ADT on overall functional status [55].

Gynecomastia Gynecomastia and mastodynia commonly occur with administration of estrogenic compounds (e.g., DES) or antiandrogen monotherapy and less frequently with LHRH agonists. Although the true prevalence of gynecomastia with LHRH agonist therapy is undefined, one study comparing LHRH analog therapy alone to orchiectomy reported gynecomastia among 24.9% and 9.7% of patients, respectively [12]. In contrast, patients treated with bicalutamide monotherapy 50– 150 mg daily reported gynecomastia (40–49%), mastodynia (40%), and a combination of one or both symptoms (90%), with gynecomastia-related symptoms identified as the rate limiting toxicity [56–60]. The underlying etiology for breast growth and tenderness may result from peripheral aromatization of testosterone to estradiol. As antiandrogens result in blockade of testosterone at the receptor level and subsequently increase circulating testosterone levels, this may account for the increased incidence of gynecomastia observed compared with LHRH agonists, which decrease both estrogen and testosterone levels. Decreased Penile/Testicular Size In addition to ED and decreased libido, ADT patients experience progressive reductions in penile length and testicular volume. Following 24 months of ADT administered as primary therapy J Sex Med 2013;10(suppl 1):84–101

Trost et al. for prostate cancer, patients developed reduced penile length from 10.76 cm to 8.05 cm, with a plateau achieved after 15 months [61]. Concomitant reductions in erectile function were reported from 41% with normal function to 10.5% at 24 months. Interestingly, those with preserved potency experienced less penile shortening. A similar study of patients undergoing ADT followed by radiation therapy for prostate cancer demonstrated gradual shortening of the penis from 14.2 cm to 8.6 cm after 18 months of therapy [62]. Long-term treatment with LHRH agonists is associated with testicular atrophy and impaired spermatogenesis. History of testicular specimens obtained following 6 months of ADT demonstrate severe atrophy of the seminiferous tubules/ seminiferous epithelium and a Sertoli only pattern compared with controls [63]. No changes were noted in the number of Leydig cells between groups, and subsequent human chorionic gonadotropin (HCG) stimulation of the specimen revealed preserved ability to produce testosterone. These findings suggest that observed reductions in testicular size following ADT is likely secondary to atrophy of the seminiferous tubules, which comprise 80–90% of normal testicular volume.

Hair Changes Although less frequently reported, ADT is associated with changes in hair growth, character, and distribution, with the underlying mechanism not fully elucidated. Patients managed with ADT report increases in scalp hair, loss of body hair, and softening of the beard with less frequent shaving required [64]. These changes may return to normal patterns within 3–6 months of discontinuation of therapy. Periodontal Disease Periodontal disease is more frequently noted in patients treated with ADT (80.5% compared with 3.7% in prostate cancer controls) with greater probing depth and plaque scores reported [65]. This finding is independent of bone mineral density (BMD) status. See Table 2 for summary of physical changes associated with ADT and available treatments. Comorbid Disease Development In addition to symptomatic complaints and physical changes, administration of ADT is associated with development of comorbid states including bone (osteopenia/osteoporosis with associated

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Androgen Deprivation Therapy Table 2

Summary of physical changes with androgen deprivation therapy

Adverse effect

Summary of effects

Treatment

Notes

Weight gain/body composition Changes

Increase in body fat% (4.3% at 12 weeks, 9.4–14% at 48–52 weeks; average 7.7%) Increased weight 1.8–2.4% Increased subcutaneous abdominal fat 11.1–13% Increased visceral fat 22% Reduced lean body mass 2.7–3.8%

Discontinue/intermittent ADT Physical aerobic/resistance exercise Nutritional counseling

Duration of therapy associated with severity of effects

Functional performance

Reduced chair rise/walking tests 20–27% Decreased aerobic fitness 7% Loss of muscular strength 24%

Discontinue/intermittent ADT Physical aerobic/resistance exercise

Findings correlate to 10- to 20-year difference in age-related abilities

Gynecomastia/ mastodynia

Gynecomastia 9.7–24.9% (LHRH or orchiectomy) Gynecomastia 40–49% (antiandrogen) Mastodynia 40% (antiandrogen)

SERM Prophylactic treatment superior Radiation (prophylactic only) Surgery (established gynecomastia)

More common with antiandrogens than LHRH agonists Rate-limiting toxicity of antiandrogens

Penile/testicular size

Reduced penile length from 10.8–14.2 cm to 8–8.6 cm Testicular atrophy

Hair changes

Increased scalp hair Loss of body hair Softening of beard, reduced shaving

Periodontal disease

Prevalence 80.5% [65]

Plateau of penile size reduction at 15 months Discontinue/intermittent ADT

Return to normal patterns after 3–6 months of discontinuation Finding is independent of bone mineral density status

ADT = androgen deprivation therapy; LHRH = luteinizing hormone-releasing hormone; SERM = selective estrogen receptor modulator

fractures) and metabolic abnormalities (insulin insensitivity/DM, hyperlipidemia, anemia, and CV disease).

Osteoporosis At baseline, men presenting with nonmetastatic prostate cancer have osteopenia in 39–53% and osteoporosis in 5–40% [66–68]. Initiation of ADT results in reductions of BMD, with concomitant increases in markers of bone turnover, and increased risk of eventual development of osteoporosis [46,68–72]. Changes in BMD begin within months of initiating ADT, with the greatest loss occurring within the first year [71,72]. In evaluating the effect of treatment duration, Morote and colleagues noted a progressive decline in BMD over time with a relative risk of 1.76 at 4 years, 2.67 at 6 years, and 3.48 at 8 years [71]. Wadhwa and colleagues reported significant decreases in BMD among men with pretreatment normal and osteopenic bone densities (1 year 1.2% and 1.8%; 3 years 6.5% and 8.0%; 5 years 9.9% and 11.5%), with preserved levels in osteoporotic men (1 year 0.5%; 3 years +1.2%; 5 years 1.7%) [67]. Similar to osteopenia, the rates of osteoporosis increase from a baseline of 35.4% of patients to 42.9%, 59.5%, and 80.6% following 2, 6, and 10 years of ADT, respectively [68]. Normal BMD, conversely, decreases from 19.4% of patients to

0% after 10 years of therapy, with rates of loss estimated to be 5–10¥ higher than the general population [72–75]. Fracture risks, similarly, are elevated compared with matched controls [76–80]. Taylor and colleagues performed a pooled analysis with follow-up ranging from 36 to 69 months and described a 23% increased risk of developing a skeletal fracture and 39% of vertebral fractures [81]. These findings correlate to an increased absolute risk of fracture from 6.5 to 7.2 events per 100 person years [79,80]. Shahinian and colleagues reported on 50,613 men from the Surveillance, Epidemiology, and End Results database and noted a fracture rate of 19.4% vs. 12.6% among patients treated with ADT and surviving at least 5 years from the diagnosis of prostate cancer [78].

DM and Insulin Resistance Reductions in testosterone are associated with elevated rates of DM and insulin resistance. Although the exact mechanisms responsible for the development of DM and insulin resistance with hypogonadism are not fully elucidated, inflammatory cytokines are likely one contributing factor. Pro-inflammatory cytokines, including tumor necrosis factor (TNF) and IL-6, are inversely associated with testosterone levels and have been associated with development of DM, insulin resistance, increased fat mass, and J Sex Med 2013;10(suppl 1):84–101

90 decreased lean body mass [82,83]. The presence of testosterone results in downregulation of IL-6 and has an inhibitory effect on macrophage TNF production [84,85]. Among hypogonadal men with DM, testosterone replacement resulted in decreased TNF, IL-1 (IL-6 precursor), and IL-6 levels [86,87]. In men receiving ADT, insulin levels increase by 26–65% within 3 months of treatment with fasting glucose levels unchanged for the first 6 months, indicating compensatory changes [7,49,88–90]. Treatment with ADT for 12 months or longer is associated with an estimated increased risk for development of DM of 16–49% [91–94]. Several retrospective studies examining large numbers of patients treated with ADT for ⱖ6 months report hazard ratios (HR) for the development of DM of 1.16–1.44 [91,93–95]. Lage and colleagues noted an increasing prevalence of DM associated with longer durations of ADT with relative risks of patients receiving treatment for 12 and 18 months of 1.36 and 1.49, respectively [92]. In patients with preexisting DM, increases in antihyperglycemic treatments are often required with worsened glycemic control reported [96,97].

Hyperlipidemia The association between low testosterone and abnormal lipid profiles is well reported with initial studies identifying elevated total cholesterol, lowdensity lipoprotein (LDL), and triglyceride (TG) levels in patients with low testosterone and subsequent improvements following testosterone supplementation [98,99]. However, the overall effect on lipid profiles remains unclear and may relate to duration of therapy. Braga-Basaria and colleagues reported lipoprotein profiles following 12 months of ADT compared with prostate cancer and healthy controls and noted higher total cholesterol (213 ng/dl [ADT] vs. 205 [non-ADT] and 173 [healthy controls]), LDL (132 vs. 120 and 101), and similar high-density lipoprotein (HDL) and TG levels [100]. Increasing duration of therapy (48 weeks) results in further elevations with an increase in total cholesterol by 9%, LDL by 7.3%, TG by 26.5%, and HDL by 11.3% [48]. Several contrasting studies with shorter-term therapy have failed to demonstrate consistent effects of ADT on lipid profiles. Yannucci and colleagues performed a pooled analysis of three prospective clinical trials of LHRH agonists and found inconsistent changes in LDL levels, increased HDL levels, and increased total choJ Sex Med 2013;10(suppl 1):84–101

Trost et al. lesterol, which were attributed to the elevated HDL levels [101]. Additional studies identified either no changes or increased HDL, with no changes in total cholesterol, LDL, or TG levels [89,102,103].

Metabolic Syndrome (MetS) The development of MetS (varyingly defined as the combined presence of several comorbid states including elevated fasting glucose, insulin resistance, DM, hypertension, dyslipidemia, obesity, and/or increased waist circumference) is associated with hypogonadal states [104,105]. The etiologic processes resulting in MetS is likely secondary to a combination of factors including the release of pro-inflammatory molecules resulting from dyslipidemia, increased visceral adipose tissue, and decreased testosterone levels [82,83, 106,107]. Limited studies exist examining the association of MetS and ADT. Among men undergoing ADT for prostate cancer, the presence of MetS was identified in 55% (11/20) compared with 22% and 20% in prostate cancer without ADT and controls, respectively [108]. Despite the increased prevalence among ADT patients, metabolic changes associated with ADT are distinct from those identified with MetS. In an open-label, prospective evaluation of 26 men treated with ADT, Smith and colleagues noted an increase in BMI and waist circumference without changes in waistto-hip ratios and blood pressure, and an increase in HDL cholesterol [109]. These findings would indicate that although ADT may increase the development of contributing factors toward MetS, it likely results in a distinctive state, which is not fully described by the MetS. Figure 2 demonstrates the relationship of testosterone to MetS factors. Anemia Anemia with ADT is common, with an average of 1–2 g/dL drop reported beginning 30–90 days after initiation of therapy [33,110–113]. The mechanism of hypogonadal-induced anemia is unknown and has not been shown to be secondary to hemolysis, blood loss, malignant bone marrow suppression, or anemia of chronic disease. Anemia following ADT may occur in up to 90% of patients with 13% in one report identifying anemia-related symptoms [113]. Anemia resulting from ADT is typically normochromic, normocytic in nature and returns to baseline levels following discontinuation of therapy.

Androgen Deprivation Therapy

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Figure 2 Interaction of low testosterone and factors of metabolic syndrome

CV Morbidity/Mortality Multiple studies have examined the role of ADT in CV morbidity and mortality with varying results. Three radiation therapy oncology group trials examining men randomized to radiotherapy and ADT vs. radiotherapy alone (varied ADT duration) demonstrated no increased risk of CV events in the ADT groups, including those undergoing a longer duration (24 months) of treatment (HR 0.73–1.09) [114–116]. A European Organization for Research and Treatment of Cancer trial reviewing immediate ADT vs. delayed ADT at the time of symptomatic progression or serious complications (median time to deferred treatment of 7 years) found no significant difference in CV-related events between groups [117]. An additional, population-based study reviewing 19,079 patients undergoing ADT compared with controls and found no increased risk of myocardial infarction or sudden cardiac death [91]. Chung and colleagues further reviewed 365 patients with 5-year follow-up and noted cerebrovascular accidents in 17.2% of ADT patients vs. 18.9% controls (HR 1.09; confidence interval [CI] 0.80–1.50), concluding that there was no evidence that ADT increased the risk of stroke [118]. In contrast to the above studies, several authors have identified statistically significant increases in CV events in patients undergoing ADT. Keating and colleagues performed a population-based review of 14,597 men treated with ADT and found an increased risk of heart disease (HR 1.19), myo-

cardial infarction (12.8 events per 1,000 person years vs. 7.3), sudden cardiac death (HR 1.35), and stroke (HR 1.22) [93]. Antiandrogen therapy alone was not found to have an increased incidence of CV events. A follow-up study examining the impact of comorbidities on CV outcomes found that CV comorbidities did not significantly modify the risk associated with ADT [95]. Additional studies have reported a 20% increased risk of CV morbidity overall, with a 37% increased risk among patients treated for over 12 months compared with less than 12 months, shorter time to fatal myocardial infarctions, and increased risk of death from CV causes, even after controlling for CV disease risk factors [119–121]. In reviewing the risk for development of cerebrovascular accidents, a population-based study reviewing 22,310 patients treated with LHRH agonists vs. bilateral orchiectomy at a mean follow-up of 3.9 years reported a relative risk of experiencing a stroke of 1.18 (LHRH agonist) and 1.77 (orchiectomy; CI 1.25–2.39), concluding that ADT may increase the subsequent risk of experiencing a stroke [122]. In an attempt to consolidate conflicting data, a systematic review and pooled analysis of four articles reported a 17% increased risk of CV events in patients treated with ADT (HR 1.17, 95%) [81,94,114,120,121]. Conversely, a metaanalysis of eight randomized studies (N = 4,141), Nguyen and colleagues found no increased risk of CV events with ADT use [123]. Many of the above J Sex Med 2013;10(suppl 1):84–101

92 Table 3

Trost et al. Summary of comorbid diseases with androgen deprivation therapy

Adverse effect

Summary of effects

Treatment

Notes

Osteopenia/ osteoporosis

Baseline osteopenia 39–53% Baseline osteoporosis 5–40% BMD decline relative risk 1.76 (4 years), 2.67 (6 years), 3.48 (8 years) Osteoporosis increase 35.4% (baseline), 42.9% (2 years), 59.5% (6 years), 80.6% (10 years)

Discontinue/intermittent ADT Physical aerobic/resistance exercise Nutritional counseling Consider pharmacotherapy if T-score ⱕ -2.5 or FRAX with 10-year estimate risk of fracture > NOF threshold Bisphosphonates Denosumab SERMs

Greatest loss of BMD in first year Continued progressive loss during duration of treatment Preserved BMD noted in men at baseline osteoporotic levels Bone loss 5–10¥ rate of general population

Skeletal fractures

Increased risk of skeletal fracture 23% and vertebral fracture 39%

Physical aerobic/resistance exercise Nutritional counseling

Correlates to estimated 3,000 additional fractures annually attributable to ADT

Diabetes/insulin resistance

Insulin levels increase 26–65% DM 16–49% (hazard ratio 1.16–1.44)

Physical aerobic/resistance exercise Nutritional counseling Referral to primary care physician

Longer duration of ADT associated with increased risk

Hyperlipidemia

Reports conflicting with no consensus

Physical aerobic/resistance exercise Nutritional counseling Referral to primary care physician

Anemia

1–2 g/dL drop after 30–90 days therapy Prevalence 90% Symptomatic anemia 13%

Discontinue/intermittent ADT Referral to primary care physician

Cardiovascular morbidity/ mortality

Reports conflicting with no consensus

Discontinue/intermittent ADT Physical aerobic/resistance exercise Nutritional counseling Referral to primary care physician

ADT = androgen deprivation therapy; BMD = bone mineral density; FRAX = fracture risk assessment tool; NOF = National Osteoporosis Foundation; SERM = selective estrogen receptor modulator

studies have significant limitations including variable follow-up periods, nonrandomized design, a small number of events, varying ADT treatments, and potential confounders such as comorbidities. Although it remains unclear if ADT increases the risk of CV events, the clinically relevant absolute risk likely remains low, particularly given that the most common cause of death in men with prostate cancer is CV-related events, regardless of therapy [124,125]. Using a baseline risk of 9–10 deaths per 1,000 person years and assuming a 17% increased risk as reported by Taylor and colleagues, the risk of death would increase to 10.5– 11.7 deaths per 1,000 person years [81,94]. Other reported estimates reveal an increase in up to 5–10 additional events per 1,000 person years [126]. See Table 3 for summary of comorbid diseases associated with ADT and available treatments. Treatment of ADT-Related Adverse Effects

Several therapies have been evaluated for the treatment of ADT-related adverse effects with varying degrees of efficacy. Available treatment strategies include altering treatment cycle length, providing biophysical treatments, oral medications, and radiation/surgery for select cases. As an extended J Sex Med 2013;10(suppl 1):84–101

review of available therapeutic options is beyond the scope of the current article, general treatment categories will be reviewed with brief description of individual medications/treatments provided.

IADT IADT has been suggested as one viable option to decrease or reverse ADT-related effects. Mottet and colleagues reported a multicenter study involving 58 treatment centers in Europe to compare IADT vs. continuous ADT (CADT) following a 6-month induction phase [127]. Patients receiving IADT experienced fewer adverse events including decreased headaches and hot flashes with no differences in overall or progression-free survival. A randomized, controlled study comparing IADT to CADT similarly reported no overall difference in survival, with CADT patients experiencing an increased rate of CV deaths (52 vs. 41) and IADT patients experiencing more cancerspecific deaths (106 vs. 84) [128]. Compared with continuous therapy, patients in the intermittent arm experienced improved sexual activity with no clinically apparent impairment in QOL. Additional supporting studies have demonstrated improvements and partial to complete recovery in

Androgen Deprivation Therapy BMD, libido, masculinity, and erectile function in patients treated with IADT while off therapy [13,129]. Abrahamsson performed a systematic review of 19 phase two studies and interim data from eight phase three trials and noted a majority of trials reporting improvements in QOL during offtherapy periods, including improved sexual function [130]. Outcomes including biochemical progression, progression-free survival, and overall survival were generally comparable between therapies. In a recent abstract reporting on the largest phase three trial comparing IADT to CADT (N = 1,386), Crook et al. noted overall comparable mortality rates among men with nonmetastatic disease with a rising PSA after radiation therapy at a median follow-up of 6.9 years [131]. The intermittent arm had more disease related (122 vs. 97) and fewer unrelated (134 vs. 146) deaths. IADT patients had better QOL in physical function, fatigue, urinary problems, hot flashes, desire for sexual activity, and erectile function. A second abstract reporting on QOL questionnaires administered to 1,248 patients treated with IADT or CADT demonstrated significantly more ED, decreased libido, and worsened emotional function in patients treated with continuous therapy [132]. The ideal candidate for IADT among patients with metastatic disease remains unclear. One study reviewing patients with metastatic prostate cancer treated with intermittent vs. continuous therapy demonstrated a trend toward decreased side effects in the intermittent group, including hot flashes, nausea, constipation, dyspnea, and depression [133]. However, subgroup analysis of patients on intermittent therapy achieving a low PSA nadir were found to have an elevated 2-year risk of progression compared with continuous therapy patients, leading to a conclusion that intermittent therapy may not be preferred in patients with metastatic carcinoma [134].

Biophysical Treatment Several studies have demonstrated beneficial effects with biophysical therapy including exercise, nutrition modification, and counseling. Ideally, biophysical therapies should begin prior to onset of ADT to optimize preventative effects of dietary changes and exercise. Physical aerobic and resistance exercise, particularly when performed in a group setting with physical therapists/licensed trainers provide mul-

93 tiple benefits in men undergoing ADT. A systematic review of 12 studies examining the effects of exercise in men with prostate cancer reported grade A evidence supporting beneficial effects in improving muscular endurance, aerobic endurance, fatigue, and overall QOL [55]. Grade B evidence suggested improvements in muscle mass, muscular strength, functional performance including walking and sit to stand speed, as well as health-related, social, and physical QOL indicators. Additional studies have confirmed beneficial effects with even short-term exercise plans (12 weeks) [135]. In addition to the direct effects on symptoms and QOL, exercise improves CV risk factors including resting blood pressure, glycemic control, and lipid profiles, among others. Weight bearing and resistance-training exercises further reduce BMD loss and risk of falls in elderly males [136–138].

Counseling Patients receiving ADT should undergo nutritional counseling, including discussion of possible supplementation with calcium (1,200 mg daily) and vitamin D (800–1,000 international units [IU] daily) and reduction of caffeine, sodium, and nicotine to minimize BMD loss and reduce fracture risks [68,139–144]. Patients may further benefit from a baseline assessment of preexisting or concomitant depression occurring during ADT with referrals made for psychological counseling as appropriate. Those experiencing ED secondary to ADT may similarly benefit from additional counseling on sexual rehabilitation, partner communication, and intimacy issues, as well as couples counseling as to anticipated expectations and available therapies. Pharmacotherapy Vasomotor Symptoms Several supplements/medications are commonly used to treat ADT-related vasomotor symptoms [145]. Progesteronal agents including megestrol acetate and depo medroxyprogesterone acetate are among the most studied agents for improvement of hot flashes. Loprinzi and colleagues reported an 85% reduction in hot flashes compared with 21% among controls in patients treated with megestrol acetate 20 mg twice daily [146]. Depo medroxyprogesterone, similarly, results in a 90% improvement and 48% elimination of hot flashes, J Sex Med 2013;10(suppl 1):84–101

94 with improved efficacy compared with selective serotonin reuptake inhibitors (SSRIs) [147,148]. Side effects include sexual dysfunction, salt retention, weight gain, chills, and possible increases in PSA and prostate cancer progression, indicating ongoing need for close monitoring while on therapy [149,150]. Estrogen-based compounds including DES and estradiol patches have demonstrated improvements in vasomotor symptoms in up to 83% of patients with complete relief in 50% [22,151,152]. Complications include increased risk of thromboembolism, myocardial infarction, stroke, gynecomastia, and nipple tenderness, some of which may be improved with reduced dosing [153]. Nonhormonal medications commonly used for ADT-induced hot flashes include SSRIs, gabapentin, and clonidine. Sertraline has demonstrated mixed outcomes in patients with breast cancer with no currently available studies performed in prostate cancer patients [154,155]. Venlafaxine has demonstrated reductions in hot flashes in up to 68% of patients with a possible faster onset of action and reduced efficacy when compared with clonidine [148,156–158]. SSRIs may be particularly helpful in cases of concomitant vasomotor symptoms and depression. Gabapentin similarly improves hot flashes in 45–50% of patients with few adverse effects reported [159–161]. Small, randomized studies of dietary supplements including soy, black cohosh, and crushed flaxseed have demonstrated a reduction in hot flashes among prostate cancer patients and menopausal women [162–165].

Osteoporosis Patients undergoing ADT should undergo baseline assessments and routine interval monitoring of BMD given the increased risk of osteopenia/ osteoporosis [9,75]. Patients with T-scores ⱕ -2.5 or among those with a 10-year absolute risk of fracture (as determined by FRAX) exceeding National Osteoporosis Foundation thresholds are recommended to undergo pharmacotherapy [166– 169]. It is noteworthy that this algorithm likely underestimates the true risk of fracture, as it does not account for ADT use. Several agents are currently available for the treatment of osteoporosis, with bisphosphonates most commonly utilized. A Cochrane review of 10 studies involving 1,955 patients undergoing bisphosphonate treatment in advanced prostate cancer demonstrated a pain response rate of 27.9% J Sex Med 2013;10(suppl 1):84–101

Trost et al. vs. 21.1%, skeletal-related events of 37.8% vs. 43%, and significant increase in nausea among bisphosphonate-treated patients compared with controls [170]. No significant difference was identified with prostate cancer death, disease progression, or radiological response. Data were inadequate to recommend one bisphosphonate or treatment schedule over another. Individual randomized, controlled trials of pamidronate, zoledronic acid, alendronate, and risedronate demonstrate stable or increased BMD at the lumbar spine (up to 8%) and hip (up to 2%) compared with a 2–8% loss in controls [9,171–180]. Denosumab, a human monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand is currently the only FDAapproved agent for the prevention of fractures in patients undergoing ADT. Smith and colleagues reported a phase three study comparing denosumab with placebo among prostate cancer patients on ADT with T-scores < -1.0. Results demonstrated improvements in BMD at the hip (4.8%), femoral neck (3.9%), and distal radius (5.5%) with a reduction in vertebral fractures to 1.5% compared with 3.9% in controls [181]. Selective estrogen receptor modulators (SERM) raloxifene and toremefine have similarly been shown to increase BMD by 1.1–1.8% compared with decreases in controls [182,183]. To date, neither denosumab or any SERM has been compared in a head-to-head trial with bisphosphonates.

Gynecomastia Medication-induced gynecomastia may be treated with several modalities including pharmacotherapy, radiation, and surgery. A recent multicenter trial evaluating bicalutamide and daily vs. weekly tamoxifen reported gynecomastia in 31.7% in the daily group compared with 74.4% in weekly tamoxifen patients [184]. A second, randomized trial comparing prophylaxis to treatment with tamoxifen demonstrated improvements (reduction from 78.3% to 27.7% in the treatment group) among both schedules of therapy with prophylaxis being favored for gynecomastia and breast pain [185]. Alternative therapies for established gynecomastia include prophylactic radiation (10 Gy) or liposuction/subcutaneous mastectomy [64,186]. Monitoring Therapy

Due to the risk of CV-related events, comorbid conditions, and osteopenia/osteoporosis, patients

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Androgen Deprivation Therapy treated with ADT should undergo initial testing including BMD assessment, fasting glucose/ HbA1c, lipids, weight, and blood pressure measurements. Subsequent testing is dependent on initial testing and an assessment of the patient’s concomitant risk factors/comorbid status [7,9,75,93]. In October of 2010, the FDA warned of potential increased risks of DM- and CV-related events associated with LHRH agents. Further recommendations included the need for monitoring of serum glucose, HbA1c, lipids, blood pressure, and weight, improving exercise and diet, treating associated comorbidities (hyperlipidemia, hypertension, DM, tobacco use), and early referral to primary care physicians where indicated. A similar consensus document provided by the American Heart Association, Council on Clinical Cardiology, Council on Epidemiology and Prevention, American Cancer Society, and American Urologic Association concluded that the decision to initiate ADT in patients with cardiac disease is determined by the treating physician with emphasis on risks and benefits of therapy and early referral to primary care for ongoing monitoring and periodic follow-ups [126]. Conclusions

ADT for management of prostate carcinoma is increasingly utilized for both localized and advanced disease. Adverse effects of ADT include decreased libido/ED, vasomotor symptoms, cognitive and psychological impairments, reduced QOL, weight gain and body composition changes, gynecomastia, reduced penile/testicular size, hair changes, periodontal disease, osteoporosis, DM/insulin resistance, hyperlipidemia, anemia, and CV morbidity/mortality. Available treatment options for adverse effects of ADT include changing to an intermittent schedule of therapy, biophysical treatments of exercise and strength training, dietary and psychological counseling, and pharmacologic agents. Patients treated with ADT should undergo initial and subsequent monitoring of ADT-related effects including routine BMD assessments and assessment of CV risk factors. Corresponding Author: Wayne J.G. Hellstrom, MD, Tulane University Health Sciences Center, Department of Urology, 1430 Tulane Ave., New Orleans, LA 70112, USA. Tel: (504) 988-5372; Fax: (504) 988-5059; E-mail: [email protected]; [email protected] Conflict of Interest: None.

Statement of Authorship

Category 1 (a) Conception and Design Landon W. Trost (b) Acquisition of Data Landon W. Trost; Brian J. Linder (c) Analysis and Interpretation of Data Landon W. Trost; Ege Serefoglu; Ahmet Gokce; Brian J. Linder; Wayne J.G. Hellstrom

Category 2 (a) Drafting the Article Landon W. Trost; Brian J. Linder (b) Revising It for Intellectual Content Landon W. Trost; Ege Serefoglu; Ahmet Gokce; Brian J. Linder; Wayne J.G. Hellstrom

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