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EUROPEAN UROLOGY 67 (2015) 825–836
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Platinum Priority – Collaborative Review – Prostate Cancer
Editorial by Fred Saad on pp. 837–838 of this issue
Adverse Effects of Androgen Deprivation Therapy and Strategies
to Mitigate Them
Paul L. Nguyen a,*, Shabbir M.H. Alibhai b, Shehzad Basaria c, Anthony V. D’Amico a,
Philip W. Kantoff d, Nancy L. Keating e, David F. Penson f, Derek J. Rosario g,
Bertrand Tombal h, Matthew R. Smith i
a
Department of Radiation Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, USA;
b
Department of Medicine, University Health
Network, Toronto, Canada; c Section on Men’s Health, Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;
d
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;
e
Division of General Internal Medicine, Department of Medicine, Brigham and Women’s Hospital, and Department of Health Care Policy, Harvard Medical
School, Boston, MA, USA; f Department of Urologic Surgery and the Center for Surgical Quality and Outcomes Research, Vanderbilt University, and the VA
Tennessee Valley Geriatric Research, Education, and Clinical Center, Nashville, TN, USA; g Academic Urology Unit, Department of Oncology, Royal Hallamshire
Hospital, University of Sheffield, Sheffield, UK; h Division of Urology, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium;
i
Department of Hematology-Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA
Article info
Abstract
Article history:
Accepted July 11, 2014
Context: Androgen-deprivation therapy (ADT) is a key component of treatment for aggressive
and advanced prostate cancer, but it has also been associated with adverse effects on bone,
metabolic, cardiovascular, sexual, and cognitive health as well as body composition.
Objective: To review the current literature on the adverse effects of ADT and strategies for
ameliorating harm from ADT.
Evidence acquisition: The Medline database (through PubMed) was searched from inception
to August 1, 2013, for studies documenting the side effects of ADT and for randomized and
prospective trials of interventions to mitigate those side effects.
Evidence synthesis: Adverse effects of ADT include decreases in bone mineral density;
metabolic changes such as weight gain, decreased muscle mass, and increased insulin
resistance; decreased libido and sexual dysfunction; hot flashes; gynecomastia; reduced
testicle size; anemia; and fatigue. Several observational studies suggest an increased risk
of diabetes and cardiovascular events, although most published studies report that ADT is not
linked to greater cardiovascular mortality. Randomized trials have found value in treatments
for some adverse effects including bone loss (bisphosphonates, denosumab, selective estrogen
receptor modulators), markers of metabolic syndrome (exercise, diet, metformin), gynecomastia (tamoxifen, prophylactic radiation), muscle loss (resistance and aerobic exercise), and
hot flashes (venlafaxine, medroxyprogesterone, cyproterone acetate, gabapentin).
Conclusions: ADT is often a necessary component of the treatment of aggressive prostate
cancer, yet it has known harms that can impair health and quality of life. Clinicians should be
aware of interventions that can help mitigate these adverse effects.
Patient summary: Androgen deprivation therapy is a critical component of the management of
aggressive and advanced prostate cancer, but it causes adverse effects including bone loss,
metabolic changes, gynecomastia, muscle loss, hot flashes, and possibly increased cardiovascular
events. Clinicians should be aware of interventions that can help mitigate these adverse effects.
# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords:
Androgen deprivation therapy
Prostate cancer
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* Corresponding author. Department of Radiation Oncology, Dana-Farber/Brigham and Women’s
Cancer Center, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA. Tel.: +1 617 732 7936;
Fax: +1 617 975 0912.
E-mail address: [email protected] (P.L. Nguyen).
http://dx.doi.org/10.1016/j.eururo.2014.07.010
0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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1.
EUROPEAN UROLOGY 67 (2015) 825–836
Introduction
2.
Androgen deprivation therapy (ADT) is a mainstay of
prostate cancer treatment and has been shown in randomized trials to improve overall survival when used with
radiation for intermediate- and high-risk localized disease
[1,2], as well as locally advanced [3,4] and node-positive
disease [5], and after surgery for node-positive disease [6].
Although ADT can improve survival, it can also cause
significant morbidity and a decrement in quality of life
(QOL). This narrative review describes the adverse consequences of ADT and provides an up-to-date summary of
evidence-based interventions that can prevent or reduce
these side effects (Tables 1 and 2).
Q3
Evidence acquisition
A Medline search was conducted to identify original
articles and review articles published from January 1,
1966, to August 1, 2013, that focused on the side effects of
ADT and methods to mitigate those side effects. Keywords
included androgen deprivation therapy and side effects.
The articles with the highest level of evidence within each
of the side effect categories examined were identified
with the consensus of all of the collaborative authors
and were reviewed. For the treatment of ADT-related side
effects, the initial selection of articles within each category
was limited to randomized controlled trials and then
expanded to prospective noncontrolled trials only if
Table 1 – Summary of randomized trials testing mitigation strategies for androgen deprivation therapy side effects
Problem
Bone health
Metabolic syndrome
Sexual dysfunction
Gynecomastia
Intervention
Patients, n
Outcome
47
104
106
112
191
48
1468
Prevents decrease in bone mineral density on ADT
Raloxifene
Denosumab
Smith et al. [15]
Choo et al. [16]
Smith et al. [17]
Greenspan et al. [18]
Klotz et al. [19]
Smith et al., 22]
Smith et al. [21]
Toremifene
Smith et al. [23]
1284
Resistance training
Segal et al. [40]
Resistance vs aerobic
exercise
Santa Mina et al. [41]
Cognitive-behavioral
therapy for exercise
Metformin and exercise
Carmack Taylor et al. [42]
Nobes et al. [39]
40
Intermittent ADT
Crook et al. [73]
1386
Hussain et al. [74]
1535
Pamidronate
Risedronate
Zoledronic acid
Alendronate
Aerobic and resistance
exercise
Breast radiation
Hot flashes
Cormie et al. [77]
155
66
134
57
Increase in bone mineral density while on ADT
Increase in bone mineral density while on ADT;
decreased fracture risk
Increase in bone mineral density while on ADT;
decreased fracture risk. Increased risk of DVT
Increase in upper and lower body fitness; no effect
on BMI or waist circumference
Aerobic-training group engaged in significantly
more physical activity than the resistance-training
group
No increase in exercise or QOL
Decrease in abdominal girth, BMI, weight. and
systolic BP
Increased libido; no decrease in survival compared
with continuous ADT in nonmetastatic men
Increased erectile function, but treatment failed
noninferiority for survival in metastatic patients
Maintained sexual activity and interest in sex
Widmark et al. [80]
Tyrrell et al. [78]
Boccardo et al. [81]
Di Lorenzo et al. [82]
253
106
114
102
Perdona et al. [83]
Galvão et al. [88]
151
57
Reduced fatigue compared with usual care
Aerobic and resistance
exercise plus diet advice
Gabapentin
Venlafaxine/
medroxyprogesterone/
cyproterone
Segal et al. [40]
Culos-Reed et al. [90]
Bourke et al. [62]
155
100
50
Reduced fatigue compared with usual care
Loprinzi et al. [92]
Irani et al. [93]
214
311
Soy protein/Venlafaxine
Vitolins et al. [95]
120
Tamoxifen
Breast radiation vs
tamoxifen
Fatigue
Study
Aerobic and resistance
exercise
Significant reduction in gynecomastia
RT and tamoxifen both reduce gynecomastia
compared with observation, but tamoxifen
reduces it more
High-dose gabapentin reduced hot flash frequency
All treatments reduced hot flashes;
medroxyprogesterone reduced more than
venlafaxine and interfered with ADT less than
cyproterone
Neither soy protein or venlafaxine, or a
combination of the two, reduced hot flashes
ADT = androgen deprivation therapy; BMI = body mass index; BP = blood pressure; DVT = deep vein thrombosis; QOL = quality of life; RT = radiation therapy.
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EUROPEAN UROLOGY 67 (2015) 825–836
Table 2 – Summary of evidence-based strategies to reduce androgen deprivation therapy side effects
Side effect
Decreased bone health
Metabolic consequences
Increased diabetic risk
Cardiovascular events
Sexual dysfunction
Gynecomastia
Reduced penile/testis size
Fatigue
Hot flashes
Cognitive changes
Anemia
Evidence-based strategies to reduce effects
Calcium (1000–1200 mg daily from diet and supplements)
Vitamin D (800–1000 IU daily)
For men with FRAX risk of hip fracture >3%:
" Denosumab (increased BMD and decreased fractures)
" Zoledronic acid (increased BMD, alternative if denosumab not available)
" Alendronate (increased BMD, alternative if denosumab not available)
Exercise (aerobic and resistance)
ATP III and AHA/ACC guidelines for lipids
ADA guidelines for screening high-risk patients
Closer monitoring of control among those with preexisting diabetes
–
Intermittent ADT for rising PSA after radiation
Use shortest acceptable duration of ADT
Prophylactic radiation
Prophylactic tamoxifen
–
Exercise (aerobic and resistance)
Medroxyprogesterone
Venlafaxine
Gabapentin
–
–
References
[14]
[14]
[21]
[17,20,27]
[18,19]
[39–41,43,44]
[36,47]
[45,46]
[73]
[76]
[78,80]
[81,82]
[87–91]
[93]
[93]
[92]
ADA = American Diabetes Association; ADT = androgen-deprivation therapy; AHA/ACC = American Heart Association/American College of Cardiology;
ATP III = Adult Treatment Panel III; BMD = bone mineral density; FRAX = World Health Organization Fracture Risk Assessment Tool; PSA = prostate-specific
antigen.
randomized trials were not available in that particular
category.
3.
Evidence synthesis
3.1.
Impact of androgen deprivation therapy on bone health
and strategies for prevention
ADT is associated with decreases in bone mineral density
(BMD) and increased risk of fracture. Prospective studies
suggest that BMD decreases by 5–10% in the first year after
initiating ADT for prostate cancer [7–10]. Two studies based
on the Surveillance Epidemiology and End Results (SEER)–
Medicare database reported an increased fracture risk with
ADT that increased with longer duration of ADT. One study
noted a 21% relative increase in clinical fractures with ADT
use [11], and another study of > 50 000 men reported a
fracture rate among men surviving at least 5 yr of 19.4%
with ADT versus 12.6% without ADT [12].
Calcium and vitamin D are commonly recommended for
men receiving ADT, although no randomized trials have
tested whether supplementation improves BMD for men on
ADT. A 2012 systematic review found that 12 clinical trials
testing other agents for BMD preservation used calcium
(500–1000 mg/d) and vitamin D (200–500 IU/d) in the
control arms (doses likely too low to prevent bone loss) [13].
A calcium intake of at least 1200 mg daily (from diet and
supplements) and supplemental vitamin D of 800–1000 IU/d
is currently recommended for all men > 50 yr of age by the
National Osteoporosis Foundation and would be a reasonable
recommendation for all men on ADT [14].
Bisphosphonates have been shown in randomized trials
to increase BMD or reduce BMD loss in men receiving ADT.
In 2001, a randomized trial of 47 men found that in men
assigned to leuprolide alone, there was a 3.3% decrease in
BMD at the lumbar spine, 2.1% in the trochanter, and 1.8% in
the hip, but no decreased BMD in the group receiving
leuprolide plus pamidronate 60 mg every 12 wk [15].
Similarly, a recent trial of risedronate versus placebo
found no significant loss in BMD after 2 yr of ADT in the
risedronate arm compared with bone loss in the control arm
[16]. Increased BMD has been seen with zoledronic acid or
alendronate given with ADT. In a 2003 randomized trial,
4 mg zoledronic acid given every 3 mo for 1 yr increased
mean BMD by 5.6% in men receiving zoledronic acid; BMD
decreased by 2.2% in the placebo group ( p < 0.001), and
similar results were seen in the femoral neck, trochanter,
and total hip [17]. Increases in BMD with alendronate were
seen in two randomized trials [18,19]. The most recent,
published in 2013, found that compared with calcium
100 mg and vitamin D 400 IU, the addition of weekly oral
alendronate 70 mg improved spine BMD by 1.7% versus a
!1.9% change in the placebo group ( p < 0.001), with similar
findings in the hip [19]. A systematic review and metaanalysis published in 2012 found that in 15 trials of 2634
participants, bisphosphonates as a class showed a substantial effect in preventing fractures (risk ratio [RR]: 0.80;
p = 0.005) and osteoporosis (RR: 0.39; p < 0.00001) [20].
Denosumab is a humanized monoclonal antibody against
the receptor activator of nuclear factor-kB ligand that blocks
the maturation of preosteoclasts to osteoclasts. A large
randomized trial of 1468 men published in 2009 found that
60 mg subcutaneous denosumab increased lumbar spine
BMD at 24 mo by 5.6% compared with a 1.0% loss in the
placebo group ( p < 0.001). Similar results were seen in the
total hip, femoral neck, and radius. In addition, denosumab
led to a decreased incidence of new vertebral fractures at
3 yr (1.5% vs 3.9%; RR: 0.38; 95% confidence interval [CI],
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EUROPEAN UROLOGY 67 (2015) 825–836
0.19–0.78); p = 0.006) with no difference in adverse events
[21]. Denosumab is approved to prevent bone loss during
ADT for prostate cancer in >30 countries.
The selective estrogen receptor modulators raloxifene
and toremifene have also been tested in men on ADT. In a
12-mo randomized trial of 48 men on ADT, 60 mg/d
raloxifene improved mean BMD of the total hip by 1.1%
(#0.4%) compared with a 2.6% (#0.7%) loss in men not on
raloxifene ( p < 0.001), and similar results were seen in the
femoral neck and trochanter [22]. In a phase 3 study of >1200
men, those randomized to 80 mg oral toremifene daily had a
50% reduction in the 2-yr incidence of new vertebral fractures
(4.9% for placebo vs 2.5% for toremifene; p < 0.001), although
venous thromboembolic events occurred more frequently in
the toremifene group (1.1% for placebo vs 2.6% for toremifene)
[23]. Raloxifene and toremifene are not currently approved by
the US Food and Drug Administration (FDA) for the indication
of preventing ADT-related bone loss.
Finally, two trials examined bone loss with bicalutamide
monotherapy (150 mg daily) versus leuprolide. One trial of
52 men found that BMD of the lumbar spine increased by
2.5% in the bicalutamide group; it decreased by 2.5% at 1 yr
in the leuprolide group [24]. A second trial of 103 men found
that bicalutamide increased BMD in the lumbar spine by
2.42% at 2 yr versus a 5.40% loss with placebo [25]. However,
this strategy cannot be routinely recommended because a
meta-analysis of 2717 patients found that compared with
luteinizing hormone-releasing hormone [LHRH] agonists,
antiandrogen monotherapy was associated with a nearsignificant decline in overall survival (hazard ratio [HR]:
1.21; 95% CI, 0.99–1.50) in the metastatic setting [26].
Based on the data just cited, in addition to vitamin D and
calcium supplementation for all men on ADT, the current
National Comprehensive Cancer Network guidelines recommend treatment with either denosumab (60 mg subcutaneously every 6 mo), zoledronic acid (5 mg intravenously
annually), or alendronate (70 mg orally weekly) for men
with a 10-yr risk of hip fracture $3% based on the Fracture
Risk Assessment Tool algorithm released by the World
Health Organization [27]. A baseline BMD scan should also
be obtained in these high-risk men, and a follow-up scan
after 1 yr of therapy is recommended by the International
Society for Clinical Densitometry for men on long-term
ADT [28].
3.2.
Metabolic consequences of androgen deprivation therapy
The metabolic consequences of ADT have been established
in both prospective and population-based studies.
An early prospective study of 32 men newly exposed to
12 mo of gonadotropin-releasing hormone (GnRH) agonists found a 2.4% weight gain, 9.4% increase in body
fat percentage, and 2.7% decrease in lean body mass at
12 mo [29]. A subsequent prospective study of 25 patients
without diabetes found that just 12 wk of combined
androgen blockade resulted in a 12.8% decrease in insulin
sensitivity and a 25.9% increase in fasting plasma insulin
[30]. Also, a cross-sectional study of 18 men on >1 yr
of ADT and 35 age-matched controls found that men on
long-term ADT had significantly higher fasting glucose
(131 vs 103; p < 0.01) and greater insulin resistance (17 vs
6; p < 0.01), and that 44% of the men on ADT had fasting
glucose in the diabetic range (>126 mg/dl) compared with
11–12% for the controls [31].
The concern about the possible link between ADT and
diabetes raised by the patient-level studies was later
confirmed by several large population-based studies. First,
a study based on 73 196 men >65 yr of age with prostate
cancer in the US-based SEER-Medicare database found
that men being treated with a GnRH agonist had a 44%
increased risk of incident diabetes [32]. These findings were
confirmed in another US-based study of 37 443 veterans
with prostate cancer. In this study, 36% of the men were
treated with ADT, and among those receiving GnRH
agonists, there was a 28% increase in the risk of incident
diabetes (36.1 events per 1000 person-years with GnRH
agonist vs 21.1 events per 1000 person-years for no ADT)
[33,34]. A large study from the administrative databases in
Ontario, Canada, examined 19 079 men $66 yr of age who
received either bilateral orchiectomy or $6 mo ADT and
found that ADT was associated with a 16% increase in the
risk of incident diabetes [35].
The constellation of the metabolic effects of ADT shares
some features of the hallmarks of metabolic syndrome. Per
the Adult Treatment Panel III (ATP III) guidelines, the
diagnosis of metabolic syndrome requires the presence of
three of the following five criteria: (1) serum triglycerides
$150 mg/dl, (2) high-density lipoprotein (HDL) < 40 mg/dl,
(3) fasting serum glucose >110 mg/dl, (4) waist circumference $40 inches, and (5) blood pressure $130/85 [36]. As
noted earlier, patients receiving ADT are at risk for higher
fasting serum glucose and increased waist size due to
central weight gain. Triglycerides have also been reported
to rise by 26.5% (#10%; p = 0.01) with 1 yr of ADT [29].
Although ADT has not consistently been linked to increased
blood pressure, a prospective study of 22 men on ADT for 6 mo
found an increase in arterial stiffness [37]. Not surprisingly, an
increase in the incidence of metabolic syndrome was observed
in a cross-sectional study of 58 men that found metabolic
syndrome was present in >50% of men on long-term ADT and
that this rate was significantly higher than patients with
prostate cancer not on ADT ( p < 0.01). This difference was
driven largely by men on ADT meeting the hyperglycemia,
abdominal girth, and elevated triglycerides criteria, rather
than the hypertension or HDL criteria [38]. It should be noted
that the metabolic profile resulting from ADT differs slightly
from the metabolic syndrome in that ADT appears to result in
an increase in HDL rather than a decrease, although it is
unclear if this has any cardioprotective effect [29].
Several trials have examined whether various exercise
strategies can counteract the metabolic effects of ADT.
Nobes et al. found that among 40 men beginning ADT for the
first time, 6 mo of metformin and exercise led to significant
improvements in abdominal girth ( p = 0.05), weight
( p < 0.001), body mass index ( p < 0.001), and systolic
blood pressure ( p = 0.01) compared with control, although
there was no difference in the biochemical markers of
insulin resistance [39]. Prior to that, Segal et al. reported
EUROPEAN UROLOGY 67 (2015) 825–836
that randomization to 12 wk of resistance training versus
observation resulted in higher levels of upper body
( p = 0.009) and lower body ( p < 0.001) muscular fitness,
although there was no difference in body weight, body mass
index, waist circumference, or subcutaneous skinfolds [40].
A recently reported randomized trial compared resistance
training with aerobic exercise in men on ADT and found that
the aerobic group engaged in significantly more physical
activity than the resistance group, although the resistance
group had significant improvements in health-related QOL
[41]. The challenges of encouraging physical activity were
demonstrated in a randomized trial of 134 men on ADT that
found that a lifestyle program implementing a cognitivebehavioral curriculum focused on increasing physical
activity did not result in increases in routine physical
activity or changes in QOL [42]. Given the relatively
small sample sizes and preliminary nature of many of
these studies, larger randomized trials are needed to assess
the benefit of strategies to mitigate metabolic syndrome in
men on ADT. Additional randomized trials of exercise
versus observation are currently in progress for this patient
population [43,44]. Another promising strategy is the use of
metformin, although currently there is insufficient evidence
to support its routine use in this setting.
It remains uncertain exactly to what degree exercise can
alleviate the metabolic harms of ADT; nevertheless, both
aerobic and resistance exercises are very rational recommendations for all men undergoing ADT. There are
currently no specific recommendations regarding the
management of insulin resistance and lipid increases for
men on ADT. Given the increased risk of diabetes associated
with ADT, one strategy would be to consider men on ADT as
high risk for developing diabetes and follow the American
Diabetic Association recommendations for screening in
high-risk individuals [45]. Similarly, given the worsening of
diabetes control among men treated with ADT [46], regular
monitoring of diabetes control and adjustment of medications when needed is recommended for men with existing
diabetes treated with long-term ADT. Lipid abnormalities
can be treated per the ATP III guidelines [36], or clinicians
may consider the new American Heart Association (AHA)/
American College of Cardiology guidelines that deemphasize the specific low-density lipoprotein (LDL) targets of ATP
III and instead recommend initiating statin therapy based
on a combination of LDL levels, diabetes, and current and
future risk of atherosclerosis [47].
3.3.
The controversy about cardiovascular harm
Whereas the metabolic consequences of ADT are reasonably
well established, whether ADT also increases the risk of
cardiovascular (CV) events and CV mortality has been more
controversial. Awareness of the problem began in 2006 with
the publication of the observational SEER-Medicare study
by Keating et al. [32]. In addition to the increased risk of
diabetes, it also found a 16% increased risk of coronary heart
disease, 11% increased risk of myocardial infarction (MI),
and a 16% increased risk of sudden cardiac death among
men receiving ADT compared with prostate cancer patients
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not on ADT. Interestingly, this risk of excess events was not
seen with orchiectomy, raising the possibility that the
events could be related to the GnRH agonists themselves,
although relatively few men underwent orchiectomy [32].
Further retrospective data from the Cancer of the Prostate
Strategic Urologic Research Endeavor (CaPSURE) registry
suggested that among men >65 yr of age receiving radical
prostatectomy, those who also received ADT had a
significantly higher risk of fatal CV events [48]. Another
study examined CV mortality among men on ADT by
pooling data from two randomized trials, the Dana-Farber
Cancer Institute 95-096 and TROG 96-01, and found that
among the subgroup of men >65 yr of age, assignment to
the 6-mo ADT arms resulted in a significantly shorter time
to fatal MI ( p = 0.017), although the total number of cardiac
events by 7 yr was the same [49]. Another study identified
an association between ADT and coronary heart disease,
MI, sudden cardiac death, and stroke in a US veterans’
population [33,34]. These studies led to a science advisory
jointly released in 2010 by the American Urological
Association, the AHA, American Cancer Society, and
American Society of Radiation Oncologists stating that ‘‘at
this point, it is reasonable, on the basis of the above data, to
state that there may be a relation between ADT and
cardiovascular events and death’’ [50]. That same year, the
FDA issued a drug safety communication requiring manufacturers of GnRH agonists to modify their labeling to warn
of an ‘‘increased risk of diabetes and certain cardiovascular
diseases (heart attack, sudden cardiac death, stroke)’’ [51].
Since this report, additional large observational studies
have been published finding an association between ADT
and CV disease and related outcomes including stroke in a
UK database [52], peripheral arterial disease and venous
thromboembolism in the SEER-Medicare database [53], CV
disease in the Swedish national prostate cancer register
[54], and MI and stroke in the Danish cancer registry [55].
However, not all studies have found the same results.
Notably, the case-control study from Ontario reported by
Alibhai et al. of nearly 20 000 men did not find ADT to be
associated with acute MI (HR: 0.91; 95% CI, 0.84–1.00) for
ADT vs no ADT) or sudden cardiac death (HR: 0.96; 95% CI,
0.83–1.10) [35].
Although most of the published large observational
studies found an association between ADT and CV events,
most studies examining CV death did not find an association
with ADT. A retrospective analysis of the CaPSURE database
using propensity matching to adjust for possible confounders among 1391 men did not demonstrate any difference
in CV mortality associated with ADT [56]. Similarly, several
reanalyses of randomized trials comparing ADT with no
ADT did not find an association between ADT and increased
CV death, including a reanalysis of RTOG 85-31 that
compared radiation plus lifelong ADT versus radiation
alone and found no increase in CV death on the ADT arm
(8.4% with ADT vs 11.4% without ADT; p = 0.17), even after
censoring patients in the control arm who received salvage
ADT [57]. There was also a reanalysis of RTOG 86-10
comparing radiation plus 4 mo of ADT versus radiation
alone showing 12.5% versus 9.1% fatal cardiac events at
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EUROPEAN UROLOGY 67 (2015) 825–836
10 yr with and without ADT, respectively ( p = 0.32) [58],
and a reanalysis of TROG 96.01 showing 6.44% versus 7.54%
fatal cardiac events at 10 yr with and without 6 mo of ADT
( p = 0.65) [59]. In addition, a reanalysis of RTOG 92-02 did not
find excess CV death in long-term (28 mo) versus short-term
(4 mo) ADT [60]. These findings were supported by a metaanalysis of 4141 patients in eight randomized trials of ADT
versus no ADT or delayed ADT in men with nonmetastatic
prostate cancer that found the risk of CV death on the ADT
arms (11.0%) was not different than the risk on the no-ADT
arms (11.2%) (RR: 0.93; 95% CI, 0.79–1.10; p = 0.41 [61].
It has been noted that in the meta-analysis just cited,
many of the patients in the control arm eventually received
ADT, which may have limited the ability to detect a
difference in CV mortality. Also, these trials were not
specifically powered to detect a difference in CV outcomes
[62]. In addition, the meta-analysis was not able to stratify
by baseline comorbidity, and so it remains possible that
there is a vulnerable subpopulation of men with high levels
of existing comorbidity who could experience increased CV
death when treated with ADT. Evidence for this hypothesis
comes from a stratified reanalysis of the Dana-Farber
randomized trial in which men with minimal or no
comorbidity by the Adult Comorbidity Evaluation-27 index
[63] had a highly significant survival benefit with ADT, but
men with moderate to severe baseline comorbidity (24%
of the study population) had a near-significant increase
(HR: 1.85; p = 0.08) in all-cause mortality (ACM) on ADT,
presumably due to an increase in CV death [1]. Similarly, a
retrospective analysis of >5000 men treated with radiation
found that ADT use was associated with an increase in ACM
only among the small subgroup (5% of study population) of
patients who had a prior MI or diagnosis of congestive heart
failure (CHF) (HR for ACM: 1.96; 95% CI, 1.04–3.71; p = 0.04)
[64], and another retrospective study suggested the
increased risk of ACM with ADT in men with CHF or prior
MI (9% of study population) also held for men with high-risk
prostate cancer (HR: 2.57; 95% CI, 1.17–5.67; p = 0.019)
[65]. However, a large SEER-Medicare study did not find
that baseline comorbidity modified the impact of ADT on
the risk of MI [66], although men with preexisting CV
disease had a greater absolute risk of MI. This larger
absolute risk could explain why some smaller studies
observed differences only in higher risk subgroups. In
addition, separate reanalyses of the RTOG 85-31 and RTOG
92-02 by comorbidity did not find that men with
preexisting CV disease had excess CV deaths due to either
short- or long-course ADT [57,60].
To summarize, the available data suggest that ADT
results in unfavorable metabolic changes and may increase
risk for CV events, although most published studies report
that ADT is not linked to greater CV mortality. Further
investigation into the precise populations of men who may
experience the greatest harm from ADT and the precise
mechanism of harm is needed.
Currently, the best way to limit the CV harms of ADT is to
avoid using it in patients who do not need it from a cancer
perspective. It is also possible that the exercise interventions mentioned in the metabolic section will eventually
translate into prevention of excess CV events. Another
possible consideration is to evaluate alternatives to GnRH
agonists because much of the data for the CV harms of ADT
have been in men receiving mainly GnRH agonists. For
example, in both the SEER-Medicare study and the Danish
registry study, the excess risk of CV events on ADT was
seen only in men receiving GnRH agonists and not in men
receiving orchiectomy [32,55], raising the possibility that
orchiectomy may be associated with lower CV risk. There
has also been recent interest in GnRH antagonists as an
alternative to GnRH agonists and whether they could have
a different risk profile. One randomized trial of 1 yr of
leuprolide versus degarelix found no significant differences
in CV events [67]. A pooled analysis of 1708 patients who
participated in trials of degarelix found that for the overall
population, the rate of CV events was similar before and
after administration of degarelix (5.5 vs 6.1 per 100 personyears; p = 0.45), although among the subset of men with
baseline CV disease, the event rate was significantly higher
after degarelix (5.3 vs 10.5 events per 100 person-years;
p = 0.0013) [68]. Most recently, a study that pooled 2328
patients from six randomized trials of degarelix versus
leuprolide found that degarelix was associated with a lower
risk of CV events than leuprolide (HR: 0.60; 95% CI, 0.38–
0.94; p = 0.025) and that this effect was particularly seen in
the 705 men (31% of patients) with baseline CV disease (HR:
0.476; 95% CI, 0.260–0.871; p = 0.016) but not in the men
without a history of CV disease [69]. This raises the
possibility that GnRH antagonists could be a good alternative to GnRH agonists for men with preexisting CV disease.
However, some caution is needed because this was a post
hoc analysis of pooled data, and further follow-up is needed
to fully evaluate the long-term efficacy of GnRH antagonists
versus GnRH agonists.
3.4.
Sexual dysfunction
The decrease in testosterone due to ADT results in both loss
of libido in a large proportion of men and a decrease in
erectile function due to venous leakage, decreased arterial
flow, and impaired nitric oxide, leading to sexual dysfunction in >90% of men [70–72]. Two strategies that are
sometimes considered to try and reduce the sexual sequelae
are the use of intermittent androgen deprivation, the use
of shorter courses of ADT, or the use of antiandrogen
monotherapy as an alternative to GnRH agonists.
Intermittent ADT may be a viable option for men with
rising prostate-specific antigen (PSA) after local therapy but
no evidence of metastases. This strategy was tested in a
1386-patient noninferiority trial that randomized patients
with rising PSA after either primary or salvage radiotherapy
to continuous ADT versus intermittent ADT and found no
difference in overall survival with a 6.9-yr median followup (HR for death: 1.02; 95% CI, 0.86–1.21). However, desire
for sexual activity was significantly better in the intermittent group ( p < 0.001) [73]. For men with metastatic
disease, intermittent ADT cannot be recommended as a
strategy to reduce sexual dysfunction. In a randomized
noninferiority trial of 1535 men with newly diagnosed
EUROPEAN UROLOGY 67 (2015) 825–836
nonmetastatic prostate cancer, intermittent versus continuous ADT was associated with significantly better erectile
function ( p < 0.001), but after a median follow-up of 9.8 yr
it was not possible to conclude that intermittent therapy
was noninferior to continuous therapy because the CI of the
HR for death did not exclude the upper bound of 1.20 (HR:
1.10; 90% CI, 0.99–1.23) [74].
Reducing the duration of ADT could also provide
improvements in sexual function, but it cannot be recommended in situations where this would lead to a survival
decrement. For example, the European Organization for
Research and Treatment of Cancer (EORTC) performed a
noninferiority trial of radiation plus 6 versus 36 mo of ADT in
men with high risk to locally advanced prostate cancer and
found a significant improvement in sexual function and
activity with the shorter course of ADT ( p < 0.001), but there
was also a significant increase in mortality (HR for death:
1.42; 95.71% CI, 1.09–1.85) [75]. Although there is no direct
QOL comparison between 18 and 36 mo of ADT, the TROG 0304 trial randomized men to 6 versus 18 mo of ADT and found
that on the 18-mo arm of ADT, sexual activity was worse at 18
mo but not significantly worse by 36 mo. This seems to
compare favorably with the 36-mo arm of the EORTC trial
where sexual symptoms remained qualitatively worse than
the 6-mo arm even at 3.5 yr, suggesting that 18 mo would
provide sexual health benefits as compared with 36 mo [76].
Whether 18 mo can be recommended as an alternative to 36
mo remains an open question. A recent study reported in
abstract form randomized 630 men with high-risk or locally
advanced prostate cancer to radiation plus 18 versus 36 mo of
ADT, and it did not find a difference in overall survival (HR:
1.15; 95% CI, 0.83–1.59; p = 0.398), but it was underpowered
and not designed as a noninferiority trial. The current 95% CI
suggests it is not possible to rule out up to a 59% increase in
the risk of death on the 18-mo arm as compared with the 36mo arm, and further follow-up and more events will be
needed to narrow this CI.
A third option to limit sexual side effects would be to use
antiandrogen monotherapy instead of a GnRH agonist. A
randomized trial of leuprolide versus bicalutamide 150 mg
found less of a decline in sexual interest in the bicalutamide
group [24]. However, as noted in the bone section, this
strategy cannot be routinely recommended given the data
suggesting that currently available antiandrogen monotherapy is not oncologically equivalent to GnRH agonists in
a primarily metastatic setting [26]. Whether they are
oncologically equivalent in the high-risk or locally advanced
or biochemically recurrent settings remains untested.
Finally, there may be some significant benefit of exercise
therapy. Cormie et al. investigated the effect of a 12-wk
exercise program on sexual activity in 57 prostate cancer
patients undergoing ADT. There was a significant
( p = 0.045) adjusted group difference in sexual activity
following the 12-wk intervention. At baseline, 20.6% and
22.2% of participants in the exercise and control groups,
respectively, reported a major interest in sex. Following the
intervention, the exercise group had a significantly higher
percentage of participants reporting a major interest in sex
(exercise: 17.2% vs control: 0%; p = 0.024) [77]. Further
831
confirmation of these results in larger randomized studies
will be helpful in further assessing these strategies.
3.5.
Gynecomastia
Gynecomastia and breast pain can be bothersome side
effects for men on ADT. The incidence of gynecomastia was
as high as 85% in a randomized trial of men receiving highdose antiandrogen monotherapy (bicalutamide 150 mg
daily) [78], although the incidence is substantially lower
(13–22%) in men receiving combined androgen blockade
[79]. Prophylactic radiotherapy and prophylactic tamoxifen
are the two main strategies that have been tested in
randomized trials to address gynecomastia. Single-fraction
prophylactic radiation (10–15 Gy) reduced gynecomastia
from antiandrogen monotherapy from 71% to 28% at 1 yr in
one trial [80] and from 85% to 52% in another [78];
tamoxifen (20 mg/d) reduced gynecomastia from 73% to
10% in a third trial [81]. Another trial that compared
tamoxifen versus radiation versus observation found a
greater benefit of prophylactic tamoxifen (8% gynecomastia) as compared with prophylactic radiation (34% gynecomastia), although both were better than the control group
that had 67% gynecomastia. This trial also randomized
patients who developed gynecomastia to tamoxifen versus
radiation as treatment and found that once gynecomastia
develops, tamoxifen is superior to radiation in reversing
gynecomastia (only 9% still had gynecomastia 6–9 mo after
tamoxifen as compared with 54% after radiation; p < 0.05)
[82]. There were no significant differences in QOL between
tamoxifen and radiation, and similar results were seen in
another randomized trial [83].
3.6.
Reduction in penile and testicular size
A rarely discussed side effect that can be very distressing for
patients who experience it without warning is that ADT can
induce reductions in both penile and testicular size. One
pathologic study of 24 testes in men who had previously been
treated with a mean of 1 yr of buserelin found pronounced
interstitial fibrosis with total atrophy of the Leydig cells in
92% of the testes and severe generalized atrophy of the
seminiferous tubules in 50% of the testes [84]. A prospective
study of 47 men undergoing radiation plus GnRH agonists
found that stretched penile length was significantly shorter
after 18 mo, dropping from a mean of 14.2 cm to 8.6 cm
( p < 0.001) [85]. This potential side effect should be
discussed with patients before initiating ADT because
reduced penile length after prostate cancer treatment has
been associated with greater treatment regret [86]. There
are currently no known ways to mitigate this side effect.
3.7.
Fatigue
Fatigue is a noticeable side effect of ADT for many men. The
main strategy to reduce fatigue is exercise, and a number of
randomized trials reported that exercise significantly
reduced fatigue for men on ADT [87]. One randomized
trial of 57 men on ADT found that a program of resistance
832
EUROPEAN UROLOGY 67 (2015) 825–836
and aerobic exercise for 12 wk led to less fatigue ( p = 0.021)
[88], and another trial of 12 wk of resistance exercise three
times a week in 155 men had similar results ( p < 0.001)
[40]. These results were supported by a third trial of 12 wk
of aerobic and resistance exercise plus dietary advice versus
usual care in which fatigue was again significantly reduced
( p = 0.002) [89]. A trend toward improved fatigue was seen
with 16 wk of individualized aerobic and resistance training
[90]; this concept is also being tested in another ongoing
study [91].
3.8.
Hot flashes
Vasomotor flushing can be a significant impediment to QOL
for men on ADT. A randomized trial of 214 men on ADT who
received either placebo or 4 wk of 300, 600, or 900 mg daily
of gabapentin found that only the highest dose of
gabapentin reduced hot-flash frequencies compared with
placebo ( p = 0.02) [92]. Another trial randomized 311 men
on ADT with hot flashes to either venlafaxine 75 mg daily,
medroxyprogesterone acetate 20 mg daily, or cyproterone
acetate 100 mg daily. After 1 mo, hot-flash scores decreased
significantly with each treatment (!47.2% for venlafaxine,
!94.5% for cyproterone, !83.7% for medroxyprogesterone;
all p < 0.001 from baseline). Pairwise comparisons showed
that the decreases in the cyproterone and medroxyprogesterone groups were significantly larger than the decreases
in the venlafaxine group ( p < 0.001). Because cyproterone
is a prostate cancer treatment that could interfere with ADT,
the authors suggest that medroxyprogesterone should be
considered the standard treatment for ADT-induced hot
flashes [93].
Alternative remedies have also been tested to try to
reduce hot flashes. Soy protein was tested in a randomized
trial of 33 men undergoing ADT but showed no improvement in vasomotor symptoms [94]. A 2 % 2 randomized
trial of soy protein, venlafaxine, and a combination of the
two found no reduction in hot flashes for either soy protein
or venlafaxine compared with placebo [95]. Acupuncture
has also been evaluated. A systematic review identified six
studies of acupuncture for hot flashes, of which none were
randomized and placebo controlled [96]. One prospective
study of 60 men receiving auricular acupuncture weekly for
10 wk found that 95% of men experienced a decrease in
symptoms [97]. A more recent study of 14 men found that
acupuncture decreased hot-flash scores by 89.2% from
37.41 to 4.05 ( p = 0.0078) at 6 wk [98]. These results must
be considered tentative, and randomized placebocontrolled trials are needed to further evaluate the role of
acupuncture for ADT-related hot flashes.
3.9.
Cognition
Hypogonadism has been linked to cognitive declines in
several studies including a cohort study from the Baltimore
Longitudinal Study of Aging that found that among 407 men
50–91 yr of age at baseline and followed for 10 yr,
hypogonadism was associated with poorer memory and
visuospatial performance and a faster rate of decline in
visual memory [99]. The exact impact of ADT on cognition
remains a matter of ongoing study. The strongest data for a
deleterious effect come from a single trial by Green et al.
[100] in 2002 that randomized 82 men to an LHRH agonist,
cyproterone acetate, or observation. They found that half
the men assigned to therapy had a clinically significant
decline in one or more cognitive tests at 6 mo compared
with none of the men in the observation group. However,
these results were not confirmed in the largest prospective
study on the issue conducted by Alibhai et al. that enrolled
241 men with prostate cancer treated with ADT, prostate
cancer and no ADT, or no prostate cancer. After adjusting for
age and education, the study found no consistent effect of
ADT on 14 different cognitive tests across 8 cognitive
domains [101]. The study did find individual tests of
immediate memory ( p = 0.029), working memory
( p = 0.031), and visuospatial ability ( p = 0.034) that were
worse in the ADT group at 12 mo but were not confirmed by
other tests looking at the same domains. Nevertheless, given
the potential that ADT could have some subtle influences on
cognition, an ongoing randomized trial is evaluating the
impact of exercise on reducing the cognitive and psychosocial side effects of ADT [102].
3.10.
Anemia
Anemia is a very common side effect of patients receiving
ADT [103]. For example, one prospective study of orchiectomy found that 78% of men had a median decrease in
hemoglobin of at least 1 g/dl [104], another study of 110
men who received ADT prior to radiation found that
by 3 mo, average hemoglobin had dropped from 14.8 to
12.9 g/dl [105], and a third study of 250 men with a mean
hemoglobin of 14.1 g/l found that men on ADT had an
0.89 g/dl drop by 12 mo compared with a 0.056 g/dl
hemoglobin drop for prostate cancer controls [106]. For
most patients this leads to a mild asymptomatic normochromic and normocytic anemia, and the degree to which
this anemia contributes to fatigue or other QOL decrements
remains unknown [103]. Treatment with erythropoietin
would not be considered except for symptomatic patients.
Interestingly, some studies have suggested that larger
declines in hemoglobin due to ADT are associated with
poorer prostate-specific outcomes [105,107], but whether
treating this anemia could improve prostate cancer–specific
outcomes remains unknown.
4.
Conclusions
Although ADT can improve survival for men in certain
settings, ADT also has a variety of potential harms. Methods
of preventing bone loss are now well established, and
exercise may prove to be a good way to reduce the body
composition changes and fatigue from ADT, but these
results will require further confirmation. For several other
side effects, there are presently no effective mitigating
interventions. At this point, the only certain way to prevent
many of the adverse effects is to avoid using ADT for
situations in which it is not warranted, such as with radiation
EUROPEAN UROLOGY 67 (2015) 825–836
for low-risk disease [2], as monotherapy for localized
disease [108], or as neoadjuvant therapy before prostatectomy [109]. For situations in which ADT is necessary,
clinicians should intervene to reduce the harms of ADT.
Author contributions: Paul L. Nguyen had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
833
[6] Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal
therapy compared with observation after radical prostatectomy
and pelvic lymphadenectomy in men with node-positive prostate
cancer. N Engl J Med 1999;341:1781–8.
[7] Maillefert JF, Sibilia J, Michel F, et al. Bone mineral density in men
treated with synthetic gonadotropin-releasing hormone agonists
for prostatic carcinoma. J Urol 1999;161:1219–22.
[8] Berruti A, Dogliotti L, Terrone C, et al. Changes in bone mineral
density, lean body mass and fat content as measured by dual
Study concept and design: Nguyen, Smith.
energy x-ray absorptiometry in patients with prostate cancer
Acquisition of data: Nguyen, Alibhai, Basaria, D’Amico, Kantoff, Keating,
without apparent bone metastases given androgen deprivation
Penson, Rosario, Tombal, Smith.
Analysis and interpretation of data: Nguyen, Alibhai, Basaria, D’Amico,
therapy. J Urol 2002;167:2361–7.
[9] Goldray D, Weisman Y, Jaccard N, et al. Decreased bone density in
Kantoff, Keating, Penson, Rosario, Tombal, Smith.
elderly men treated with the gonadotropin-releasing hormone
Drafting of the manuscript: Nguyen.
agonist decapeptyl (D-Trp6-GnRH). J Clin Endocrinol Metab 1993;
Critical revision of the manuscript for important intellectual content:
Nguyen, Alibhai, Basaria, D’Amico, Kantoff, Keating, Penson, Rosario,
Tombal, Smith.
Statistical analysis: None.
Obtaining funding: None.
76:288–90.
[10] Daniell HW, Dunn SR, Ferguson DW, et al. Progressive osteoporosis
during androgen deprivation therapy for prostate cancer. J Urol
2000;163:181–6.
[11] Smith MR, Lee WC, Brandman J, et al. Gonadotropin-releasing
Administrative, technical, or material support: None.
hormone agonists and fracture risk: a claims-based cohort study
Supervision: Smith.
of men with nonmetastatic prostate cancer. J Clin Oncol 2005;23:
Other (specify): None.
7897–903.
[12] Shahinian VB, Kuo YF, Freeman JL, et al. Risk of fracture after
Financial disclosures: Paul L. Nguyen certifies that all conflicts of interest,
including specific financial interests and relationships and affiliations
androgen deprivation for prostate cancer. N Engl J Med 2005;
352:154–64.
relevant to the subject matter or materials discussed in the manuscript
[13] Datta M, Schwartz GG. Calcium and vitamin D supplementation
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
during androgen deprivation therapy for prostate cancer: a critical
stock ownership or options, expert testimony, royalties, or patents filed,
review. Oncologist 2012;17:1171–9.
received, or pending), are the following: Paul L. Nguyen has consulted for
[14] Clinician’s guide to prevention and treatment of osteoporosis. Na-
Ferring, Inc. and Medivation/Astellas, Inc. Shabbir M.H. Alibhai has
tional Osteoporosis Foundation Web site. http://www.nof. org/files/
received funding for an investigator-initiated trial from Sanofi-Aventis,
Shehzad Basaria has received a funding for an investigator-initiated trial
nof/public/content/file/344/upload/159.pdf.
[15] Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent
from AbbVie Pharmaceuticals and consulted for Eli Lily, Inc. Bertrand
bone loss during androgen-deprivation therapy for prostate can-
Tombal has consulted for Amgen, Astellas, Inc., and Ferring, Inc. Matthew
cer. N Engl J Med 2001;345:948–55.
R. Smith has consulted for Amgen. The remaining authors have nothing
to disclose.
Funding/Support and role of the sponsor: This study was supported by
the Prostate Cancer Foundation, Fitz’s Cancer Warriors, David and
Cynthia Chapin, Hugh Simons in honor of Frank and Anne Simons, and a
grant from an anonymous family foundation.
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