Risk stratification in the hormonal treatment
of patients with prostate cancer
Matthew A. Uhlman, Judd W. Moul, Ping Tang, Danielle A. Stackhouse and Leon Sun
Abstract: Prostate cancer (PCa) is the most common type of cancer found in American men,
other than skin cancer. The American Cancer Society estimates that there will be 186,320 new
cases of prostate cancer in the United States in 2008. About 28,660 men will die of this disease
this year and PCa remains the second-leading cause of cancer death in men. One in six men
will get PCa during his lifetime and one in 35 will die of the disease. Today, more than 2 million
men in the United States who have had PCa are still alive. The death rate for PCa continues to
decline, chiefly due to early detection and treatment, and improved salvage therapy such as
hormone therapy (HT). HT continues to be a mainstay for primary-recurrent PCa and locally-
advanced PCa. However, HT is associated with many undesirable side effects including sexual
dysfunction, osteoporosis and hot flashes, all of which can lead to decreased quality of life
(QOL). These risks are seen in both long- and short-term HT regimens. Additionally, research
in recent years has revealed trends related to clinico pathological variables and their predictive
ability in HT outcomes. Awareness of the potential adverse effects, the risks associated with HT
and the prognostic ability of clinical and pathological variables is important in determining
optimal therapy for individual patients. A rigorous evaluation of the current scientific literature
associated with HT was conducted with the goal of identifying the most favorable balance of
benefits and risks associated with HT.
Keywords: prostate cancer, recurrence, survival, hormonal therapy, toxicity, risk factors,
quality of life
Risks and benefits of hormonal therapy
Since Huggins and Hodges discovered that
prostate cancer (PCa) cell growth is androgen
dependent, hormonal therapy (HT) has been
increasingly utilized for the treatment of PCa
[Huggins and Hodges, 1972; Huggins, 1967;
Huggins and Hodges, 1941]. Approximately
30% of the existing 2 million PCa patients receive
HT in the context of adjuvant/neo-adjuvant ther-
apy before or after radical prostatectomy (RP) or
external radiotherapy (XRT) [Smith, 2007]. HT
has become an increasingly common treatment
for organ-confined PCa in the United States
Cooperberg et al. 2003]. With this increase in
popularity, patients are now receiving HT for
extended periods of time. HT is not without
risk, however, and is associated with numerous
side effects including vasomotor flushing, loss of
libido, erectile dysfunction, cognitive decline,
arterial stiffness, anemia, fatigue, gynecomastia,
mastodynia, osteoporosis leading to fractures,
obesity, sarcopenia, and cardiovascular disease
[Isbarn et al. 2008; Michaelson et al. 2008;
Higano, 2003]. More recently, metabolic compli-
cations including insulin resistance, diabetes,
been observed in patients receiving HT. These
findings have led some to suggest they are poten-
tial explanations for the increased cardiovascular
mortality seen in this population [Hakimian et al.
2008; Saigal et al. 2007; Tsai et al. 2007;
Yannucci et al. 2006], though some studies
have found no increase in cardiovascular mortal-
ity for men on androgen deprivation therapy
(ADT) [Efstathiou et al. 2009]. Given the large
side-effect profile of HT, it is understandable that
HT is associated with decreased quality of life
(QOL) [Fowler et al. 2002].
Therapeutic Advances in Medical OncologyReview
Ther Adv Med Oncol
(2009) 1(2) 79?94
! The Author(s), 2009.
Reprints and permissions:
Judd W. Moul, MD
Professor and Chief,
Division of Urologic
Surgery and Duke
Prostate Center, Duke
University Medical Center,
PO Box 3707, Durham,
Matthew A. Uhlman
Danielle A. Stackhouse
Division of Urologic
Surgery and Duke
Department of Surgery,
Duke University Medical
Center, Durham, NC 27710
Prostate-specific antigen (PSA) recurrence
Patients with biochemical recurrence or PSA
recurrence (PSAR), an increase in PSA to greater
than 0.2ng/ml following curative therapy, con-
tinue to be the main subjects utilizing HT as it
has not been shown to be superior to current
treatments as a primary therapy for PCa [Akaza
et al. 2006]. Curative treatments such as radical
prostatectomy (RP) are effective for clinically-
localized PCa, however, up to 40% of men will
have biochemical evidence of cancer progression,
evident as a detectable serum PSA level within
10 years following initial treatment [Amling
et al. 2000; Pound et al. 1999; Catalona and
Smith, 1994; Zincke et al. 1994]. As a result, it
is important to be familiar with the key risk fac-
tors for PSAR following curative treatment. Risk
factors include age, race, clinical and pathological
stage, Gleason score (GS), PSA and small pros-
tate size [Khatami et al. 2007; Freedland et al.
2005; Moul et al. 2001].
With the growing number of patients on HT
and limited data available on optimal treatment
regimens, it is important to consider the risks
and benefits associated with each therapeutic
option. This article focuses on the risks and
strategies for stratifying patients in order to
achieve maximal benefits while effectively balan-
Methods of HT
Castration remains the gold standard of HT.
It is accomplished in one of two ways that have
been shown to be equally effective ? medical and
Vogelzang et al. 1995; Kaisary et al. 1991].
Medical castration is accomplished through the
administration of a luteinizing hormone-releasing
blockade (CAB, castration+anti-androgen) or
triple androgen blockade (CAB+5a-reductase
inhibitor). Other pharmacological options are
available, but rarely utilized due to unacceptable
clinical side effects [The Veterans Administration
Co-Operative Urological Research Group, 1967]
or decreased efficacy. Surgical castration on the
other hand is accomplished through bilateral
orchiectomy. Both medical and surgical castra-
tion achieve similar therapeutic goals, although
they do so in different ways and, consequently,
have different associated risks and benefits.
Since the introduction of LHRH agonists in the
early 1980s, their use in the treatment of PCa
has continued to increase. LHRH agonists work
primarily through reducing active levels of andro-
gens. Currently available LHRH agonists include
leuprorelin, goserelin, triptorelin, and buserelin.
More recently, sustained-release formulations
that require dosing every 1?12 months have
become available. Today, LHRH agonists are
the most common form of HT [Boccon-Gibod,
2005] and the most extensively studied.
Nonsteroidal anti-androgens are another popular
form of HT, in large part due to the decreased
sexual side effects as compared to LHRH agonists
or orchiectomy [Dreicer, 2000]. Anti-androgens
work by blocking androgen receptors, which
keeps circulating androgen levels normal or
increased. Currently available agents include fluta-
mide, nilutamide and bicalutamide. With the lack
of randomized controlled trials, limited recom-
mendations for anti-androgen monotherapy exist.
Combined androgen blockade and triple
Combined androgen blockage (CAB) is a combi-
nation therapy which includes medical or surgical
castration combined with an anti-androgen. It is
also referred to as maximal androgen blockade
CAB has been investigated in many different trials,
but withconflicting results. In1989, Crawfordand
colleagues with a cohort of 603 men with dissemi-
nated, untreated PCa, showed a 25% survival
advantage (35.6 vs 28.3 months) in those receiving
leuprolide with flutamide (CAB) versus those
receiving leuprolide plus placebo [Crawford et al.
1989]. A decade later however, Eisenberger and
colleagues found no difference in survival in 1387
men with metastatic PCa who were treated with
1998]. More recently, a meta-analysis of 30 trials
showed that, at 5 years, treatment with CAB
versus castration was associated with a small, clin-
ically insignificant survival advantage of 2?3%
when compared to castration alone [Prostate
Cancer Trialists’ Collaborative Group, 2000].
These findings were confirmed in 2006 in a
systematic review by Lukka et al. [Lukka et al.
2006]. Both studies questioned the benefit of
Therapeutic Advances in Medical Oncology 1 (2)
CAB given the increased side effects and potential
decreased QOL associated with treatment. A
recent review found more support for CAB, pri-
marily due to a potential for more effective andro-
gen blockade with bicalutamide [Klotz, 2008].
Currently, monotherapy through orchiectomy or
LHRHagonist, rather thanCABis recommended
for the treatment of men with recurrent PCa.
Triple androgen blockage (TAB) is CAB with the
addition of a 5a-reductase inhibitor. TAB has
been studied far less than CAB. Initial results
from Leibowitz and Tucker in 2001 showed
TAB with finasteride maintenance to be promis-
ing [Leibowitz and Tucker, 2001]. However,
little data has been published since with no
trials supporting its use over the currently avail-
Pure LHRH antagonists
LHRH antagonists are one of the newer forms of
HTand work by blocking LHRH receptors. The
major advantage of these drugs is the absence of
biochemical flare, a transient increase in testos-
terone associated with the initiation of androgen
deprivation therapy (ADT). Abarelix, the first
LHRH antagonist, was as effective as leuprolide
at suppressing testosterone, but was taken off the
market due to an increased rate of immediate-
onset systemic allergic reactions [Trachtenberg
et al. 2002; Mcleod et al. 2001; Tomera et al.
2001]. More recently, degarelix has been intro-
duced and has not been associated with allergic
reactions [Klotz et al. 2008]. To date there have
been no long-term trials examining the efficacy of
LHRH antagonists versus the currently available
Bilateral orchiectomy as a treatment for advanced
PCa was first investigated by Huggins and
Hodges in a study of 21 patients with metastatic
PCa. Of those treated, 15 had either subjective or
objective improvement of pain or neurologic
Orchiectomy is a relatively simple, minimally-
invasive procedure that is easy to perform
[Loblaw et al. 2007]. It remains the most popu-
lar HT method in developing countries [Deng
et al. 2004]. However, with the advent of viable
medical alternatives, and because of the physical
and psychological discomforts and irreversibility
of orchiectomy, surgical castration has fallen out
of favor in developed countries [Mcleod, 2003;
Clark et al. 2001].
and Hodges, 1941].
The role of hormone therapy in prostate
Hormone therapy as a primary therapy for
localized prostate cancer
There is currently no evidence supporting the use
of HT in patients with localized PCa. Iversen and
colleagues in a randomized controlled trial with
1,218 patients showed that treatment with
150mg/day of bicalutamide in men with early,
nonmetastatic PCa did not significantly improve
survival. In fact, a trend toward decreased overall
survival was seen in the group receiving bicaluta-
Urological Association (AUA) guidelines state
that primary ADT may be employed with the
goal of providing symptomatic control of PCa
for patients in whom definitive treatment with
surgery or radiation is neither possible nor accep-
table. Today, neither the AUA or the European
Association of Urology (EAU) recommends the
use of HTas primary therapy for PCa in patients
with localized disease who are candidates for
Thompson et al. 2007].
Hormone therapy as a primary therapy for
locally advanced or metastatic disease
For patients with metastatic disease, HT has
been shown to provide quality-of-life improve-
ments including reduction in fractures, bone
pain and ureteral obstruction [Huggins et al.
1941; Huggins, 1967]. A systematic review and
meta-analysis of 24 single-therapy HT trials for
men with advanced PCa showed no difference in
survival between LHRH agonist and orchiectomy
groups, though data showed a trend toward
decreased survival in patients treated with anti-
androgens [Seidenfeld et al. 2000]. This finding
was confirmed by Tyrell and colleagues in a pro-
spective trial including 1,453 men with locally-
advanced or metastatic PCa. Treatment with
bicalutamide versus castration was found to be
less effective for patients with metastatic disease.
No survival difference was seen for patients with
locally-advanced disease [Tyrrell et al. 1998].
The authors did point out the significant
decrease in sexual side effects in patients treated
with bicalutamide and that it could be used in
patients for whom surgical and medical castra-
tion is not indicated or acceptable. Wirth and
associates recently reported 7-year results from
the Early Prostate Cancer program which rando-
mized men to standard of care (RP, radiation or
watchful waiting) +/? bicalutamide. At 7 years,
MA Uhlman, JW Moul et al.
men with locally-advanced disease receiving
bicalutamide, showed a 34% reduction in pro-
gression-free survival, but no difference in overall
survival [Wirth et al. 2007]. CAB has also been
explored in patients with metastatic disease. In
the largest trial to date, Eisenberger and collea-
gues found no difference in survival in 1,387 men
with metastatic PCa who were treated with
castration +/? flutamide [Eisenberger et al. 1998].
A number of other studies have examined the
efficacy of HT in patients with locally-advanced
or metastatic disease that looked at immediate
versus delayed treatment delivery. These studies
are discussed below. The AUA and EAU cur-
rently recommend treating patients with asymp-
tomatic metastatic PCa with HT, however, the
optimal time to initiate treatment is unknown.
For patients with symptomatic metastatic PCa,
HT should be initiated immediately.
Hormone therapy combined with radical
Neo-adjuvant therapy with prostatectomy. There
is little evidence to suggest that neo-adjuvant
LHRH agonists with RP are of any survival
benefit. Boorjian and associates showed, in a ret-
rospective trial of 507 men, 455 of which were
treated with HT, that adjuvant HT decreased the
risk of PSAR and local recurrence, but did not
significantly affect overall survival [Boorjian et al.
2007]. Recently a large Cochrane meta-analysis
demonstrated that neo-adjuvant HT (LHRH
agonists and anti-androgens) can significantly
including positive margins, and tumor stage,
but does not improve overall survival [Kumar
et al. 2006]. Currently, neo-adjuvant HT with
RP is not recommended by the AUA or EAU.
Adjuvant therapy with prostatectomy. A number
of trials have shown that adjuvant HT following
prostatectomy does not increase survival as com-
pared to prostatectomy alone. In one of the lar-
gest trials to date ? the Early Prostate Cancer
program ? Wirth and colleagues showed that
patients receiving adjuvant bicalutamide had no
advantage in survival over those receiving pla-
cebo [Wirth et al. 2007]. In another retrospective
trial by Siddiqui and colleagues, ADT following
RP was associated with increased progression-
However, it was not found to increase overall sur-
vival [Siddiqui et al. 2008]. Finally, for patients
associates found that ADT was associated with
a significantly reduced risk of PSAR and local
recurrence, but did not demonstrate a survival
advantage [Boorjian et al. 2007].
lymph-node metastases,Boorjian and
The only circumstance in which adjuvant HT
with RP has been shown to increase survival
was in a small study of 98 men with lymph-
node metastases. The study assigned patients to
immediate or delayed ADT and after nearly
12 years of follow up, found that those who
increased overall survival [Messing et al. 2006].
The study has been criticized though due to its
small size and lack of generalizability to the pop-
ulation at large.
Currently, there is no evidence to suggest that
neoadjuvant or adjuvant HT with RP provides
any overall survival benefit in patients without
lymph-node metastases and as such, neither
neo-adjuvant nor adjuvant HT with RP is cur-
rently recommended by the AUA or EAU. For
patients with lymph-node positivity, the EAU
recommends immediate ADT whereas the AUA
does not address the situation in their guidelines.
Hormone therapy combined with radiation
Neoadjuvant radiotherapy. ADT with radiother-
apy has been shown to significantly increase over-
all survival in a number of studies. Bolla, in a
randomized trial with a cohort of 415 men with
locally-advanced PCa, showed that the addition
of an LHRH agonist (goserelin) to radiotherapy
significantly improved overall survival at 5 years
(78 versus 62% with radiotherapy alone) [Bolla,
1997]. Pilepich and colleagues also found that
the addition of an LHRH agonist to radiotherapy
rates at 10 years in men with locally-advanced
disease (16 versus 22%) [Pilepich et al. 2005].
Of particular interest was the finding that
improved survival appeared preferentially in
patients with a GS of ?7. Additionally, Iversen
and colleagues showed that 150mg/day of bica-
lutamide in addition to radiation therapy reduced
the risk of death by 35% in men with locally-
shown a survival advantage in men receiving
neoadjuvant- or adjuvant-combined androgen
blockade (LHRH agonist+anti-androgen) with
Therapeutic Advances in Medical Oncology 1 (2)
Another study by D’amico and colleagues also
demonstrated a survival advantage in men receiv-
ing adjuvant HT (LHRH agonist+anti-andro-
gen) with radiotherapy [D’amico et al. 2004].
Additional studies have shown neoadjuvant HT
with radiotherapy significantly increases overall
survival [Denham et al. 2005; Laverdiere et al.
2004]. Currently, both the AUA and EAU recom-
mend neo-adjuvant and adjuvant HT for patients
with high-grade or locally-advanced PCa who
will be receiving radiotherapy [Heidenreich et al.
2008; Thompson et al. 2007].
Hormone therapy combined with other
treatment modalities for prostate cancer
HT is often given to patients before treatments
such as brachytherapy to reduce the size of the
prostate [Lee, 2002]. However, a number of stu-
dies have shown that neo-adjuvant ADT with
brachytherapy does not lead to increased survival
[Merrick et al. 2007; Machtens et al. 2006;
Galalae et al. 2004]. One retrospective study
found that men receiving neo-adjuvant ADT
with brachytherapy had significantly reduced
survival, but due to the nature of the study, the
findings must be interpreted lightly [Beyer et al.
2005]. Currently, neither the AUA nor the
EAU guidelines recommend the use of neo-
adjuvant HT with brachytherapy.
Hormone therapy following PSA recurrence
Patients with PSAR continue to be the most
common recipients of HT [Akaza et al. 2006].
However, there is little evidence guiding these
androgen-deprivation therapy reduces metastatic
complications including ureteral obstruction,
bone pain and fractures [The Medical Research
Research Group, 1967]. Although there has
never been a survival advantage demonstrated
with HT, it can provide significantly increased
However, the majority of patients receiving HT
do not have metastatic disease. HT is associated
with significant side effects that can affect QOL
negatively and, as a result, physicians are faced
with questions of when to initiate treatment and
on what schedule to continue it.
Immediate versus delayed therapy. For locally-
advanced and metastatic PCa, there is much
debate about the best time to start therapy.
Immediate or early therapy refers to the initiation
of HT as soon as a patient’s PSA begins to rise
following surgery, whereas delayed therapy gen-
erally begins when clinical signs of metastatic dis-
ease are present. Only a few randomized trials for
immediate versus delayed therapy exist today.
The Medical Research Council, with a cohort
of 983 men with locally-advanced or metastatic
PCa, randomized men to immediate or delayed
HT and found no survival difference between
therapies. Patients receiving immediate therapy,
however, did have significantly lower rates of
pathological fractures, bone pain and ureteral
obstruction [The Medical Research Council
Prostate Cancer Working Party Investigators
Group, 1997]. More recently, Moul and collea-
gues with the largest retrospective cohort to date
with 1,352 patients, found that immediate ther-
apy was associated with delayed clinical metasta-
ses in patients with a GS >7 or a PSA doubling
time <12 months. No survival advantage was
seen. A Cochrane review by Nair and colleagues
concluded that immediate HT is associated with
a small, but significant survival advantage at 10
years [Nair et al. 2002]. However, it also con-
cluded that early therapy is associated with
increased costs and more side-effects. Finally, a
review by Messing and colleagues concluded that
immediate HT may have a survival advantage for
men with non-metastatic, lymph node positive
disease [Messing et al. 2006]. Men with meta-
static disease may not see a survival advantage,
but will see improved QOL with HT.
patients are undergoing HT for increasingly
longer periods of time, providers are now faced
with the challenge of how often to administer
HT. Nearly all patients who undergo HT will
eventually develop PCa that is resistant to ther-
apy. This is termed castration-resistant PCa
(CRPC) and currently there is little that physi-
cians can do to treat the disease. A number of
trials have been conducted comparing intermit-
tent HT (IHT) with continuous HT (CHT).
A number of trials in the past have concluded
that IHT is no worse than CHT, but due to
small sizes of the trials in question, limited
recommendations have been made [Prapotnich
et al. 2009; Peyromaure et al. 2005; De La
Taille et al. 2003; Youssef et al. 2003]. A
Cochrane review completed in 2007 found that
there is not enough data to suggest that IHT is
more effective than CHT for survival or disease
progression and limited information suggests that
MA Uhlman, JW Moul et al.
IHT may have slightly reduced adverse events
[Conti et al. 2007]. A recently completed rando-
mized trial by Calais Da Silva that included 626
men with locally-advanced or metastatic disease
found that men receiving IHT versus CHT were
not significantly different with respect to survival.
The IHT group had more cancer deaths, but less
cardiovascular deaths. QOL was no different
while undergoing treatment, though men on
IHT had significantly better sexual activity and
the overall cost was significantly reduced in the
Currently the AUA does not have definitive
recommendations regarding treatment initia-
tion-time or treatment intervals for HT following
PSAR. The EAU guidelines suggest that a period
of watchful waiting may be appropriate with a
possibility of HT at a later time. They also state
that lymph node-positive disease may be an indi-
cation for immediate HT, but they do not go so
far as to recommend it. For intermittent versus
continuous therapy, the EAU guidelines state
that IHT may be acceptable for some patients,
but that randomized trials are needed.
Risks associated with hormone therapy
HT continues to be a popular treatment option
for men with recurrent or advanced PCa, how-
ever, the treatment is not without risks. Medical
and surgical castration have been shown to be
equally effective treatments for PCa [Vogelzang
et al. 1995; Kaisary et al. 1991], but today, for
multiple reasons, medical options are more often
utilized. However, regardless of therapy choice,
both forms of treatment have significant side
effects. LHRH agonists and surgical castration
both effectively reduce testosterone levels and as
a result have a similar side-effect profile, though
there have been limited reports on orchiectomy
alone. In addition there is limited data on anti-
between treatments difficult. Even with limited
data on these specific therapies, a great amount
of research has been conducted looking at LHRH
agonists and anti-androgens.
A side effect specific to LHRH agonists is the flare
hypothalamic-pituitary-gonadal axis, stimulation
of the anterior pituitary with a LHRH agonist
results in a surge of increased testosterone. The
flare reaction is not seen in patients treated with
otherforms ofcastration. Thompsonand
associates demonstrated, in a review of 765
patients from 9 studies, that 10.9% of patients
experienced a flare and 2% died [Thompson
et al. 1990]. In patients with overt metastases
who are at risk ofdevelopingsymptoms associated
with a surge in testosterone with initial LHRH
agonist administration, anti-androgen therapy
should precede or be co-administrated with the
LHRH agonist and be continued in combination
for at least 7 days [Schulze and Senge, 1990;
Labrie et al. 1987]. An exception exists for
patients at high risk of impending spinal cord
compression, for whom surgical castration is
recommended [Heidenreich et al. 2008].
Sexual side effects
Sexual side effects are the most common among
research has demonstrated differences in side-
effect rates between HT with LHRH agonists
ADT. The side effects of LHRH agonists are
comparable with those of castration, principally
due to the reduction in testosterone levels to
<50ng/dl achieved by both therapies.
The list of side effects with HT is significant and
patient considerations on QOL must be factored
into any treatment decisions. Sexual side effects
are reported at variables, but nonetheless there
are high rates with castration. Decreased libido
is reported in up to 90% of patients and erectile
dysfunction levels vary among studies ranging
between 15?72% [Diblasio et al. 2008; Potosky
et al. 2001]. In one study, Potosky and collea-
gues reported that sexual function among a
cohort of 431 men was impaired similarly in
patients undergoing either surgical or medical
castration. In the study, 63.6 and 58.0% of
patients (surgical and medical castration respec-
tively) reported ‘no interest’ in sexual activity fol-
lowing HT, up from 27.6 and 31.7% before
treatment [Potosky et al. 2001].
Diblasio, with a cohort of 359 patients, found an
erectile-dysfunction rate of only 14% of patients
following HT, but did admit that under-reporting
likely played a role in the number [Diblasio et al.
2008]. Fowler and colleagues, with a cohort of
over 1,300 men who underwent radical prosta-
tectomy with or without HT, found that men
receiving HT were significantly more likely
to have decreased libido (69 versus 29% had
‘no sex drive within the last 30 days’) and were
Therapeutic Advances in Medical Oncology 1 (2)
significantly more likely to have had no erections
since surgery (72 versus 55%) [Fowler et al.
Anti-androgens. Despite conflicting studies, the
number of men receiving oral anti-androgen ther-
apy alone has grown, in part due to the presumed
decrease in sexual side effects associated with
therapy. One study by Iversen and colleagues
much more likely to maintain sexual interest
[Iversen et al. 1998]. See and Tyrrell found that
patients given bicalutamide at a dose of 150mg/
day before radiotherapy had rates of impotence
(12.7%) and decreased libido (4%) that were not
statistically different from men receiving placebo.
These results are much lower than reported rates
for men undergoing more traditional ADT [See
and Tyrrell, 2006].
Osteoporosis and fractures
As patients continue to receive HT for longer
periods of time, osteoporosis has emerged as a
significant risk of treatment.
ADT. ADT has been shown to increase the risk of
osteoporosis and pathological fractures in multi-
ple studies [Malcolm et al. 2007; Smith et al.
2006a; Shahinian et al. 2005; Preston et al.
increased age (>70) at treatment initiation and
CHT have all been shown to increase rates of
2007]. Reported rates of osteoporosis vary
widely within the literature, with a range of
7?23% [Malcolm et al. 2007; Shahinian et al.
2005]. Rates of fractures in patients on ADT
also vary widely between studies, with a range
of approximately 5?20% with fracture rates for
0.7?12% [Malcolm et al. 2007; Smith et al.
2006a; Lopez et al. 2005; Shahinian et al.
2005; Oefelein et al. 2001; Hatano et al. 2000;
Townsend et al. 1997]. Lopez and colleagues
found a four-fold increase in fracture risk in
patients on CAB [Lopez et al. 2005]. Shahinian
and associates looking at a cohort of more than
50,000 men, found ADT was associated with a
significant increase in osteoporosis (0.59?6.92%
versus 0.46?3.59% for non-ADT patients) and
[Shahinian et al. 2005].
A number of trials have shown that the adminis-
tration of bisphosphonates during ADT can
increase bone-mineral density (BMD). Yuen and
colleagues in a review of 1,955 patients found
bisphosphonate administration led to significant
decreases in pain and skeletal events (fractures,
spinal cord compression and bone surgery)
[Yuen et al. 2006]. Others have demonstrated
that taking pamidronate during HT reduces
bone loss in the hip and lumbar spine [Diamond
et al. 2001; Smith et al. 2001]. Perhaps the most
important agent for overall skeletal health for men
with PCa, with metastases or undergoing HT, is
zoledronic acid. It has been shown to prevent
bone loss in patients with locally-advanced PCa
receiving HT [Polascik and Mouraviev, 2008;
Ryan et al. 2006]. In addition, zoledronic acid
has been shown to reduce the number of
skeletal-related events (SRE) in men with CRPC
[Polascik et al. 2005; Saad et al. 2004; 2002].
Anti-androgens. Anti-androgen therapy, unlike
ADT, has not been shown to increase the risk of
osteoporosis. A number of smaller trials have
demonstrated reduced rates of osteoporosis with
anti-androgen use versus ADT [Sieber et al. 2004;
Smith et al. 2004; Tyrrell et al. 2003]. Wadhwa
and colleagues in a prospective trial of 618 men
randomized to LHRH agonist or anti-androgen,
showed that men on anti-androgen, therapy main-
tained BMD whereas those taking a LHRH ago-
nist had a significant loss. The exact mechanism
through which anti-androgens may decrease the
risk of osteoporosis in unknown, however, it is
known that the drugs effectively block the effects
of testosterone while allowing serum testosterone
levels to remain normal or elevated. It has been
suggested that the increased testosterone levels,
through peripheral aromatization, may lead to
higher levels of estrogen which in turn may slow
the rate of bone loss [Verhelst et al. 1994].
Randomized trials are needed to confirm the
effects of anti-androgens on osteoporosis, however
preliminary findings are encouraging.
ADT is associated with significant body composi-
tion/metabolic changes including increased rates
of metabolic syndrome, diabetes, hypercholester-
olemia, hypertriglyceridemia, and coronary artery
disease (CAD) [Kintzel et al. 2008; Braga-Basaria
et al. 2006a, 2006b]. Increased body fat and
reduced lean-muscle mass are well-known effects
of ADT [Van Londen et al. 2008; Smith, 2004;
Berruti et al. 2002; Chen et al. 2002] with fat
MA Uhlman, JW Moul et al.
content increasing up to 20% in one study and
lean body mass decreasing by 3.8%. Often these
changes are evident in the first 3?6 months of
ADT [Smith et al. 2006b; Berruti et al. 2002].
Keating and colleagues showed that ADT was
(Hazard ratio (HR)¼1.44 for LHRH agonist
and 1.34 for orchiectomy), but interestingly
found that only treatment with a LHRH agonist,
increased risk for CAD, MI and sudden cardiac
death [Keating et al. 2006]. Saigal and colleagues
found that men receiving ADT for at least 1 year
were at a 20% higher risk of serious cardiovascular
morbidity than men not receiving ADT. They also
found that risk began within 12 months of treat-
ment initiation. Anti-androgen therapy has not
been associated with significant metabolic side
effects [Saigal et al. 2007].
As HT duration has increased, cognitive decline
has become a more discussed potential side
effect. Within the last decade a large number of
between HTand subtle, but significant cognitive
changes. A review performed by Nelson and
associates showed the three cognitive areas that
were affected most often by ADT were visuospa-
tial abilities, working memory and executive
functioning [Nelson et al. 2008]. To our knowl-
edge, no large studies have examined anti-
androgen therapy and cognitive decline.
Additional side effects
Gynecomastia and breast tenderness are the most
commonly reported side effects of oral anti-
androgen therapy alone with rates as high as
67.1 and 75.1%, respectively. ADT is generally
associated with significantly lower rates with
reports of gynecomastia and breast tenderness
as low as 3.8 and 1.9% respectively [Iversen
et al. 1998]. Potosky and colleagues reported
gynecomastia rates of 24.9 and 9.7% for patients
on LHRH agonists and receiving orchiectomy
respectively [Potosky et al. 2001].
Hot flashes are another unpleasant, but common
side effect of ADT with incidence rates ranging
from 50–80% [Sharifi et al. 2005; Holzbeierlein
et al. 2004; Higano, 2003; Chen et al. 2002;
Potosky et al. 2001]. Up to 30% of men on
ADT report hot flashes as the most debilitating
side effect of therapy [Sharifi et al. 2005;
Holzbeierlein et al. 2004; Chen et al. 2002].
Rates of hot flashes for medical and surgical
castration patients are similar with some reports
suggesting a slightly, but not statistically signifi-
2001; Sarosdy et al. 1999; Parmar et al. 1987].
Hot flashes are reported at much lower rates
et al. 2006; Iversen et al. 1998].
Risk Stratification for hormone therapy
For many years, patients with PSAR have effec-
tively fallen into their own category making further
treatment stratification difficult. This is in large
part due to a lack of randomized trials and the
resultant dearth of prognostic data for patients
who have initiated HT. As a result, knowing the
optimal balance of risks and rewards is compli-
cated. Some trials however have reported prognos-
tic factors for men undergoing HTand though the
trials are designed to look at different aspects of
HT, themes have started to emerge.
Stratification factors for HT
Trials looking at the effects of HT are increasing
in popularity as the treatment modality is becom-
ing more utilized. To date, there have been no
trials examining the effects of HT on subgroups
of patients based on clinical or pathological char-
acteristics (such as GS, PSA level, etc). However,
as research efforts have increased, trends have
started to emerge. These results and future
trials may help physicians determine who will
gain the most benefit from HT. Below is a sum-
mary of some of the factors found to be predictive
of HToutcomes. A complete list of findings from
trials is seen in Table 1.
PSA-related factors. While PSA levels have been
shown to predict PSAR and prostate cancer spe-
cific mortality (PCSM), few studies have specifi-
cally examined the predictive power of PSA as it
relates to HT. A number of studies have found
that PSA-related factors including pretreatment
PSA, PSA nadir level and PSA doubling time
(PSADT) may identify patients at higher risk of
HT failure or PCSM. In a large study that looked
at 1,076 patients with metastatic PCa, Glass and
colleagues found that a PSA<65ng/ml signifi-
cantly predicted 5-year survival in patients receiv-
ing HT [Glass et al. 2003]. A number of smaller
studies have demonstrated that factors such as a
higher PSA nadir after initiation of HT and
PSADT<12 months predict worse outcomes for
men on HT [Choueiri et al. 2009; Chung et al.
Therapeutic Advances in Medical Oncology 1 (2)
2008; Studer et al. 2008; Scholz et al. 2007;
Tenenholz et al. 2007].
Finally, Hussain, with a cohort of 1,345 men with
metastatic disease undergoing intermittent or
continuous ADT, found thata PSAnadir between
0.2?4ng/ml and PSA nadir <0.2ng/ml were sig-
nificant predictors of survival (HR¼0.30 and
HR¼0.17 respectively) [Hussain et al. 2006].
Though no specific levels have been determined,
data show that a higher PSA level at treatment
time, a higher PSA nadir following treatment and
a faster PSADT (both before definitive treatment
and HT) are all correlated with worse outcomes.
Gleason score. GS is another factor that is con-
sistently found to predict negative outcomes
both before definitive treatment and HT. A
GS>7 is generally regarded as aggressive disease.
Prapotnich and colleagues in a nonrandomized
trial including 566 men on ADT, found that a
GS>7 was predictive of increased mortality
Table 1. Summary of risk stratification results from previous hormone therapy (HT) trials.
Paper HT therapyFindings
HT after curative therapy
Glass [Glass et al. 2003]Orchiectomy +/? flutamide
Orchiectomy +/? flutamide
Orchiectomy, LHRH agonists,
anti-androgens or CAB
ADT - No further definition given
GS<8 and PSA<65ng/ml significantly predicted 5 year
African American race, GS>8 and bone pain significantly
predicted lower 5 year survival
High PSA at HT initiation, GS>7, PSA nadir >0.9ng/ml
significantly predicted PCSM
PSA nadir >0.2ng/ml and GS>7 significantly predicted
PSA time to nadir <6 months, GS>7, PSA nadir >0.2
ng/ml predicted shorter overall survival
With metastates GS>7 predicted shorter time to pro-
gression. Without metastases PSA predicted shorter
time to progression. Previous ADT predicted shorter
time to progression for both.
Pathologic stage >T3 predicted PCa specific mortality
PSA nadir >0.05ng/ml and PSADT<12 months were
predictive of PCSM
PSA>4ng/ml before HT initiation was predictive of
PSA nadir >4ng/ml after 7 months of ADT, GS>7 and
bony pain was significantly predictive of decreased
Thompson [Thompson et al.
Chung [Chung et al. 2008]
Rodrigues [Rodrigues et al. 2006]
Choueiri [Choueiri et al. 2009]Orchiectomy, LHRH agonists and
Orchiectomy, LHRH agonist and
Ross [Ross et al. 2008]
Porter [Porter et al. 2007]
Scholz [Scholz et al. 2007]
Orchiectomy or LHRH agonist
LHRH agonist +/? anti-androgen
Flutamide with or without
Banez [Banez et al. 2009]
Hussain [Hussain et al. 2006]
HT as primary treatment
Janoff [Janoff et al. 2005]Orchiectomy or LHRH agonistsAge<70 and GS >¼6 were found to be at higher risk for
GS >¼7, PSA >¼20ng/ml and a low number of
co-morbidities significantly predicting PCSM
Graff [Graff et al. 2007] Orchiectomy, LHRH agonists and
et al. 2009]
Irani [Irani et al. 2008]
CAB after primary failureAge<60, PSA >100 and GS>7 were predictive of
mortality in patients undergoing intermittent CAB
Disease progression was associated with PSA and GS.
GS was predictive of PCSM
Immediate versus delayed HT
Studer [Studer et al. 2008] Orchiectomy or LHRH agonistPSADT¼<12 months and PSA>50ng/ml at treatment
initiation were predictive of increase mortality for
patients who underwent delayed ADT
PSA>15ng/ml, PSADT ? 7 months, log of PSADT and log
PSA were predictive of overall survival. Log of PSADT
was significantly predictive of disease specific survival.
HT delayed clinical metastases in patients with GS>7
and PSADT ¼<12 months
et al. 2007]
Orchiectomy, LHRH agonist,
anti-androgen, or DES
Moul [Moul et al. 2004]LHRH agonist, orchiectomy or
ADT, androgen deprivation therapy; CAB, complete androgen blockade; DES, diethylstilbestrol; GS, Gleason score; LHRH, luteinizing hormone-
releasing hormone; PCSM, prostate cancer-specific mortality; PSA, prostate specific antigen; PSADT, PSA doubling time.
MA Uhlman, JW Moul et al.
found that a GS>7 was correlated with shorter
time to progression in patients undergoing ADT
with metastatic disease, but not in those without
metastases [Ross et al. 2008]. Finally, in a large
trial, Glass and colleagues found that a GS>7
was a significant predictor of decreased survival in
patients undergoing HT [Glass et al. 2003].
As with previously described factors, there is no
GS that has been definitively shown to predict
worse outcomes. However, increasing GS, espe-
cially above 7, has consistently been associated
with decreased survival and treatment failure.
Race. Being of African American (AA) race is a
known predictor of PSAR, but limited studies
have examined race as it pertains to HT out-
comes. In a large trial of 1,263 men with meta-
static PCa who received orchiectomy with or
without flutamide, Thompson and colleagues
found that AA race was a significant predictor
of decreased overall survival [Thompson et al.
2001]. More studies are needed to determine
why this relationship exists.
Summary of risk factors
Based on a limited number of trials reporting
factors predictive of success or failure with HT
as well as a shortage of randomized trials, it is
difficult to make definitive recommendations as
to which patients are best suited for HT.
Nevertheless, emerging trends from available
trials suggest that distinct clinico-pathological
characteristics, including elevated PSA, rapid
PSADT, high PSA nadir following therapy and
GS>7, may give prognostic information as to
which patients are likely to gain the most benefit
from HT. This information and future findings
are likely to lead to risk stratification guidelines
for men undergoing HT for PCa.
HT continues to be a common treatment option
for recurrent PCa and locally advanced PCa.
Both long- and short-term treatment courses
are associated with many undesirable side effects
which can lead to decreased QOL. There are only
a few circumstances in which HT is clearly
(1) For patients with high risk disease that are
undergoing radiation therapy;
(2) To shrink the prostate before brachytherapy
(though there has been no survival advan-
tage demonstrated); and
(3) To palliate symptoms in patients with meta-
Thompson et al. 2007].
Treatment with anti-androgens has been shown
to be inferior to ADT for patients with metastatic
disease [Tyrrell et al. 1998]. For patients with
there is little data suggesting a survival advantage
from the use of HT, however much data exists to
support the palliate ability of the treatment.
Both LHRH agonists and anti-androgens are asso-
ciated with significant side effects. Treatments
with anti-androgens have much lower rates of
sexual side effects, hot flashes and osteoporosis.
Anti-androgens are also not known to cause bio-
chemical flare. Treatment with ADT results in
lower rates of gynecomastia and breast tenderness.
Emerging research has shown that HT may be
associated with increased rates of metabolic and
cardiac complications as well as cognitive declines.
CAB has been shown to produce a small, but
significant increase in overall survival, but cost
considerations and side effects should be taken
antagonists and TAB are not well studied.
Questions remain as to the best time to initiate
treatment, the optimal duration, the best treat-
ment schedule and most importantly, which
patients are the most likely to benefit from HT.
Patient stratification based on clinical and patho-
logical factors remains ambiguous and though
results from trials are limited, some trends have
started to materialize. Patients undergoing HT
and with characteristics including a PSADT
?12 months, GS>7, PSA nadir >0.2ng/ml and
elevated PSA at time of HT may be at increased
risk of disease progression and ultimately PCSM,
though additional studies are needed to confirm
these initial findings.
In the end, communication is paramount in
patients. Before initiation of HT, clinicians
should carefully consider the factors that have
been shown to correlate with poor HToutcomes,
and patients should be made aware of the poten-
tial adverse effects and risks associated with dif-
ferent HT treatment options. This combination
of efforts gives patients and providers the best
chance at achieving the optimal balance of risk
Therapeutic Advances in Medical Oncology 1 (2)
The author Matthew Uhlman wishes to acknowl-
edge the NIH Grant TL1 RR 024126.
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