NEW DIRECTIONS IN PROSTATE CANCER MANAGEMENT
Androgen Deprivation Therapy
in the Treatment of Advanced
Mark A. Perlmutter, MD, Herbert Lepor, MD
Department of Urology, New York University School of Medicine, New York, NY
This article reviews the issues and controversies relevant to the treatment
of advanced prostate cancer with androgen deprivation therapy. Initially,
diethylstilbestrol was used for achieving androgen deprivation, but was
replaced by luteinizing hormone-releasing hormone (LHRH). Adverse events
associated with LHRH agonists include the flare phenomenon, hot flashes,
loss of libido, erectile dysfunction, depression, muscle wasting, anemia, and
osteoporosis. Intermittent therapy has been advocated to reduce morbidity
of treatment. The addition of an antiandrogen provides maximum androgen
blockade. There remains controversy regarding the timing of the addition
of an antiandrogen. Secondary hormonal therapies include antiandrogens,
adrenal androgen inhibitors, and estrogens.
[Rev Urol. 2007;9(suppl 1):S3-S8]
© 2007 MedReviews, LLC
Key words: Advanced prostate cancer • Androgen deprivation therapy • Diethylstilbestrol •
LHRH agonists • Maximum androgen blockade
dramatic.1ADT is universally accepted as first-line treatment of symptomatic
metastatic prostate cancer.2There is also compelling evidence that neoadjuvant
ADT increases disease-specific and overall survival in men with high-grade,
clinically localized prostate cancer who undergo radiotherapy.3,4Although ADT
he role of androgen deprivation therapy (ADT) in the management of
prostate cancer is highly controversial. The beneficial clinical effects of
ADT in men with symptomatic metastatic prostate cancer are rapid and
VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY S3
ADT in Advanced Prostate Cancer continued
S4 VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY
is indicated by the US Food and Drug
Administration only for the palliation
of symptomatic metastases and as
neoadjuvant therapy for radiation
therapy, ADT is widely used in the
community setting to treat men with
clinically localized prostate cancer,
biochemical (prostate-specific antigen
[PSA]) recurrence after radical prosta-
tectomy, locally advanced disease,
lymph node metastases, and asympto-
matic metastatic disease. The benefits
of ADT for these unapproved indica-
tions have not been definitively as-
certained owing to the requirement
for performance of large-scale, multi-
center, randomized trials with long-
Today, the time to initiate ADT, the
benefits of maximum androgen
blockade (MAB), the management of
adverse events associated with ADT,
the role of intermittent ADT, and the
benefits of secondary hormonal ther-
apies remain unresolved. This article
will focus on these issues and on con-
troversies relevant to the treatment of
advanced prostate cancer with ADT.
Huggins and Hodges first reported the
dramatic clinical effects of suppress-
ing serum testosterone levels in men
with advanced prostate cancer in
1941.1ADT was achieved by surgical
castration or suppression of luteiniz-
(LHRH) production at the level of the
hypothalamus with diethylstilbestrol
(DES). Both surgical and pharmaco-
logic castration resulted in dramatic
palliation of painful bony metastases,
decreases in the postvoid residual
urine, and improved quality of life.
Within a short period, hormonal
therapy became widely accepted as
the treatment of advanced prostate
cancer. Huggins and Hodges were
awarded the Nobel Prize in 1967 for
this pioneering work.
The Veterans Administrative Coop-
erative Urological Research Group
(VACURG) was initiated in 1959 with
the goal of investigating the role of
ADT in the treatment of prostate can-
cer, using randomized clinical trials.5
The major conclusions of VACURG
were as follows: 5 mg of DES was as-
sociated with significant cardiovascu-
lar toxicity; orchiectomy plus DES
provided no benefit over DES alone;
1 mg and 5 mg of DES had equivalent
effects on prostate cancer survival;
1 mg of DES was associated with re-
duced cardiovascular toxicity; 1 mg
of DES did not reliably achieve cas-
trate levels of testosterone; and there
was no survival advantage of early
versus delayed initiation of hormonal
therapy in advanced disease. A post
hoc analysis of the VACURG survival
data suggested that there was a sur-
vival advantage for early initiation of
ADT in men with high-grade disease.6
The primary objectives of ADT for
advanced prostate cancer were to
avoid surgical castration, achieve cas-
trate levels of testosterone, and mini-
mize cardiovascular toxicity. A daily
dose of 3 mg DES was thought to best
achieve these objectives and ulti-
mately became the accepted regimen
for pharmacologic castration.
Schally and associates7purified the
hormone, also referred to as LHRH, in
1971. Chronic exposure to LHRH ulti-
mately suppressed testosterone by de-
sensitizing pituitary cells through
downregulation of the LHRH recep-
tors.8Substitutions at the sixth amino
acid position of LHRH resulted in
significantly more potent LHRH ago-
nists.9The monthly depot of leupro-
lide was the first LHRH agonist eval-
uated as a treatment for advanced
prostate cancer. In a randomized clin-
ical trial, leuprolide was equivalent to
3 mg of DES in reducing serum
testosterone to castrate levels.10The
advantage of leuprolide was a lower
incidence of cardiovascular toxicity.
Leuprolide ultimately replaced DES
and orchiectomy as the preferred ap-
proach to androgen deprivation.
Over the next 30 years, substitu-
tions at the sixth amino acid position
yielded goserelin, triptorelin, and
histrelin, which are the commercially
available LHRH agonists in the United
States (Table 1).11LHRH agonists are
The time to initiate ADT, the benefits of maximum androgen blockade, the
management of adverse events associated with ADT, the role of intermittent
ADT, and the benefits of secondary hormonal therapies remain unresolved.
Hormonal Therapies Available in the United States
* (Wyeth-Ayerst; Philadelphia, PA)
From Lepor H.11
ADT in Advanced Prostate Cancer
VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY S5
differentiated by their route of admin-
istration (intramuscular injection vs
subcutaneous injection vs subcuta-
neous implant) and frequency of ad-
ministration (1-12 months). All of
these LHRH agonists seem to have
similar side effect profiles and the
ability to lower serum testosterone to
castrate levels. There has only been 1
study directly comparing different
LHRH agonists.12Overall survival
was significantly greater with trip-
torelin compared with leuprolide, 97%
vs 90.5% survival at 9 months, re-
spectively (P ? .033). Although not
statistically significant, there was a
trend for triptorelin to better main-
tain castrate levels of testosterone
over a 9-month interval.
Adverse Events of LHRH Agonists
The adverse events associated with
LHRH agonists can be categorized as
immediate, acute, and chronic. The
optimal use of ADT requires an effort
to prevent or treat these adverse
One of the limitations of LHRH
agonists is the initial “flare” phe-
nomenon, which is attributed to a
surge of serum testosterone levels
due to the initial stimulation of LHRH
receptors.13The flare phenomenon
may be life threatening if an LHRH
agonist is administered to men with
high-volume metastatic disease. The
clinical consequence of the flare is pre-
vented by pretreatment with an anti-
androgen, which inhibits the stimula-
tory effect of the testosterone surge at
the level of the androgen receptor.14
The acute adverse events associated
with LHRH agonists become evident a
few weeks after initiation of therapy
and coincide with the achievement of
castrate levels of testosterone. These
acute adverse events include hot
flashes, loss of libido, and erectile
dysfunction.15Hot flashes can be ef-
fectively treated with hormonal
agents, including low-dose estrogens,
megestrol acetate, medroxyproges-
terone acetate, and cyproterone
acetate.15Approximately 60% of men
will experience significant hot
flashes.11The overwhelming majority
of men taking LHRH agonists will de-
velop erectile dysfunction. Erectile
dysfunction can be treated with phos-
phodiesterase inhibitors, vacuum
devices, or intracavernous therapy.
Although these pharmacologic and
mechanical approaches may restore
the ability to achieve an erection, the
lack of libido often limits patients’
enthusiasm for pursuing treatment to
The chronic adverse events associ-
ated with LHRH agonists include
musculoskeletal, hematologic, and
cardiovascular events. There is in-
creasing awareness that men are
prone to developing osteoporosis and
related fractures with advancing
age.16Several investigators have re-
ported significantly increased risk of
fractures in men undergoing andro-
gen deprivation therapy compared
with controls.17,18All men taking
LHRH agonists should be advised to
modify their lifestyle to prevent or
minimize osteoporosis. Lifestyle mod-
ifications include cessation of smok-
ing, decreasing alcohol consumption,
performance of resistance exercises,
and taking calcium supplementation.
Bone mineral density should be mon-
itored at least annually.18If bone
mineral density significantly de-
creases, treatment options include
selective estrogen-receptor modula-
tors have also been shown to protect
against the osteoporotic side effects
of ADT.20,21Advanced prostate cancer
directly predisposes men to the devel-
opment of fractures due to skeletal
metastases. It is therefore important
to prevent or minimize the osteo-
porotic effects of LHRH agonists to
decrease the risk of fractures.
Men with advanced prostate cancer
are also predisposed to developing
anemia due to hematuria from locally
advanced prostate cancer and to bone
marrow infiltration by metastatic dis-
ease. Testosterone increases produc-
tion of erythrogenesis-stimulating
proteins.22Therefore, LHRH agonists
may cause or exacerbate anemia by
indirectly inhibiting erythrogenesis.
Progressive muscle loss has been
associated with declining testosterone
levels in men.15Men receiving LHRH
agonists for prostate cancer demon-
strate significant increases in muscle
fatigue.23Resistance exercises may
limit the consequences of LHRH ago-
nists on muscle function.
Hormonal therapy has also been
shown to cause neurologic impair-
ment, manifested by decreased cogni-
tive function.15There is some evi-
dence that hormonal ADT may also
Keating and colleagues24recently
reported increased cardiovascular
morbidity and mortality associated
with LHRH agonists. The increased
cardiovascular toxicity was hypothe-
sized to be mediated through changes
in lipoproteins, arterial stiffness, and
QT interval prolongation.
In summary, men with advanced
prostate cancer are predisposed to de-
veloping osteoporosis, anemia, mus-
cle wasting, and depression as a direct
consequence of their metastatic dis-
ease. LHRH agonists may directly ex-
acerbate these problems, resulting in
significant morbidity and mortality.
Acute adverse events associated with LHRH agonists become evident a few
weeks after initiation of therapy and coincide with the achievement of
castrate levels of testosterone.
ADT in Advanced Prostate Cancer continued
S6 VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY
Every effort should be made to recog-
nize and correct these conditions to
optimize the treatment of men with
advanced prostate cancer.
Owing to the adverse events associ-
ated with ADT, intermittent therapy
has been advocated as a measure to
reduce morbidity of treatment.25It is
reasonable to assume that both the
acute and chronic complications of
LHRH agonists would be minimized
by intermittent therapy. Several large
studies have demonstrated the return
of potency and resolution of anemia
with an intermittent ADT regimen.26,27
The unresolved issue is whether
prostate cancer survival is negatively
impacted by intermittent therapy.
Currently there are 3 phase III trials
directly comparing continuous and
intermittent hormonal therapy regi-
mens. One of these phase III trials
(Southwest Oncology Group 9346) is
comparing intermittent ADT with con-
tinuous ADT in men with newly diag-
nosed metastatic prostate cancer.25
Maximum Androgen Blockade
Androgens are produced by the
testes and the adrenal glands. Ninety
to 95 percent of the androgens are
produced by the testes and only 5%
to 10% by the adrenals.28LHRH ago-
nists reduce testosterone to castrate
levels by suppressing only androgens
produced by the testes. The impact of
the adrenal androgens on prostate
cancer in men with LHRH agonists is
highly controversial. Huggins and
Scott29demonstrated a clinical ben-
efit of surgical adrenalectomy in
men with disease recurrence after
MAB can be achieved pharmaco-
logically by combining an LHRH ag-
onist with an antiandrogen. The an-
tiandrogens flutamide, bicalutamide,
and nilutamide block the effects of
adrenal androgens at the androgen
receptor. There is a general consen-
sus that MAB has a role in the treat-
ment of advanced prostate cancer.30
The controversy is whether MAB
should be the initial form of ADT or
whether the antiandrogen should be
offered after the patient has had dis-
ease progression with LHRH agonist
Three randomized studies have
demonstrated the advantage of initi-
ating MAB at the time of diagnosis
for metastatic prostate cancer.31-33The
mean increase in overall survival at-
tributable to MAB demonstrated in
these studies was approximately 7
months. This modest increase in sur-
vival far exceeds that attributable to
cytotoxic agents, such as the combi-
nation of docetaxel and estramustine,
initiated for androgen-independent
prostate cancer.34It is also important
to recognize that several studies have
failed to show an advantage of MAB
initiated at the time of diagnosis for
metastatic prostate disease.35
Secondary Hormonal Therapy
It is inevitable that the overwhelming
majority of men treated with pharma-
cologic or surgical castration will
develop disease progression due to
development and propagation of
androgen-independent prostate can-
cer cells. The first step is to measure
the serum testosterone level in those
men taking LHRH agonists, to en-
sure that castrate levels of testos-
terone are being achieved.
Second-line nonsteroidal antian-
drogens are typically administered at
the time of biochemical disease
progression.36For men who were
initially treated with MAB, the an-
tiandrogen should be withdrawn.37
Approximately 15% to 30% of men
will exhibit a greater than 50% de-
cline in serum PSA level simply by
withdrawal of the antiandrogen.37-39
Unfortunately, the serum PSA decline
is short lived—generally between 3
and 5 months.37-39When the PSA
level begins to rise after antiandrogen
withdrawal, it is reasonable to initiate
treatment with a second-line antian-
drogen.40This intervention is often
associated with clinical, biochemical,
and radiographic responses.
Inhibitors of adrenal androgen pro-
duction include ketoconazole, corti-
costeroids, and aminoglutethimide.41
Ketoconazole is the preferred agent
for secondary hormonal therapy
because of its better tolerability.41
Approximately 50% of men exhibit-
ing disease progression while taking
LHRH and antiandrogen therapy will
exhibit up to a 50% reduction in
PSA level, with a median response
of 30 weeks after initiation of treat-
ment with an inhibitor of adrenal an-
Estrogen therapy was the initial
mainstay of hormonal therapy and
then lost favor after reports of signif-
icant cardiovascular toxicity. Recently,
there has been renewed interest in this
approach to achieving androgen
deprivation. In 2005, Ockrim and
colleagues42reported no cardiovascu-
lar events in 20 men treated with
transdermal estradiol for locally ad-
vanced or metastatic prostate cancer
over a 2-year period. Furthermore,
this study showed an improvement in
coagulation factor levels from base-
line, suggesting protection against
Ultimately, men will develop dis-
ease that is refractory to all hor-
monal manipulations. This is termed
androgen-independent prostate can-
cer. There is no consensus as to
whether LHRH agonists should be
Approximately 15% to 30% of MAB-treated men will exhibit a greater than
50% decline in serum PSA level simply by withdrawal of the antiandrogen.
ADT in Advanced Prostate Cancer
VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY S7
withdrawn at this time. The ratio-
nale for withdrawing the LHRH ago-
nist would be to improve quality of
life and possibly diminish any os-
teoporosis, muscle wasting, anemia,
and depression that might be associ-
ated with the LHRH agonist.
1. Huggins C, Hodges CV. Studies on prostatic
cancer II: the effects of castration on advanced
carcinoma of the prostate gland. Arch Surg.
2. Trachtenberg J. Hormonal management of stage
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3. Roach M 3rd, DeSilvio M, Lawton C, et al. Phase III
trial comparing whole-pelvic versus prostate-only
radiotherapy and neoadjuvant versus adjuvant
combined androgen suppression: Radiation
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Snyder PJ, Peachey H, Berlin JA, et al. Effects of
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Bhandari MS, Crook J, Hussain M. Should inter-
• Androgen deprivation therapy (ADT) is widely used in the community setting to treat men with clinically localized prostate cancer,
biochemical recurrence after radical prostatectomy, locally advanced disease, lymph node metastases, and asymptomatic metasta-
tic disease. The benefits of ADT for these unapproved indications have not been definitively ascertained.
• The dramatic clinical effects of suppressing serum testosterone levels in men with advanced prostate cancer were first reported
in 1941. A daily dose of 3 mg diethylstilbestrol (DES) eventually became the accepted regimen for pharmacologic castration.
• The monthly depot of leuprolide was the first luteinizing hormone-releasing hormone (LHRH) agonist evaluated as a treatment for
advanced prostate cancer. Leuprolide ultimately replaced DES and orchiectomy as the preferred approach to androgen deprivation.
• Leuprolide, goserelin, triptorelin, and histrelin are the commercially available LHRH agonists in the United States and are differ-
entiated by the route and frequency of administration. All of these LHRH agonists seem to have similar side effect profiles and
the ability to lower serum testosterone to castrate levels.
• Adverse events associated with LHRH agonists can be categorized as immediate (initial “flare” phenomenon), acute (hot flashes,
loss of libido, and erectile dysfunction), and chronic (musculoskeletal, hematologic, and cardiovascular events). Owing to the
adverse events associated with ADT, intermittent therapy has been advocated as a measure to reduce morbidity of treatment.
• There is a general consensus that maximum androgen blockade (MAB) has a role in the treatment of advanced prostate cancer.
The controversy is whether MAB should be the initial form of ADT or whether the antiandrogen should be offered after the patient
has had disease progression with LHRH agonist monotherapy.
• Ultimately, men will develop disease that is refractory to all hormonal manipulations (androgen-independent prostate cancer).
There is no consensus as to whether LHRH agonists should be withdrawn at this time.
ADT in Advanced Prostate Cancer continued
S8 VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY
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Prostate Cancer Trialists’ Collaborative Group.
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