Download CHAPTER 14 - Hormonal therapy of prostate cancer

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Progress in Brain Research, Vol. 182
ISSN: 0079-6123
Copyright 2010 Elsevier B.V. All rights reserved.
CHAPTER 14
Hormonal therapy of prostate cancer
Fernand Labrie
Research Center in Molecular Endocrinology, Oncology and Human Genomics, Laval University and Laval University
Hospital Research Center (CRCHUL), Qu�ebec, Canada
Abstract: Of all cancers, prostate cancer is the most sensitive to hormones: it is thus very important to
take advantage of this unique property and to always use optimal androgen blockade when hormone
therapy is the appropriate treatment. A fundamental observation is that the serum testosterone
concentration only reflects the amount of testosterone of testicular origin which is released in the blood
from which it reaches all tissues. Recent data show, however, that an approximately equal amount of
testosterone is made from dehydroepiandrosterone (DHEA) directly in the peripheral tissues, including
the prostate, and does not appear in the blood. Consequently, after castration, the 95–97% fall in serum
testosterone does not reflect the 40–50% testosterone (testo) and dihydrotestosterone (DHT) made
locally in the prostate from DHEA of adrenal origin. In fact, while elimination of testicular androgens
by castration alone has never been shown to prolong life in metastatic prostate cancer, combination of
castration (surgical or medical with a gonadotropin-releasing hormone (GnRH) agonist) with a pure antiandrogen has been the first treatment shown to prolong life. Most importantly, when applied at the
localized stage, the same combined androgen blockade (CAB) can provide long-term control or cure of
the disease in more than 90% of cases. Obviously, since prostate cancer usually grows and metastasizes
without signs or symptoms, screening with prostate-specific antigen (PSA) is absolutely needed to
diagnose prostate cancer at an ‘early’ stage before metastasis occurs and the cancer becomes noncurable. While the role of androgens was believed to have become non-significant in cancer progressing
under any form of androgen blockade, recent data have shown increased expression of the androgen
receptor (AR) in treatment-resistant disease with a benefit of further androgen blockade. Since the
available anti-androgens have low affinity for AR and cannot block androgen action completely,
especially in the presence of increased AR levels, it becomes important to discover more potent and
purely antagonistic blockers of AR. The data obtained with compounds under development are
promising. While waiting for this (these) new anti-androgen(s), combined treatment with castration and
a pure anti-androgen (bicalutamide, flutamide or nilutamide) is the only available and the best
scientifically based means of treating prostate cancer by hormone therapy at any stage of the disease
with the optimal chance of success and even cure in localized disease.
Keywords: intracrinology; anti-androgens; androgen blockade; early diagnosis; cure; long-term control
Corresponding author.
Tel.: (418) 652-0917; Fax: (418) 651-1856;
E-mail: [email protected]
DOI: 10.1016/S0079-6123(10)82014-X
321
322
Introduction
One in eight men will be diagnosed with prostate
cancer during their lifetime with 192 280 new cases
being predicted in the United States in 2009
(Jemal et al., 2009). Despite the 33% decrease in
deaths from prostate cancer in the United States
during the 15 years between 1992 and 2007 as
estimated by the American Cancer Society
(Jemal et al., 2007), prostate cancer remains the
second cause of cancer deaths with 27 360 deaths
predicted for 2009 in the United States alone
(Jemal et al., 2009). Prostate cancer is thus a
major medico-social problem comparable to that
of breast cancer in women.
The main objective of physicians managing
patients with cancer is to permanently free
them from the disease. It is thus a major progress
to see that androgen blockade is now increas­
ingly recognized as curative, conditional to its
use in localized (when it is curable) instead of
advanced and metastatic (when it has become
non-curable) disease. These news are particu­
larly timely since more than 95% of patients
can now be diagnosed by simple PSA screening
and can thus be treated at the localized and only
potentially curable stage (Labrie et al., 1996b),
thus providing an explanation for the important
decrease in prostate cancer deaths observed
since 1992 (Jemal et al., 2007).
The extremely long delay in recognizing the
curative potency of androgen blockade can be
explained by two misinterpretations concerning
androgen blockade which, unfortunately, are still
at the basis of the official guidelines of some uro­
logical associations distributed to guide the clinical
practice of their members. These two common
misinterpretations are as follows:
1. Application to localized prostate cancer of
observations made in advanced disease which
are characteristics specific to metastatic disease
and which do not apply to localized disease. As
well indicated by Professors Akaza and Namiki
(Akaza, 2008; Namiki et al., 2008), the
erroneous belief of a temporary efficacy of
androgen blockade due to the relatively rapid
development of resistance to treatment is a
characteristic typical and limited to advanced
and metastatic disease. There have never been
valid reasons to apply to localized prostate
cancer these observations of resistance to
treatment which exclusively belong to
advanced disease. In fact, contrary to the
situation in metastatic prostate cancer, a
continuous and very long-term positive
response with the high probability of a cure is
observed in localized disease (Akaza, 2008;
Labrie et al., 2002; Namiki et al., 2008) when
optimal or CAB is used. This possibility of cure
is however conditional to the start of CAB
sufficiently early at time of diagnosis (Labrie
et al., 2002).
The conclusion that androgen blockade can
be curative and does not simply delay
progression has been reached in many studies
including a meta-analysis of the controlled
clinical trials performed as adjuvant hormonal
treatment in non-metastatic prostate cancer
(Fleshner et al., 2007). The author of this meta­
analysis has concluded that androgen blockade
given as adjuvant to surgery or radiotherapy
should be classified as a treatment of curative
intent for patients with poor prognosis
non-metastatic prostate cancer. It should be
mentioned that such positive results could even
be observed using a non-optimal androgen
blockade, namely monotherapy, while much
better results are achieved with CAB without
additional negative effects (Akaza, 2008; Akaza
et al., 2007; Labrie, 2004; Labrie et al., 2002;
Namiki et al., 2008).
2. A second extremely common error, not to say
generalized, is the use of monotherapy as
first treatment, a treatment much inferior to
CAB even though a significant rate of cure
(33%) can be obtained with monotherapy in
localized prostate cancer (Peto and Dalesio,
2003). However, a major limitation of
monotherapy (castration alone or an antiandrogen alone) is that 40% of active
androgens are left in the prostate under
monotherapy (Labrie, 2007; Labrie et al.,
2009a; Labrie et al., 1985). These androgens
made locally in the prostate continue
to stimulate prostate cancer after any
323
treatment limited to castration or an antiandrogen alone, thus permitting continued
stimulation of cancer proliferation and
metastasis at distance where resistance to
treatment always develops and cure becomes
impossible (Huggins and Hodges, 1941).
prostate cancer is almost always possible with current androgen blockade …’.
At the metastatic stage, on the other hand, while
monotherapy first used by Huggins and Hodges
(1941) has not been shown to prolong survival, a
20% prolongation of prostate cancer-specific survival
can be obtained with CAB applied at start of treatment (Bennett et al., 1999; Caubet et al., 1997; Craw­
ford et al., 1989; Denis et al., 1998; Janknegt et al.,
1993; Labrie et al., 1996a; Labrie et al., 1982; Labrie
et al., 1985; Prostate Cancer Triallists’ Collaborative
Group, 2000). It is important to indicate that since the
anti-androgen was generally added at time of
progression following castration alone, the above­
mentioned studies compare early versus late CAB
and not placebo versus CAB as generally believed.
In localized disease, the simple addition to castration of a pure anti-androgen in order to block the
action of the androgens made locally in the prostate
increases the potential of cure from 33% observed
with monotherapy (Fleshner et al., 2007; Peto and
Dalesio, 2003; Prostate Cancer Triallists’ Collaborative Group, 2002) to more than 90% (Labrie,
2007; Labrie et al., 2002) (Fig. 1B). It is very important to read Professor Akaza (2008) saying: ‘cure of
A. Metastatic prostate cancer
1. Monotherapy
Non-statistically significant effect
0
20
40
60
80
100%
2. Combined androgen blockade
*
First and only statistically
significant treatment
0
20
40
60
80
100%
B. Localized prostate cancer
1. Monotherapy
*
Statistically significant
0
20
40
60
80
100%
80
100%
2. Combined androgen blockade
Cure in > 90%
0
20
40
60
Fig. 1. Comparison of the efficacy on prostate cancer-specific survival of monotherapy (castration alone or anti-androgen alone at
high dose) (1) and combined androgen blockade (CAB) (castration þ pure anti-androgen) (2) administered in metastatic (A) and
localized (B) prostate cancer.
A1: No positive study available
A2: Bennett et al. (1999), Caubet et al. (1997), Crawford et al. (1989), Denis et al. (1998), Janknegt et al. (1993), Labrie et al.
(1985) and Prostate Cancer Triallists’ Collaborative Group (2000)
B1: Peto and Dalesio (2003) and Prostate Cancer Triallists’ Collaborative Group (2002)
B2: Labrie et al. (2002)
The asterisk () indicates that since the anti-androgen was added at time of progression following castration, these studies
compare early versus late CAB and not placebo versus CAB.
324
In other words, a greater difference in survival, even
at the advanced metastatic stage, should have been
obtained if a true comparison between placebo and
CAB had been studied. It is, in fact, well recognized
that a significant number of positive responses are
observed when a pure anti-androgen is added at time
of progression in patients who had castration as first
treatment (Labrie et al., 1988). These responses
observed at time of addition of the anti-androgen
decrease the difference between the castration
alone and CAB groups.
Discovery of the local formation of androgens
from DHEA of adrenal origin by the action of the
enzymes of intracrinology (Labrie, 1991; Labrie
et al., 1989b) has indicated the need to develop
CAB (Labrie et al., 1982; Labrie et al., 1985), a
treatment which adds to castration (medical or
surgical) a pure anti-androgen in order to block
the action of the androgens made locally in the
prostate from DHEA. In fact, all the enzymes
required to make androgens from DHEA are
expressed in the prostate (Luu-The et al., 2008;
Pelletier, 2008).
It is important to mention that recent data indi­
cate that androgen blockade is important, not only
as first line therapy in both localized and meta­
static diseases, but could also play a role in pros­
tate cancer which has become resistant to first line
androgen blockade (Chen et al., 2004; Scher and
Sawyers, 2005; Taplin and Balk, 2004).
Two sources of androgens of approximately equal
importance are present in men: castration
removes only 60% of androgens in the prostate
while bicalutamide (Casodex) alone, at the 150 mg
daily dose, has an effect similar to castration
Intracrinology
An important advance in our understanding of the
biology and endocrinology of prostate cancer is the
observation that humans are unique among animal
species in having adrenals that secrete large
amounts of the inactive precursor steroids DHEA,
and its sulfate DHEA-S, which are converted into
active androgens in a large series of peripheral
tissues, including the prostate (Fig. 2).
Intact – normal
GnRH
Testosterone
Pituitary
gland
LH
ACTH
Testosterone
Testis
DHEA
DHT
Prostate
Adrenal
Fig. 2. Schematic illustration of the two sources which provide
approximately equal amounts of androgens to the normal
prostate and prostate cancer. (1) The testicles secrete
testosterone released in the blood stream while (2) the
adrenals secrete dehydroepiandrosterone (DHEA) in the
circulation, the precursor being converted into testosterone
and then into dihydrotestosterone (DHT) in the prostate.
The local synthesis of active steroids in per­
ipheral target tissues has been named intracri­
nology (Labrie, 1991; Labrie et al., 2004; Labrie
et al., 2003; Labrie et al., 1989a). The active
androgens made locally exert their action by
binding to the prostatic AR without being
released in significant amounts in the extracel­
lular environment or general circulation. Most
importantly, the active androgens made in per­
ipheral tissues are inactivated locally as glucur­
onides before their elimination through the
circulation (Fig. 3). Contrary to the previous
belief that the testes are responsible for 95%
of total androgen production in men (as could
be inferred from the 95–97% decrease in serum
testosterone observed after castration) (Fig. 4),
it is now well established that the prostate
makes the androgens testo and DHT locally in
relatively large amounts.
Very limited effect of castration on total androgen
availability in the prostate
While the serum levels of testo are reduced by
97.4% following castration in 69–80-year-old
325
GnRH
CRH
LH
ACTH
Adrenal
gland
Testo
Circulation
DHEA
DHEA
Testo
4-Dione
E1
ADT–G
3α–diol–G
Testis
Circulation
E2
DHT
E2
ADT–G
E1S
Testo E
2
Circulation
A-Dione
3α–Diol–G
Peripheral target tissues
Circulation
DHEA
Fig. 3. Schematic representation of the testicular and adrenal
sources of sex steroids in men. The adrenal glands – as well as
secreting cortisol that decreases CRH secretion, which otherwise
stimulates ACTH levels – secrete large amounts of DHEA; this
precursor is converted in specific target tissues into androgens
and/or estrogens via the process of intracrinology. Only small
amounts of these peripherally made sex steroids diffuse into the
circulation. The androgens are metabolized into the metabolites
ADT and 3a-diol which are then further transformed into the
more water-soluble glucuronide derivatives and released into the
blood where they can be measured as parameter of total
androgenic activity. Approximately 60% of androgens are made
in the testicles as testosterone which is distributed in the
peripheral
tissues
by
the
circulation.
ACTH,
adrenocorticotropin; CRH, corticotrophin-releasing hormone;
DHEA, dehydroepiandrosterone; 4-dione, androstenedione;
A-dione, 5a-androstanedione; DHT, dihydrotestosterone; E1,
estrone; E1S, estrone sulfate; E2, estradiol; GnRH,
gonadotropin-releasing hormone; LH, luteinizing hormone;
testo, testosterone; ADT-G, androsterone glucuronide;
3a-diol-G, androstane-3a-diol-3 or 17-glucuronide.
men (Fig. 4A), the sum of the metabolites of
androgens (ADT-G, 3a-diol-3G and 3a-diol­
17G), the only accurate and valid parameter of
total androgenic activity measurable in the circu­
lation (Labrie et al., 2006), is only reduced by
58.9% (Fig. 4B), thus indicating that a very impor­
tant amount (41.1%) of androgens is still present
in the prostate after complete elimination of testi­
cular androgens. Such data are in close agreement
with the concentration of intraprostatic DHT that
shows that, on average, 39% of DHT is left in the
prostate after castration in various studies, namely
45% (Labrie et al., 1985), 51% (Bélanger et al.,
1989), 25% (Nishiyama et al., 2004) and 35%
(Mostaghel et al., 2007). In another study, it was
observed that intraprostatic DHT levels remained
at 50% of pre-treatment values after castration
(Yoon et al., 2008).
The observations based upon the best and vali­
dated parameters of androgenic activity, where all
steroids are measured by the mass spectrometry
technology show that ~40% of androgens are
made in the prostate in 69–80-year-old men.
Since serum DHEA decreases markedly with age
starting in the thirties (Labrie et al., 2005), and
testicular androgen secretion decreases only
slightly, it is most likely that intraprostatic androgens of adrenal origin have an even greater relative and absolute importance at younger ages. The
logical conclusion from these data is that castra­
tion is an insufficient treatment for prostate cancer
since, on average, it eliminates only 60% of andro­
gens in the prostate.
Very limited blockade of total androgens
achieved with an anti-androgen alone
Since an anti-androgen used alone can, like castra­
tion, show easily detectable effects on serum PSA
and also clinically, due to the particularly high
sensitivity of prostate cancer to androgen depriva­
tion, it is important to remember that, at best,
administration of an anti-androgen alone can
only partially block androgens, thus leaving an
important amount of DHT free to stimulate AR
and prostate cancer growth and metastasis.
In fact, the data obtained from phase III stu­
dies have shown that daily 150 mg bicalutamide
monotherapy provides a survival outcome simi­
lar, and sometimes inferior, to that observed
326
A.
B.
C.
5
40
100
30
75
3
ng/ml
−97.4%
ng/ml
4
−58,9%
−61%
20
50
10
25
2
1
0
0
0
Intact
Castrated
Testosterone
Intact
Castrated
ADT–G + 3α–diol–3G+17G
Intact
Castrated
DHT in prostate
Fig. 4. Effect of castration on the concentration of serum testo (A), total androgen pool (sum of serum ADT-G, 3a-diol-3G and
3a-diol-17G) (B) and intraprostatic DHT, the predominant androgen in the prostate (C). Data in C are the average of values
published in Bélanger et al. (1989), Labrie et al. (1985), Mostaghel et al. (2007) and Nishiyama et al. (2004). Data are presented as
means + SEM (Labrie et al., 2009b).
with castration alone in patients with locally
advanced (no metastases) disease (Iversen
et al., 2001; Iversen et al., 2000; Tyrrell et al.,
1998; Wirth et al., 2004). The 50 mg dose of
bicalutamide, on the other hand, has been
shown to be clearly inferior to castration (Bales
and Chodak, 1996). Very unfortunately, the
50 mg daily dose of bicalutamide used alone is
the approved dose in the United States, Canada
and most other countries. In Japan, the
approved dose is 80 mg.
Because, as mentioned above, 40–50% of andro­
gens are left in the prostate following castration
(Fig. 4C), two conclusions are obvious. First,
when used in association with medical or surgical
castration, bicalutamide should be used at the
150 mg daily dose to efficiently block the action of
the 40–50% of androgens left in the prostate after
castration. On the other hand, monotherapy with a
daily dose of 150 mg bicalutamide leaves, like cas­
tration, about 40–50% of androgens free to con­
tinue to stimulate the AR, thus indicating the need
to simultaneously block the secretion of testicular
androgens by a GnRH agonist or orchiectomy.
Accordingly, although the use of a non-steroidal
anti-androgen alone provides some advantages in
terms of secondary effects, especially loss of libido
and sexual dysfunction compared to castration, an
anti-androgen alone is only a partial therapy of
prostate cancer with the high risk of negative con­
sequences on survival.
It is relevant to mention that no PSA progres­
sion has been observed for up to 7 years in
patients with localized or locally advanced pros­
tate cancer who received CAB with a GnRH ago­
nist and 250 mg flutamide 3 times daily (Labrie,
Cusan, Gomez, Belanger and Candas, 1999). Such
results are quite different from the data obtained
following monotherapy with bicalutamide at the
dose of 150 mg daily (Wirth et al., 2004) where
clinical progression already occurred in 8.5% of
patients at 5.3 years of follow-up, whereas 14.0%
had progressed in the placebo group (p < 0.0001).
Although statistically significant, due to the large
number of patients (8113 patients), a 5.5% differ­
ence in disease progression between monotherapy
with bicalutamide and placebo is a small effect
compared with the data obtained with CAB in
327
patients at a comparable stage of the disease
where no (0%) PSA progression occurred before
7 years of treatment (Labrie et al., 2002; Labrie
et al., 1999).
Although not randomized, this last study per­
formed in a small number of patients is highly
suggestive of the marked superiority of CAB in
localized and locally advanced disease compared
with monotherapy. In fact, an even greater dif­
ference was seen in the group of patients chosen
for watchful waiting where 29.4% of patients
with localized disease progressed with bicaluta­
mide whereas 44.2% of those with locally
advanced disease progressed with bicalutamide
(Wirth et al., 2004), thus clearly demonstrating
the high risk of watchful waiting and the super­
iority of CAB where, as mentioned above, no
progression occurred in a group of 26 men until
7 years of follow-up (Labrie et al., 2002; Labrie
et al., 1999).
Clinical effects of monotherapy versus combined
androgen blockade as first line therapy in
localized disease
Monotherapy (GnRH agonist alone, orchiectomy
alone or anti-androgen alone) has a significant
but far from optimal effect on localized prostate
cancer
The availability of a safe and highly efficient
method of medical castration has generated
renewed interest in the treatment of prostate can­
cer and has stimulated an unprecedented number
of clinical trials, which rapidly led to the world­
wide commercialization of a series of GnRH
agonists having equivalent characteristics,
mechanisms of action and efficacy. This marked
the end of the requirement for surgical castration,
a procedure that is psychologically difficult to
accept by the majority of men. Most importantly,
this was the end of the need to administer high
doses of estrogens to achieve medical castration at
the expense of serious cardiovascular effects
(Peeling, 1989; Robinson and Thomas, 1971;
VACURG, 1967).
The importance of medical castration achieved
with GnRH agonists was well recognized by
Jacobi and Wenderoth (1982) who stated: ‘What
medical developments have urologists witnessed
since orchiectomy and estrogen treatment by Huggins 40 years ago? Gestagens, antiandrogens,
adrenal inhibitors, antiprolactins, antiestrogens,
cytotoxic agents? In principle, the gain in terms
of efficacy and the loss as a result of toxicity have
never been balanced to a degree which could
establish one of the aforementioned drugs as the
generally accepted standard treatment to replace
estrogens. GnRH analogues may prove to be the
first nontoxic medical castration measure applic­
able for general use in the future’.
Major progress achieved by the introduction of
medical castration with GnRH agonists
Clinical effects observed with monotherapy
Medical castration with a GnRH agonist
achieved in 1980 in the first prostate cancer
patient who received this treatment (Labrie
et al., 1980) has been a landmark in the field of
prostate cancer. Soon after our observation that
administration of the GnRH agonist buserelin
led to an almost complete inhibition of serum
testosterone and DHT levels within 2 weeks of
administration by the intranasal route, a less
than optimal route of administration, a detailed
comparison of the effect of various doses of the
same GnRH agonist was performed comparing
the intranasal and subcutaneous routes (Faure
et al., 1982).
Since prostate cancer is the most sensitive of all
cancers to hormone therapy, a positive effect on
serum PSA and on the clinical evolution of the
cancer can be easily observed with such a sub­
optimal blockade of androgens. Physicians and
their patients should not, however, be satisfied by
a sub-optimal positive result obtained with monotherapy, since such an effect is only a fraction of
what can be achieved by more complete androgen
blockade. In fact, although significant positive
results are observed with monotherapy, much bet­
ter results and even cure of the cancer can be
achieved by CAB applied to localized disease.
328
Following the meta-analysis of androgen block­
ade with monotherapy in localized prostate cancer
(Fig. 1B1), Peto stated that ‘prostate cancer is
usually treated with surgery or radiation, but a
few cancer cells may remain and cause an oftenfatal recurrence. Since the mid-80s, oncologists
have increasingly followed up with either surgical
removal of the testes, or with newer anti-hormone
drugs’ (Peto and Dalesio, 2003). The meta-analy­
sis which looked at several studies involving 5000
men showed that 74% of patients who received
early hormone monotherapy were still alive 10
years later, compared with 62% of those who
did not (Arnst, 2003; Peto and Dalesio, 2003)
(Fig. 1B1).
The conclusion of this meta-analysis on the
effect of monotherapy in localized and locally
advanced prostate cancer was that the risk of
dying from prostate cancer within 10 years
decreased by one-third if hormonal treatment
was given immediately rather than after the dis­
ease had progressed (Peto and Dalesio, 2003).
Since patients originally on placebo were treated
by monotherapy at time of progression, this onethird decrease in the risk of dying from prostate
cancer was not the result of the comparison
between castration and placebo (or no androgen
blockade), but between early and late androgen
blockade. It is also very important to consider that
these results were obtained with only partial
blockade of androgen or monotherapy. These
data led Peto to the conclusion that ‘Hormone
treatment as a whole works much better than
previously thought’.
In fact, all clinical trials of androgen blockade
have shown prolongation of life or a reduced
death rate from prostate cancer in patients with
localized or locally advanced disease (Table 1).
During 3.7–9.3 years of follow-up, the first six
studies have shown reductions in deaths from
prostate cancer ranging from 37.5 to 81% (Bolla
et al., 1997; Granfors et al., 1998; Hanks et al.,
2000; Labrie et al., 1999; Messing et al., 1999;
Pilepich et al., 1997). A seventh study provided
no data on cancer-specific deaths, but a 45%
decrease in overall deaths was reported (D’Amico
et al., 2004).
Simple addition of a pure anti-androgen to
castration (Fig. 1B2) can achieve cure in more
than 90% of localized prostate cancers instead of
the 33% decrease in deaths obtained by
monotherapy (Fig. 1B1).
Clinical data
With today’s knowledge, monotherapy (castration
alone or anti-androgen alone) can achieve only
50–60% of androgen blockade (Fig. 4). As
Table 1. Effect of the use of androgen blockade on prostate cancer death rates
Study
Advantage
Median follow-up
(years)
p
EORTC
415 patients
RTOG 85-31
276 patients
Laval University Screening Trial
21 400 subjects
Messing et al. (1999)
98 patients
Granfors et al. (1998)
91 patients
RTOG 92-02
1554 patients
D’Amico et al. (2004)
201 patients
77% decrease in cancer-specific death
3.7
0.01
37.5% decrease in cancer-specific death for
Gleason score 8–10
67% decrease in cancer-specific death
4.5
0.03
8
0.0002
81% decrease in cancer-specific death
7.1
0.001
39% decrease in cancer-specific death
9.3
0.06
59% decrease in cancer-specific death for Gleason
score 8–10
45% decrease in overall death
5
0.007
4.5
0.04
329
Table 2. Androgen blockade in prostate cancer
Combined androgen
blockade
GnRH agonist alone
GnRH antagonist alone
Orchiectomy
DES
Proscar alone
Proscar þ castration
Cyproterone acetate alone
Cyproterone acetate
with castration
Flutamide alone
Ninutamide alone
Bicalutamide alone
Megace
Medroxyprogesterone
acetate
GnRH agonist,
GnRH antagonist
or
Orchiectomy
þ
Flutamide
or
Nilutamide
or
Bicalutamide
(150 mg or more daily)
mentioned above, although GnRH agonist ther­
apy in localized prostate cancer has shown impor­
tant benefits in terms of survival in localized
prostate cancer, the knowledge that 40% of
androgens (Fig. 4C) remain in the prostate after
castration indicates that superior results should be
expected from the use of CAB or the combination
of an GnRH agonist with a pure anti-androgen
(Table 2). Early data already indicated that the
benefit of CAB versus monotherapy is greater for
patients with minimal metastatic disease than for
those with extensive metastatic disease (Crawford
et al., 1989; Denis et al., 1998). The availability of
GnRH agonists which are much more acceptable
than surgical castration or high doses of estrogens
(Labrie et al., 1980) has greatly facilitated or even
permitted the development of androgen blockade
at the localized stage.
It has been of major importance to observe that
CAB can achieve long-term control or cure of pros­
tate cancer in at least 90% of patients with localized
or locally advanced disease (Fig. 5) provided that
treatment is given continuously, uninterrupted,
for at least 7 years (Labrie et al., 2002) (Table 2).
The effect of CAB on long-term control or pos­
sible cure of prostate cancer was evaluated by the
absence of biochemical failure or the absence of
PSA rise for at least 5 years after cessation of con­
tinuous treatment (Fig. 5). A total of 57 patients
with localized or locally advanced disease received
Long-term control or cure (%)
Monotherapy or
combination
100
11/12
7/8
80
60
40
1/3
3/8
20
0/11
0
0
2
4
6
8
Continuous CAB (years)
10
12
Fig. 5. Effect of duration of treatment of localized prostate
cancer with continuous combined androgen blockade (CAB)
on the probability of long-term control or ‘cure of the disease’
illustrated by no recurrence of PSA rise for at least 5 years after
cessation of CAB. The point at 4.75 years of treatment (33%)
refers to the three patients treated with CAB for 3.5–5.0 years
and followed for at least 5 years, while the point at 5.75 years
refers to the eight patients treated continuously with CAB for
5.0–6.5 years before cessation of treatment. The point at 8.25
years, on the other hand, refers to the eight patients treated
continuously for 6.5–9.0 years while the point at 11 years refers
to the thirteen patients treated for 10.0–11.7 years with
continuous CAB before stopping treatment. All patients were
followed for at least 5 years after cessation of continuous CAB
or until PSA rise. Only 1 patient has died from prostate cancer
while 18 have died from other causes (Labrie et al., 2002).
CAB for periods ranging from 1 to 11 years. With a
minimum of 5 years of follow-up after cessation of
long-term CAB, only two PSA rises occurred
among 20 patients with Stage T2–T3 cancer who
stopped treatment after continuous CAB for more
than 6.5 years, for a non-failure rate of 90% (Fig. 5).
On the other hand, for the 11 patients who had
received CAB for 3.5–6.5 years, the non-failure
rate was only 36%. The serum PSA increased
within 1 year in all 11 patients with stage B2/T2
treated with CAB for only 1 year, thus indicating
that active cancer remained present after shortterm androgen blockade despite undetectable
PSA levels. Most importantly, in all patients who
had biochemical failure after stopping CAB, serum
PSA rapidly decreased again to undetectable levels
when CAB was restarted and PSA remained at
such low levels afterward. Of these patients, only
one patient had died of prostate cancer at last
follow-up (Labrie et al., 2002).
330
With the knowledge of the above-described
data, it seems reasonable to suggest that the
minimal duration of continuous CAB in localized
prostate cancer should be 6 years, thus providing
an ~50% probability of long-term control or pos­
sible cure of the cancer. With longer duration of
CAB, the probability increases to about 90% at
8–10 years of treatment. The present data indi­
cate that possible cure of the disease can be
obtained in almost all patients with localized
prostate cancer treated continuously with CAB
for 7 years or more, thus raising hope for the
successful treatment of patients who fail after
surgery, radiotherapy or brachytherapy where
no or minimally effective alternative therapeutic
approach exists.
A series of recent studies performed in Japan
clearly illustrate the very high efficacy of CAB in
localized disease (Akaza, 2008; Akaza et al., 2006;
Egawa et al., 2004; Namiki et al., 2008; Ueno et al.,
2006). In a prospective study performed in stages C
and D prostate cancer patients (Akaza, 2006; Akaza
et al., 2004) comparing GnRH agonist monotherapy
and CAB (GnRH agonist þ bicalutamide 80 mg/
day), the effect of CAB was more pronounced in
patients with C than with D disease. In fact, only
5.8% (3/52) of patients progressed under CAB com­
pared to 42.6% (20/47) with monotherapy, thus
showing a marked superiority of CAB compared
to monotherapy, especially in stage C or locally
advanced disease. These data strongly support our
results showing an even much greater advantage of
CAB in stage B disease (Labrie et al., 2002).
Based upon the above-summarized data, at
least for older men, primary hormone therapy is
a valid therapeutic option for localized or locally
advanced prostate cancer (Akaza et al., 2006). A
similar conclusion was reached in a retrospective
study of 447 stage B prostate cancer patients who
received androgen blockade alone or radical pros­
tatectomy combined with androgen blockade. No
difference in disease-specific survival was found at
9.2 years, thus indicating the predominant effect of
androgen blockade and the absence of effect of
prostatectomy in men receiving androgen block­
ade (Egawa et al., 2004).
Data on the current treatment of prostate can­
cer in Japan show that primary androgen blockade
is the treatment chosen for localized and locally
advanced prostate cancer in a high proportion of
cases. In the survey of the Japanese Urological
Association published in 2005, androgen blockade
alone was used as primary treatment in 40% of T1
patients and over 50% of T2 patients. Moreover,
from the data collected in 2001–2003 by the Japa­
nese Prostate Cancer Surveillance Group (J-CaP)
(Akaza et al., 2004), about 60% of patients who
receive androgen blockade receive CAB. In addi­
tion, about 70% of patients who receive androgen
blockade receive hormone therapy as first treat­
ment. A similar trend is seen in the United States
from the Cancer of the Prostate Strategic Urologic
Research Endeavour (CaPSURE) (Cooperberg
et al., 2003).
No resistance or loss or lack of response to CAB
exists for the treatment of localized disease
Recognition of the absence of development of
resistance to androgen blockade in localized pros­
tate cancer is extremely important. In fact, it is very
frequently stated that androgen blockade should
not be administered early because resistance to
treatment will develop and one might as well wait
to use androgen blockade at a later stage of the
disease. In fact, deferring treatment is a very ser­
ious error since it implies that, very often, it will
then be too late to achieve an otherwise possible
cure. In fact, when the cancer has reached the
bones, the resistance to treatment can no more be
avoided and cure has become impossible. It should
be realized that when prostate cancer is first
detected, even by screening, the cancer is not
small since its diameter is of the order of 1 cm or
more. This is the only appropriate time to start
treatment with the very strong hope of a cure.
Combined androgen blockade in advanced
prostate cancer
Although androgen blockade should move to the
treatment of localized disease, metastatic disease
remains frequent and will always be a therapeutic
challenge. Again, it is important to indicate that
331
the observations made with metastatic disease,
especially the relatively short duration of response
to CAB and the appearance of resistance to treat­
ment should not be applied to localized disease.
The results obtained in a large series of clinical
trials in patients with advanced prostate cancer
have demonstrated that CAB compared to castra­
tion alone has the following advantages: (1) more
complete and partial responses, (2) improved
control of metastatic pain, (3) longer disease-free
survival and (4) longer survival. As already men­
tioned, the combination of a pure anti-androgen
(e.g. flutamide, nilutamide or bicalutamide) with a
GnRH agonist was the first treatment shown to
prolong life in patients with advanced prostate
cancer (Bennett et al., 1999; Caubet et al., 1997;
Crawford et al., 1989; Denis et al., 1998; Labrie
et al., 1982; Labrie et al., 1985; Prostate Cancer
Triallists’ Collaborative Group, 2000).
Analysis of all the studies performed with flu­
tamide and nilutamide associated with medical or
surgical castration compared with castration plus
placebo shows that overall survival is increased
by an average of 3–6 months (Bennett et al.,
1999; Caubet et al., 1997; Crawford et al., 1989;
Denis et al., 1993; Denis et al., 1998; Dijkman
et al., 1997; Janknegt et al., 1993; Prostate Cancer
Triallists’ Collaborative Group, 2000; Schmitt
et al., 2001) (Fig. 6). It is essential not to include
the data obtained with cyproterone acetate, a
compound showing intrinsic androgenic activity
in all in vitro and in vivo assays (Labrie et al.,
1987; Luthy et al., 1988; Plante et al., 1988).
These preclinical data have translated into a
shortened survival when cyproterone acetate
was added to castration and compared with cas­
tration alone in men with metastatic disease
(Prostate Cancer Triallists’ Collaborative Group,
2000).
Since about 50% of patients in that age group
die from causes other than prostate cancer, this
3–6-month difference in overall survival trans­
lates into an average of 6–12 months of life
gained when cancer-specific survival is ana­
lyzed. These additional months, or sometimes
years, of life can be obtained by simply adding
a pure anti-androgen (flutamide, nilutamide or
bicalutamide at a proper dose) to castration.
These data demonstrate the particularly high
level of sensitivity of prostate cancer to andro­
gen deprivation, considering that such statisti­
cally significant benefits on survival are
obtained, even at the very advanced stage of
metastatic disease.
Favours CAB
Favours castration
PCTCG: nilutamide (n = 1751)
PCTCG: flutamide (n = 4803)
PCTCG: nilutamide + flutamide (n = 6554)
*
**
Caubet: NSAA (n = 3732)
*
Caubet: NSAA (n = 1978)
**
Caubet: NSAA (n = 2357)
**
Klotz: NSAA (n = 5015)
*
Debruyne: nilutamide (n = 1191)
*
Bennett: flutamide (n = 4128)
*
0.5
*2p < 0.05; **2p < 0.01
1.0
2.0
Hazard ratio and 95% confidence limits
Fig. 6. Summary of meta-analyses comparing combined androgen blockade [combination of medical or surgical castration associated
with a pure anti-androgen (NSAA), namely flutamide or nilutamide] versus medical or surgical castration alone. Adapted from Klotz
et al., 2001.
332
With the clinical data summarized above, the
controversy or uncertainty concerning CAB
should be part of history and the addition of a
pure anti-androgen at a proper dose should be
recognized by all as providing an average advan­
tage of 3–6 months of life in metastatic disease at a
time when no alternative treatment even exists.
Further improvement of the hormonal therapy
of metastatic disease is very difficult. By far the
best and today’s only possibility of improvement
for the prostate cancer patient is treatment of
localized disease. In fact, in analogy with the treat­
ment of all other types of cancers, the beneficial
effects are much greater when the same treatment
is applied at an earlier stage of the disease.
In the United States, where three million of all
men currently alive are expected to die from pros­
tate cancer (Statbite, 2004), 6 additional months of
life per individual correspond to 1.5 million years
overall, whereas 12 additional months correspond
to 3 million years.
Resistance to treatment in metastatic disease
Contrary to the situation in localized disease
where resistance to CAB practically does not
exist, resistance to hormone therapy is the stan­
dard observation in metastatic prostate cancer,
thus creating a major and unresolved therapeutic
challenge. In fact, recent evidence indicates that
AR functioning is required for the growth of
prostate cancer at all stages, including castra­
tion-resistant disease (Taplin, 2007). These data
show that endocrine therapy-resistant prostatic
carcinomas generally display uniformly high AR
expression (Ruizeveld de Winter et al., 1994; van
der Kwast et al., 1991). In a recent study, a sig­
nificant increase in AR mRNA levels was
observed in the cancerous prostatic cells com­
pared with the benign tissue biopsies (Levesque
et al., 2009). Treatment with flutamide has
already been shown to decrease AR expression
in prostatic carcinoma tissue (van der Kwast
et al., 1996).
Even at time of progression in patients with
metastatic prostate cancer treated by castration
alone, the benefits of additional androgen
blockade are illustrated by the observation of a
positive response in 30–60% of patients in pro­
gression by hypophysectomy, adrenalectomy or
aminoglutethimide (Drago et al., 1984; Labrie
et al., 1985; Maddy et al., 1971; Murray and Pitt,
1985). In a relatively large-scale study of 209 meta­
static prostate cancer patients showing disease
progression after orchiectomy or treatment with
high doses of estrogens or a GnRH agonist alone,
the addition of flutamide permitted to achieve
complete, partial and stable responses in 6.2, 9.6
and 18.7% of cases, respectively, for a total clinical
benefit of 34.5%. The mean duration of response
was 24 months (Labrie et al., 1988).
Contrary to the generalized opinion that
patients in relapse after castration have exclu­
sively ‘androgen-insensitive’ tumors, the abovementioned data suggest that ‘androgen-sensitive’
tumors are present at all stages of prostate can­
cer in all patients and that maximal androgen
blockade should always be administered. Instead
of being ‘androgen insensitive’, most of the
tumors which continue to grow after castration
are androgen sensitive and able to grow in the
presence of the ‘low’ level of androgens of adre­
nal origin left after ‘castration’ (Labrie et al.,
1988). ‘Control of their growth requires further
androgen blockade’. This affirmation was well
supported by already available clinical data and
fundamental observations (Labrie and Veilleux,
1986). As evidence for the androgen sensitivity
of prostate cancer progressing under androgen
blockade, Fowler and Whitmore (1981) have
observed a rapid and severe exacerbation of
the disease in 33 out of 34 patients in relapse
within the first 3 days of testosterone adminis­
tration, thus clearly showing that at least part of
prostate cancer cells remain androgen sensitive
even at the advanced stage of progression under
androgen blockade (Fowler and Whitmore,
1981).
Based upon the above-summarized data, it
becomes important to develop more potent but
always pure blockers of androgen formation or
action, the blockade of AR being the most
obvious and therapeutically well-supported target.
Positive clinical data have recently been reported
with a new anti-androgen (Tran et al., 2009),
333
although the true role of this compound used in
relapsing patients where the anti-androgen was
apparently stopped at time of administration of
the new agent remains to be assessed. Similar
uncertainty applies to the 50% (or more)
decrease in serum PSA in 28 (67%) of 42
patients observed following administration of
abiraterone in patients relapsing under antiandrogen treatment (Attard et al., 2009). Con­
sidering the well-demonstrated clinical benefits
and the important decrease in serum PSA
which follow simple cessation of administration
of the anti-androgen (Dupont et al., 1993; Kelly
et al., 1997), the true clinical benefits of these
compounds remain undefined. It is clear, how­
ever, that a more potent blocker of AR having
pure antagonistic activity could play an impor­
tant role in prostate cancer therapy at all stages
of the disease.
More potent anti-androgens, the key to more
successful treatment of prostate cancer
While androgen blockade has been known for a
long time to be efficacious as first line therapy at
all stages of prostate cancer (Akaza, 2008;
Huggins and Hodges, 1941; Janknegt et al., 1993;
Labrie et al., 2002; Labrie et al., 1985; Namiki
et al., 2008), recent data indicate a continuous
role of the AR in treatment-resistant metastatic
disease (Chen et al., 2004).
While the percentage of objective responses
in patients with metastatic prostate cancer is
higher and the duration of response is longer
when CAB is used (Crawford et al., 1989; Jan­
knegt et al., 1993; Labrie et al., 1985), progres­
sion of the disease always occurs if the patients
have metastatic disease at start of treatment.
Somewhat surprisingly, however, it was found
that a large percentage of patients show a posi­
tive clinical response upon discontinuation of
the anti-androgen with a decrease in serum
PSA by more than 90% in 47% of patients
(Dupont et al., 1993). This paradoxical phenom­
enon became generally recognized (Collinson
et al., 1993; Herrada et al., 1996; Kelly and
Scher, 1993; Kelly et al., 1997). A possible
explanation of the paradoxical effect of antiandrogen withdrawal is the development of
hypersensitivity to androgens (Labrie and Veil­
leux, 1986; Labrie et al., 1988), or intracellular
changes making the anti-androgen act as a par­
tial androgen agonist.
The traditional therapeutic approach for
metastatic disease which has become resistant
to a specific androgen blockade, usually partial
androgen blockade achieved by medical or sur­
gical castration or an anti-androgen alone,
deserves re-evaluation following the observa­
tions of higher AR levels and/or maintenance
of responsiveness to androgens in treatmentresistant cancer (Chen et al., 2004; Harris
et al., 2009; McPhaul, 2008; Mostaghel et al.,
2009; Mulders and Schalken, 2009; Scher and
Sawyers, 2005; Taplin and Balk, 2004). While
addition of an anti-androgen was the usual
approach in patients showing resistance to
monotherapy by castration, the patients who
had become resistant to CAB were not consid­
ered candidates for further hormonal manipula­
tions and were treated by non-hormonal
approaches, specially chemotherapy with no
clear success (Eisenberger et al., 1985). In fact,
elevated AR expression has been found to lead
to resistance to anti-androgen therapy in mouse
xenograft prostate cancer models (Chen et al.,
2004). In any case, such data indicate that AR
blockade could well remain an important ther­
apeutic target even at the last stage of the dis­
ease when resistance to various forms of
androgen blockade has developed.
Although the available anti-androgens fluta­
mide, bicalutamide and nilutamide have pure
AR antagonistic activity and have shown major
benefits in prostate cancer therapy (Crawford
et al., 1989; Janknegt et al., 1993; Labrie et al.,
1985; Prostate Cancer Triallists’ Collaborative
Group, 2000), the affinity of all these com­
pounds for AR is very low (Labrie et al.,
1997; Labrie et al., 1999; Luo et al., 1996;
Simard et al., 1997) and leaves an estimated
5–10% of DHT free to continue to stimulate
AR and prostate cancer growth (Labrie et al.,
1987). There is thus the need to discover and
develop novel anti-androgens having higher
334
affinity for the human AR in order to take
optimal advantage of the well-demonstrated
sensitivity of prostate cancer to androgens.
Using the structural information on the ligandbinding domain (LBD) of the human AR (Cantin
et al., 2007; Pereira de Jesus-Tran et al., 2006), we
have synthesized a long series of novel molecules
having higher or much higher affinity for the
human AR and/or higher anti-androgenic potency
in intact cell models than flutamide, bicalutamide
or nilutamide, the only presently pure AR antago­
nists available for therapeutic use in men suffering
from prostate cancer.
In addition to the increased AR levels, the local
and autonomous synthesis of androgens may
explain the observation that androgen deprivation
in prostate cancer xenograft models demonstrated
only transient cell cycle arrest, with little evidence
of apoptosis, followed by rapid progression (Agus
et al., 1999). Moreover, as mentioned above,
cancerous prostate tissue was found to synthesize
more DHT than the benign prostatic tissue
(Nishiyama et al., 2007).
With the above-summarized information, it is
reasonable to believe that the drug most
urgently needed for prostate cancer is a more
potent blocker of AR. With the available weak
anti-androgens, only partial androgen blockade
can be achieved – true total androgen blockade
needs more potent compounds. As mentioned
above, the problem with current anti-androgens
is their low potency which leaves 5–10% of
DHT in the prostate cancer tissue (Fig. 7) free
to continue to stimulate cancer growth and
metastasis. Moreover, with the available pure
but weak anti-androgens (Labrie et al., 1997;
Labrie et al., 1999; Luo et al., 1996; Simard
et al., 1997), CAB must be continued for many
years (six or more), even in localized disease
(Fig. 5). With a more potent anti-androgen,
complete apoptosis and cell death should be
achieved more rapidly, thus greatly facilitating
cure of localized disease. The compounds which
we have synthesized are designed to impede
repositioning of the mobile carboxy-terminal
helix 12, which blocks the ligand-dependent
transactivation function (AF-2) located in the
AR ligand-binding domain (ARLBD). Using
Intraprostatic DHT
%
100
75
Cancer growth
decreases but
continues −
resistance
develops 50
25
0
Intact
Monotherapy
castration or
anti-androgen alone
Combined
androgen blockade
castration +
anti-androgen
Fig. 7. Comparison of the intraprostatic concentrations of
DHT in intact men, in men castrated or receiving an antiandrogen alone (monotherapy) and in men receiving
combined androgen blockade (castration þ a pure antiandrogen having relatively low potency, namely flutamide,
bicalutamide or nilutamide).
crystal structures of the human ARLBD
(hARLBD), we first found that H12 could be
directly reached from the ligand-binding pocket
(LBP) by a chain positioned on the C18 atom of
an androgen steroid nucleus. A set of DHTderived molecules bearing various C18 chains
were thus synthesized and tested for their capa­
city to bind to human androgen receptor (hAR)
and act as antagonists. Although most of those
having very high affinity for hAR were agonists,
several very potent antagonists were obtained,
confirming the structural importance of the C18
chain. To understand the role of the C18 chain
in their agonistic/antagonistic properties, the
structure of the hARLBD complexed with one
of these agonists, EM-5744, was determined at a
1.65 Å resolution (Cantin et al., 2007). We have
identified new interactions involving Gln738,
Met742 and His874 that explain both the high
affinity of this compound and the inability of its
bulky chain to prevent the repositioning of H12.
These structural information were helpful to
refine the structure of the chains placed on the
C18 atom in order to obtain efficient H12-direc­
ted steroidal anti-androgens.
With the aim of designing such new antiandrogens, we decided to make use of earlier
335
structural findings on the human estrogen recep­
tor (hER), a receptor structurally related to the
hAR. The hER is unable to interact with co­
activator partners when a ligand bearing a welloriented bulky chain is bound to its ligand-bind­
ing site (Brzozowski et al., 1997). Indeed, as
revealed by comparison of the crystal structures
of the hER ligand-binding domain (hERLBD) in
complex with a natural estrogen [estradiol (E2)]
and a potent SERM (selective estrogen receptor
modulator, raloxifene), agonist and antagonist
molecules bind at the same site within the
LBD. However, they exhibit different binding
modes, inducing a distinct conformation in the
transactivation domain (AF-2) characterized by
a different positioning of H12. More precisely,
the size and structure of raloxifene prevent the
molecule from being completely confined within
the steroid-binding cavity. Consequently, its
bulky side chain protrudes from the cavity and
impedes H12 from adopting the position found
in the E2–hERLBD complex structure, a confor­
mation essential for interaction with transcrip­
tional co-activators.
Concerning hAR, the crystal structures of its
LBD (hARLBD) in complex with the natural
androgens DHT and testo (Pereira de Jesus-Tran
et al., 2006; Sack et al., 2001) have shown that H12
occupies therein the same position as that
observed in the E2–hERLBD structure. Such
data suggest that this helix is essential for the
function of the AF-2 of hAR and, like in the
hER, participates in the interaction with co-acti­
vators. This has been confirmed by the structure
of the liganded hARLBD in complex with a pep­
tide derived from physiological co-activators
(Estebanez-Perpina et al., 2005; He et al., 2004;
Hur et al., 2004).
Using all the available structural information of
the hAR, we then proceeded to molecular model­
ling studies to find the best position on an andro­
gen nucleus (here DHT) for introducing a bulky
chain able to reach the site normally occupied by
H12. Finally, the combined data from molecular
modelling and structure/activity relationship stu­
dies served as a basis for the design and improve­
ment of the chain structure, with the aim of
maximizing the affinity of these steroidal-based
compounds for hAR. This rational approach
yielded several different DHT-based ligands able
to bind hAR with high affinity (many folds over
that of DHT). In our in vitro tests, a small sub­
group proved to be very efficient antagonists of
DHT stimulation, thus indicating that the particu­
lar structure of the bulky chain is of paramount
importance for its activity.
Hormone therapy is greatly underused in prostate
cancer
Despite the fact that it is well recognized since
1940s (Huggins and Hodges, 1941) that the stan­
dard and even the only efficient treatment of
metastatic prostate cancer is androgen blockade,
a recent survey of 9110 men aged 65 years or
older who died from prostate cancer between
1991 and 2000 has surprisingly indicated that
38% of black and 25% of white men in the
United States did not receive hormone therapy
before dying from prostate cancer (Lu-Yao
et al., 2006).
If such a large proportion of patients with
metastatic prostate cancer do not receive hor­
mone therapy, one can understand the difficulty
to implement CAB instead of the partial and
limited blockade obtained with monotherapy
(Table 3). This deficient use of androgen block­
ade in prostate cancer can be contrasted with the
respective 93.5 and 98% rates of use of beta
blockers after myocardial infarction (National
Committee for Quality Assurance, 2003, p. 60)
and tamoxifen in estrogen-receptor-positive
breast cancer (Buzdar and Macahilig, 2005).
This deficiency in the field of prostate cancer
may be due to the fact that doctors underesti­
mate the risks of death from prostate cancer
compared to other causes of death.
Table 3. Frequent errors related to androgen blockade
1. Monotherapy (GnRH agonist alone, orchiectomy alone or
anti-androgen alone) instead of combined androgen blockade
2. Too short duration of treatment
3. Treatment started too late
4. Intermittent treatment
336
Early diagnosis is essential in order to be able to
apply the available curative treatments of prostate
cancer
It is very important to realize that the use of the
currently available approaches for the diagnosis
and treatment of prostate cancer can virtually
eliminate death from this disease. With the cur­
rent techniques, screening can detect prostate can­
cer at a clinically localized stage in 99% of cases
(Labrie et al., 1996b). Radical prostatectomy,
radiotherapy or brachytherapy can be instituted
immediately with curative intent following such
early diagnosis. Moreover, excellent results can
be expected with CAB alone, particularly in
older patients where the choice of CAB can be
easier. In fact, CAB can also be used alone as
primary therapy with excellent results, as shown
in important recent studies (Akaza et al., 2006;
Egawa et al., 2004; Homma et al., 2004; Labrie
et al., 2002; Ueno et al., 2006).
Most importantly, CAB must be used immedi­
ately in patients for whom radical prostatectomy,
radiotherapy or brachytherapy fails. As men­
tioned above, it is often erroneously believed
that resistance will develop to androgen blockade
in localized disease and that this treatment should
therefore be delayed until a later stage of the
disease. This belief is incorrect. In fact, the use of
CAB to treat localized prostate cancer does not
lead to resistance to treatment as long as the can­
cer is limited to the prostate or to tissue near the
prostate at time of starting treatment. However, as
mentioned above, if the treatment is deferred, the
possibility of cure is very often lost because the
cancer has the opportunity to metastasize to the
bones where cure is practically impossible. In
metastatic disease, the response to androgen
blockade is short and resistance to treatment can­
not be avoided. It should be appreciated that
when prostate cancer is first detected, even by
screening, the tumor is not small. Immediate treat­
ment is the only treatment that offers a strong
hope of cure. In fact, CAB must be started imme­
diately at time of diagnosis.
While showing the high efficacy of hormonal
therapy in localized prostate cancer, the present
data clearly indicate that long-term treatment with
the best available drugs, somewhat similar to the 5
years of tamoxifen in breast cancer, is required for
optimal control of prostate cancer. Great caution
should be taken, however, when using serum PSA
as surrogate marker. In fact, serum PSA rapidly
and easily decreases to undetectable levels under
androgen blockade although the cancer remains
present for much longer periods of time, usually
for many years as demonstrated in our recent
study (Labrie et al., 2002). For this reason, inter­
mittent therapy should not be recommended
outside prospective and randomized clinical trials.
Conclusion
With the present knowledge, it is clear that all
available means should be taken to diagnose pros­
tate cancer early and to use efficient therapy
immediately in order to prevent prostate cancer
from migrating to the bones when cure or even
long-term control of the disease is an exception. It
is clear that the only means of preventing prostate
cancer from migrating to the bones and becoming
incurable is efficient treatment at the localized
stage. In fact, since radical prostatectomy, radio­
therapy and brachytherapy (implantation of
radioactive seeds in the prostate) can achieve
cure in about 50% of cases, these approaches are
all equally valid choices as first treatment of loca­
lized prostate cancer with a curative intent.
Androgen blockade should also be considered as
first line treatment of curative intent, especially
for elderly men and those having other serious
health problems. The most important, however,
is to follow closely serum PSA after surgery,
radiotherapy and brachytherapy and to start
CAB as soon as signs of recurrence of the cancer
appear. It is also clear from the data summarized
above that CAB alone could well be the most
efficient therapy of localized prostate cancer
while it has already been recognized as the best
therapy for metastatic disease.
Clearly, the rational use of the presently avail­
able diagnostic and therapeutic approaches could
decrease prostate cancer death by at least 60%
(Labrie et al., 1996b; Labrie et al., 1999). As an
example, between 1991 and 1999, the death rate
337
from prostate cancer has decreased by 38% in
Quebec City and its metropolitan area (Candas
and Labrie, 2000) while the death rate has
decreased by 62% in the group of men who have
been screened.
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