DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1764
SECTION VIII
CHEMOTHERAPY AND TARGETED THERAPY OF NEOPLASTIC DISEASES
(Keating et al., 2006). However, retrospective analyses have not
revealed a compelling increase in cardiovascular mortality due to
GnRH agonists (Efstathiou et al., 2008; Efstathiou et al., 2009).
Skeletal-related events due to ADT, including fractures, may be mitigated
by bisphosphonate therapy, such as zoledronic acid (ZOMETA)
(Saad et al., 2002) or inhibitors of osteoclast activation, such as denosumab
(Smith et al., 2009).
Anti-androgens, when compared with GnRH agonists, cause
more gynecomastia, mastodynia, and hepatotoxicity but less vasomotor
flashing, and loss of bone mineral density (BMD) (McLeod,
1997). Estrogens cause a hypercoagulable state and increase cardiovascular
mortality in prostate cancer patients and are no longer standard
treatment options (Byar and Corle, 1988).
Gonadotropin-Releasing Hormone
Agonists and Antagonists
The biosynthesis of androgens, primarily in the testes
and adrenals, is described in Chapter 41, and the regulation
of Leydig cell synthetic activity by the hypothalamic–
pituitary axis is considered there as well.
Pharmacological castration was first reported in 1982
(Tolis et al., 1982). In the U.S., the most common form
of ADT involves chemical suppression of the pituitary
gland with GnRH agonists. Synthetic GnRH analogs
(Table 63–2) have greater receptor affinity and reduced
susceptibility to enzymatic degradation than the naturally
occurring GnRH molecule and are 100-fold more
potent (Schally et al., 1980). GnRH (also termed
luteinizing hormone–releasing hormone, LHRH) agonists
bind to GnRH receptors on pituitary gonadotropinproducing
cells, causing an initial release of both LH
and FSH and a subsequent increase in testosterone production
from testicular Leydig cells. After ~1 week of
therapy, GnRH receptors are downregulated on the
gonadotropin-producing cells, causing a decline in the
pituitary response (Conn and Crowley, 1991). The fall in
serum LH leads to a decrease in testosterone production
to castrate levels within 3-4 weeks of the first treatment.
Subsequent treatments maintain testosterone at castrate
levels (Limonta et al., 2001).
During the transient rise in LH, the resultant testosterone surge
may induce an acute stimulation of prostate cancer growth and a
“flare” of symptoms from metastatic deposits. Patients may experience
an increase in bone pain or obstructive bladder symptoms lasting
for 2-3 weeks (Waxman et al., 1985). The flare phenomenon can be
effectively counteracted with concurrent administration of 2-4 weeks
of oral anti-androgen therapy, which may inhibit the action of the
increased serum testosterone levels (Kuhn et al., 1989).
Current depot forms of GnRH agonists are the
result of progressive improvements in drug development.
GnRH agonists in common use include leuprolide
(LUPRON, others), goserelin (ZOLADEX), triptorelin (TREL-
STAR), histrelin (VANTAS), and buserelin (SUPREFACT; not
available in the U.S.). Long-acting preparations of both
leuprolide and goserelin are available in doses that are
approved for 3-, 4-, and 6-month administrations.
Leuprolide and goserelin have been compared with orchiectomy
in randomized trials. A meta-analysis of 10 such randomized
trials found equivalence in overall survival, progression-related outcomes,
and time to treatment failure (Kaisary et al., 1991; Seidenfeld
et al., 2000; Turkes et al., 1987; Vogelzang et al., 1995).
Combined androgen blockade (CAB) requires administration
of ADT with an anti-androgen. The theoretical advantage is that the
GnRH agonist will deplete testicular androgens, while the anti-androgen
component competes at the receptor with residual androgens
made by the adrenal glands. CAB provides maximal relief of androgen
stimulation. Numerous large trials have compared CAB with
ADT monotherapy, with variable results. Several meta-analyses of
these trials suggest a benefit for CAB in 5-year survival but not at
earlier time points (Samson et al., 2002; Schmitt et al., 1999). Toxicity
and costs associated with CAB are higher than with ADT alone.
GnRH antagonists have been developed to suppress testosterone
while avoiding the flare phenomenon of GnRH agonists. Other
than avoidance of the initial flare, GnRH antagonist therapy offers
no apparent advantage compared with GnRH agonists. The first available
GnRH antagonist, abarelix (PLENAXIS), rapidly achieves medical
castration (Trachtenberg et al., 2002). However, local reactions and
anaphylaxis have discouraged its clinical acceptance and have led to
its withdrawal from the market. A second GnRH antagonist, degarelix,
is not associated with systemic allergic reactions and is approved
for prostate cancer in the U.S. (Klotz et al., 2008).
Anti-Androgens
Anti-androgens bind to ARs and competitively inhibit
the binding of testosterone and dihydrotestosterone.
Unlike castration, anti-androgen therapy by itself does
not decrease LH production; therefore, testosterone levels
are normal or increased. Men treated with antiandrogen
monotherapy maintain some degree of
potency and libido and do not have the same spectrum
of side effects seen with castration.
Currently, anti-androgen monotherapy is not indicated
as first-line treatment for patients with advanced
prostate cancer. Numerous studies have examined the
effectiveness of anti-androgens compared with surgical
castration, GnRH agonists, or treatment with diethylstilbestrol
(DES; discontinued in the U.S.). A metaanalysis
of eight trials indicated that nonsteroidal
anti-androgens had equivalent overall survival relative
to castration, although the association between nonsteroidal
anti-androgens and decreased survival approached
statistical significance (Seidenfeld et al., 2000). Antiandrogens
most commonly are used in clinical practice
as secondary hormone therapy or in CAB.