©TheCanadian Journal ofUrology™: International Supplement, April 2014
LHRH analogues
ThedecapeptideLHRHwasfirstdiscovered in1971by
Dr. Schally, who further demonstrated that synthetic
analogueswouldbind to their receptors in theanterior
pituitary to result in agonist activity.
2
Physiologic
activityoccursviaLHRHreleasefromthehypothalamus
in a pulsatile manner.
3
It then acts on the anterior
pituitary to induce the release of luteinizinghormone
(LH) and follicle stimulatinghormone (FSH),which in
turnact on the testes. Ninety toninety-fivepercent of
circulatingandrogensareproducedby the testes,with
the remainder coming from theadrenal glands.
4
With
prolonged exposure to LHRH, the anterior pituitary
downregulates LH and FSH, which in turn leads to
lower testosterone, thus forming thebasis formodern
medicalADT in the treatment ofprostate cancer.
5
Up to this time, however, bilateral orchiectomy
constituted the gold standardof hormone therapy for
prostate cancer, but estrogenic compounds were also
beingusedtolowertestosterone(e.g.,diethylstilbesterol,
DES). Once LHRH analogues were deemed safer
than estrogens (fewer thromboembolic side effects
and cardiovascular events) and palliated advanced
prostate cancer patients well, LHRH agonist therapy
supplanted estrogens and bilateral orchiectomy.
6
Bilateral orchiectomy remains an option, and the side
effect profile is similar toLHRH therapies (vasomotor
symptoms, weight gain, mood lability, gynecomastia,
fatigue, cognitive changes, and loss of libido). While
bilateral orchiectomy is very efficacious and more
cost effective at rapidly lowering total testosterone (t
½
45minutes, mean serum testosterone nadir 14 ng/dL
seen in about 8.6 hours ± 3.2 hours), is not frequently
performed in the modern era for a few reasons:
the procedure is irreversible, and men are thought
to experience significant psychological impact.
7-10
When given the choice of medication versus bilateral
orchiectomy, one study noted 78% would choose
medication toavoid surgeryandout of convenience.
11
The reversiblenatureof LHRHanalogueswas further
enhancedwith the introductionofdepot formulations,
which lastanywherefrom1-12monthsbeforerequiring
re-dosing. Ameta-analysisof27randomizedcontrolled
trials demonstrated similar efficacy between surgical
andmedicalmodalitiesofADT.
12
ADT isnow standardof care inadvancedprostate
cancer,but ithasbeenstudied inothersettingssuchas
monotherapy for localizeddisease,earlystagedisease,
neoadjuvantandadjuvanttherapy incombinationwith
surgeryorradiation therapy. Thepracticingphysician
will undoubtedly encounter patients with various
disease states and preferences. Below, we endeavor
to summarize and reviewpertinent questions related
to themodern accepteduses forADT.
ADT asprimary therapy
Some men may wish to avoid the side effects of
definitive local therapy (radical prostatectomy or
radiationtherapy). Activesurveillance isavalidoption,
particularly inmenwith low riskdisease. The use of
ADT forprimary treatment isdiscouragedon thebasis
of randomized controlled trials comparingADTalone
toADTplus radiation.
13
In one study byWidmark et
al,875patientswitheither localizedor locallyadvanced
prostate cancer received either 3 months of LHRH
agonist therapyplusnon-steroidalantiandrogenor the
same plus radiotherapy (minimum 70 Gy). After 10
years,overallmortalityfavored theADTplusradiation
arm (29.6%versus 39.4%).
14
The readerwill note that
modernADT regimensaregiven for longerdurations.
TheCAN-NCI-C-PR3 study examinedmenwithhigh
risk localizeddisease (T2N0, PSA>40ng/mLorPSA
> 20 ng/mL and Gleason ≥ 8) or locally advanced
disease (T3/T4 N0) and randomized them to either
lifelong ADT or ADT plus external beam radiation
therapy. Men treatedwithADTand radiation therapy
had significantly lower overall risk of death (hazard
ratio0.70, 95%CI 0.57-0.85, p=0.001).
15
Comparisons
ofADTalone toADTplus radicalprostatectomyshow
similar poor outcomes forADTmonotherapy but are
retrospective innature.
16-18
Despite current recommendations in the United
States (U.S.) and Europe against the use of ADT as
monotherapy for prostate cancer, 14.4% of patients
in the Cancer of the Prostate Strategic Urologic
Research Endeavor (CaPSURE) registry received
only ADT as a form of therapy for prostate cancer
in an analysis of the changing treatment patterns for
prostatecancerbetween1990and2007.
19
Interestingly
enough, guidelines in Asia endorse monotherapy
for localized prostate cancer on the basis that men
havemuch better outcomes. One recent comparison
of primary ADT patients between US and Japanese
cohorts demonstrated a hazard ratio amongst all-
cause mortality of 0.27 (95% CI 0.24-0.30) favoring
Japanesepatients.
20
Theunderlying reasons for these
disparate outcomes is not entirely clear, but is likely
multifactorial includinggenetics,environmentaland/
ordietary factors and comorbidities.
Neoadjuvant andadjuvantADT
Investigators hypothesized that giving patients
ADTprior to surgerymight improve various clinical
15
RoveandCrawford
