©TheCanadian Journal ofUrology™: International Supplement, April 2014
and 3) those with metastases and significant cancer
symptoms (who are usually candidates for palliative
chemotherapyorpotentiallyradium223).
7
AsCRPC is
incurable the focusof therapyshouldbeonoptimizing
a patient’s quality and quantity of life, and judicious
and timely use of suitable agents available in this
“pre-chemotherapy” phase is important, and is the
topicof this review. Thesegoalsof therapy shouldbe
discussedwith the patient, and an understanding of
the patient’s values is essential in creating a strategy
for how aggressively or conservatively theywish to
pursueactive therapeutics. Counselingpatientsabout
the interpretationof PSAvalueswhichmayfluctuate
andbemisleading inCRPC,andemphasizing thegoal
of optimal qualityof life is recommended.
Prior to considering SHMs, the question of
maintaining castrative therapy may be raised. A
multivariate analysis by Taylor et al
8
identified
prognostic factors associatedwithworse survival in
menwithCRPC including: poor performance status
(non-ambulatory), soft-tissue visceral involvement,
age > 65 years-old, recent weight loss of > 5%, and
discontinuation of endocrine therapy. Inadequate
gonadalandrogensuppression (androgendeprivation
therapy—ADT) has also been associated with
resistance to anticancer treatment, presumably due
to anti-apoptotic effects of androgens in prostate
cancercells.
9
There issomeevidence that intermittent
ADT may improve side effects and result in cost
savings in CRPC.
10
However, it remains the current
standard of care to maintain all men with CRPC
on continuous gonadal androgen suppression with
luteinizing hormone releasing hormone (LHRH)
agonistorantagonist if theyhavenotbeen treatedwith
bilateral orchidectomy, although theseagentsmaybe
discontinued aspatientsnear their end-of-life.
11,12
Whyuse secondaryhormonalmanipulation
in the eraof newer agents?
New hormonal agents have emerged over the past
5 years and been approved for the treatment of
CRPC, and are currently being studied earlier in
the natural history of CRPC. This raises questions
about the optimal use of these agents, and has
prompted the development of clinical practice
guidelines. The American Urological Association
has recentlypublishedaguideline forCRPC, and the
systematicreviewsupporting thisguidelineprovides
the evidence base for this review of SHMs.
13
Men
presentingwithorwhodevelop clinically significant
metastaticCRPCduringSHMsshouldbeassessed for
palliativechemotherapy, andmayneed toproceed to
chemotherapywithout furtherSHMs. Inmenwithout
evidence of CRPCmetastases there is no evidence
available fromrandomizedcontrolled trials thatSHMs
ultimately improve important disease outcomes,
and so the risk-benefit of interventions should be
considered from the view that they may merely
manipulatePSAlevelswithoutotherprovenbenefits.
13
The natural history of CRPC without metastases
was studied in men enrolled in the placebo group
of an aborted trial of zoledronic acid versus placebo
reportedbySmithetal.
14
Athirdofpatientsdeveloped
bonemetastases at 2 years. Median bonemetastasis
freesurvivalwas30months, though time tofirstbone
metastasisandoverall survivalwerenot reached. An
elevated baseline PSA (> 10 ng/mL) and rapid PSA
velocity (<6months) independentlypredictedshorter
time to bone metastasis, metastasis free survival,
andoverall survival. Careful observationoroffering
clinical trial participation to CRPC patients without
metastasesmay be considered reasonable standards
of care.
13,15
Currently there is no high level evidence
supporting the use of either SHMs or newer agents
suchasabirateroneorenzalutamide inCRPCpatients
without metastases, and clinical trials studying
these are underway. In men with relatively stable
asymptomaticorminimallysymptomaticnon-visceral
metastaticdisease, theuseof abiraterone-prednisone
mayalsobe considered.
16
Menwithbonemetastases
shouldalsobeconsidered forboneprotective therapy
as prophylaxis for skeletal-related events.
17
Agents and applications
There is not sufficient data andno clinical consensus
supporting an optimal sequencing of SHMs inmen
withearlyCRPC, sopracticalconsiderations including
patient preferences and drug availability usually
dictate treatmentoptions. Switch toanalternateSHM
shouldbeconsidered if toxicityorevidenceofdisease
progression occurs, but otherwise observation on
treatment is usually continuedwithout interruption.
As mentioned ADT should be continued despite
evidenceofCRPCandserum testosterone levelshould
be confirmed within the castrate range; if it is not,
thenaswitchofLHRHagonist/antagonistorbilateral
orchidectomy should be considered. A therapeutic
trial of a non-steroidal antiandrogen (NSAA) is
routine when biochemical evidence of CRPC is first
observed onADTmonotherapy, but there is no clear
evidence that this improvesqualityorquantityof life.
13
Generically available NSAAs include bicalutamide,
flutamideandnilutamide. Althoughno studieshave
investigated optimal dosing, bicalutamide 50mgPO
38
Secondaryhormonalmanipulation in castration resistant prostate cancer
