©TheCanadian Journal ofUrology™: International Supplement, April 2014
initiationofADT.
10
Thiseffectcan initiallybedramatic
in reducing themorbidityof symptomaticmetastatic
prostate cancer, including spinal cord compression,
bonepain, andurinary tract obstruction. Inefforts to
delay themorbidityandmortality resulting from this
advancedprostate cancer state, ADT is also initiated
in some higher risk prostate cancer patients with
asymptomatic metastases, prostate-specific antigen
(PSA) recurrence after localized therapy, concurrent
therapy with external beam radiotherapy, and/or
patientswithnodaldiseaseafterradicalprostatectomy,
Figure 1.
11
Therapies for prostate cancer that are appropriate
during one disease state may not necessarily be
extrapolated to other disease states. As a limiting
factor, the phase III IADT literature often includes
heterogeneous cohorts comprised of prostate cancer
patients inmultiplediseasestates. Additionally, there
is an uncertain indication for many trial patients to
receive any form of ADT. This blanket approach,
compoundedby thepublicationofmeta-analyses,
12,13
does not always lend itself to clinically applicable
results. Multiple systematic reviews
6,12,13
thoroughly
describe and tabulate the results of these phase
III studies of IADT versus CADT; however, this is
beyond the scopeof this review. Instead,weprovide
suggestions for clinical practice based on a critical
analysisof the IADT literatureasorganizedbydisease
state, with consideration as to whether any form of
ADT is indicatedat all.
Primary therapy for non-metastatic (M0)
prostate cancer
Local therapy is the standard of care for patients
withnon-metastatic (M0) prostate cancer that arenot
candidates for active surveillance.
14
However, given
the high rates of inappropriate PSA screening,
15
a
number of patients diagnosed with prostate cancer
areoften toooldorcomorbid tobecandidates for local
therapy. In thesepatients, adiscussionabout starting
ADT is warranted when the risk of 5 year prostate
cancermortality ishigh.
This indication issupportedbyarecentlypublished
update of the European Organisation for Research
and Treatment of Cancer (EORTC) Genitourinary
CancersGroup30891trial
16
whichrandomizedpatients
unsuitable or unwilling to have local therapy for
prostatecancerstageT0-4,N0-2,andM0 to immediate
ADT (n=492) ordeferredADT (n=493). Only5%of
patients hadknownnodalmetastases. Patientswere
followedforamedianof12.8yearswith78%ofpatients
dyingduring thestudy, including35%ofdeaths from
prostate cancer and33% from cardiovasculardisease.
Therapy was started in the deferred arm for new
symptomatic metastases, metastases resulting in
impending fractureor cordcompression,pain related
toprostatecancer,deterioration inperformancestatus,
and/oruretericobstruction. Only55%of all patients
allocated to receivedeferredADTultimately received
ADT and, on average, deferred ADT required 31%
of the total ADT treatment time of immediate ADT.
DeferredADT was worse than immediate ADT for
time tofirst objectivediseaseprogression (defined as
metastasesoruretericobstruction,10yearprogression
rates 42%versus 30%, p< 0.0001). Time to castration
resistant disease ADT did not differ significantly
between groups (p = 0.42). Overall prostate cancer
mortality did not differ significantly (10 year death
rate of 25% versus 23%; for early and deferredADT
respectively), but overall survival was superior
with immediate ADT (HR = 1.21, 95% CI 1.05-1.39,
p = 0.0085). The authors attributed the decreased
survival in thedeferredADTgroup to a significantly
higher number of prostate cancer related deaths on
deferredADTduring years 3-5 after diagnosis. PSA
doubling time < 12 months served as a significant
prognostic indicatorofearlyprostatecancerdeathwith
a 3.4-fold increased risk of dying of prostate cancer
with a PSAdoubling time less than 12monthswhen
compared to more than 24 months (21.0% at 5 year
mortality and 46% 10yearmortality).
The EORTC 30891 trial built upon previous trials
such as the Veterans’ Administration Cooperative
Urological ResearchGroup (VACURG) trial,
17
which
showed less progression in early ADT arms but no
overall survivalbenefit toearlyADT. TheVACURG2
trial
2
suggesteda survival benefit inpatients less than
age 75 started on earlyADT for high grade tumors.
Finally, the BritishMedical ResearchCouncil (MRC)
trial
18
of early versus deferred ADT suggested that
delayedADTwas associatedwithmore progression,
complications, symptoms, and prostate cancer
mortality—although there was no overall survival
benefit in the final analysis.
16
The EORTC 30891,
VACURG 2, and the British MRC trials can all be
criticizeddue to inconsistent followupresulting inan
insufficientnumberofpatientswhoreceived deferred
ADT before prostate cancer mortality, bringing into
questionwhether these trialsassessedearly versusno
ADT insteadof earlyversusdelayedADT.
19
Taken together, these trials suggest thatADTmay
reasonably be delayed in patients ineligible for local
therapyprovided thatpatientsare followedclosely for
disease progression. EarlyADT ismost beneficial in
patientswithmoreaggressivediseasewhoare likely to
30
Intermittent androgen deprivation therapy for prostate cancer: translating randomized controlled trials into
clinical practice
