©TheCanadian Journal ofUrology™: International Supplement, April 2014
die fromprostatecancerorexperienceprostatecancer
relatedmorbiditywithin their remainingyears.
The most relevant IADT trial within this disease
state is the South European Uroncological Group
(SEUG) 9901 trial which excluded patients with
prior local therapy and was comprised of 89%M0
patients.
20
A total of 918patientswere randomized to
continuous or intermittent therapy with triptoreline
andcyproteroneacetate. Ata66monthmedian follow
up, 525 (57.2%) of the patients had died. Therewas
no difference in overall survival with IADT versus
CADT (HR0.90, 95%CI 0.76-1.07–1.21 threshold for
non-inferiority).
20
Thehazardratio forprostatecancer
mortalitywasnot significantly increasedwith IADT.
Despite thesestatisticalfindings, it isuncertainhow
clinicallyrelevantSEUG9901 isbecausemanypatients
in this trialwould likelynothavebenefitted fromany
form of ADT. Approximately, 40% of patients had
Gleasongrade 6or lessprostate cancer andover 50%
had a PSAof less than 1. This trialwas not enriched
with high risk patients, with only 18% of patients
dying fromprostate cancer between the two groups.
Given such limitations, caution is still warranted in
using IADTasprimary therapy inpatientswithmore
aggressivedisease.
Biochemicalrecurrenceafterprimary therapy
Thereisapaucityofhighqualityevidencetoguidewhich
patients should receive ADT following biochemical
relapseafterprimarytherapywhenthere isnoevidence
of metastatic disease on imaging. Variables that are
thought to bemost important in this decision include
PSAdoubling timeandGleason score, as theseare felt
tobestpredict time tometastasesanddeath.
The PR7
21
trial investigated whether IADT was
non-inferior to CADT in patients who had recurred
biochemicallyafterradiotherapy. PatientswithaPSA
level of 3ng/mLmore than1year after radiotherapy
forprostatecancerandnoevidenceofmetastaseswere
eligible for inclusion. Survivalofpatients in the IADT
groupwas8.8years (n=690)versus9.1 (n=696)years
in the CADT group (HR for death 1.02, 95%CI 0.86-
1.21). The trialwas stoppedafternon-inferiority (HR
< 1.25) was demonstrated at a pre-planned analysis
and 524 deaths were reached (37.8%). The authors
concluded that IADTwasnon-inferiorbecause theHR
for deathwas less than 1.25 and the pvalue for non-
inferiority (HR<1.25)equaled0.009. In this trial, 59%
ofdeathswereunrelatedtoprostatecancerandthusthe
authors retrospectivelyanalyzed thedata fordisease-
specificsurvival. Theydemonstratedanon-significant
increasedhazardratioanda7yearcumulativeprostate
cancer disease-related death rate of 18% and 15% in
the IADT andCADT groups, respectively (p= 0.24).
Time toCRPCwas slightly longer in the IADTgroup,
but the authors acknowledged that this was related
to systematic biases in howCRPCwas diagnosed in
IADTversusCADTgroups.
The PR7 trial
21
had a number of limitations in its
follow up andmethodology. The study group only
included patients in an early clinical state of disease
with a median follow up of only 6.9 years. In the
National Cancer Institute’s SWOG 9346,
22
a trial
conducted on patients withmore advanced prostate
cancer, survival curvesonlystarted toseparateafter5
yearsand90%ofpatientshaddiedafternearly10years
of followup. In thePR7 trial, the IADTsurvival curve
appears to separate fromCADT after approximately
9 years—without further follow up and reporting of
deathevents, it isuncertainwhether this trendwould
havecontinued. Additionally,althoughnon-inferiority
wasdemonstratedbythetrialstandards, itwasdefined
liberallywitha1.8year reduction inmedian survival
required for inferiority.
22
The PR7 trial
21
was also limited because its study
populationwascomprisedof lowerriskpatients.Used
as a surrogate of PSA doubling time— at baseline,
78.3%ofallpatientsenrolled in the trialhad>3years’
time since their radiotherapy. Furthermore, Gleason
gradedistributionwas2-6 in42.6%, 7 in33.0%, 8-10 in
15.2%andunavailable in9.2%. PatientswithGleason
score 8-10 disease had a 14 month poorer median
survival with IADT. This poorer survival was not
significant, but thiswas anunderpowered subgroup.
The conclusion of the PR7 trial that IADT is non-
inferior to CADT is thus limited to a population at
lower risk of prostate cancer metastases and death.
In this population, the benefit of any form of early
ADT isuncertain. ThePR7 trialwasnotappropriately
designed toprovidesignificantconclusionsregarding
patients most likely to experience morbidity or
mortality from prostate cancer—such as those with
short PSA doubling times and high initial Gleason
scores. Given the limitations of this trial, IADTmust
beapproachedwithcaution innon-metastaticpatients
at riskof rapiddiseaseprogression.
Metastaticdisease
For patients with metastatic disease—either on
presentationor afterprimary therapy—SWOG9346
22
failed to demonstrate non-inferiority of IADT. At a
median followupof9.8years,over90%of thepatients
haddied. Survival was 5.1 years in the IADT group
(n=770) and5.8years in theCADTgroup (n=765)—
31
DasonETAL.
