©TheCanadian Journal ofUrology™: International Supplement, April 2014
regression demonstrated that men older than age 75
were less likely toreturn topre-treatment testosterone
level thanmenunder age 75. Trial participantswere
on treatment 27% of the time. The PR7 trial authors
assessed HRQOL by using a combined analysis of
responses to these questionnaires at multiple fixed
timepoints in thefirst 5yearsof treatment. Although
differences in functional HRQOL scores (physical,
role, and global health) were not significant, IADT
demonstrated improvements in hot flushes, desire
for sexual activity, urinary symptoms and a trend
towards improvement in the levelof fatigue (p=0.07).
The functionalHRQOLdata in this trial isdifficult to
interpretbecause the trialwasnotblindedandHRQOL
questionnaireswereadministeredatfixed timepoints,
regardless of whether IADT patients were on or off
treatment.
The other smaller RCTs previously noted also
generally supported improved symptomatology and
sexual function during IAD. TheHRQOL scores did
not differ between groups in SEUG 9901,
20
although
symptomatologywas less frequently reported. In the
FinnProstate
29
study, HRQOL scores were generally
better in the IADTgroup in termsofactivity limitation,
physical capacity and sexual functioning. In the Tap
22 study,
26
which included only metastatic patients,
HRQOLscoresdidnotdifferbetweengroups,although
rates of hot flushes and headache were lower in the
IADT group. Therewas a trend towards lower rates
ofhotflushes in theTULP trial.
23
Improvements inhot
flushes and erectile function were also suggested by
deLeval et al.
24
Long term complications ofADT
Sensitive measures of bone health outcomes were
not incorporated into available phase III trials.
Nonetheless, the trialsdid reportadverseevents, and
fracture rates did not tend to differ. Retrospective
datadoessupport lesserbonemineraldensity (BMD)
declinesduringoff-treatment periods and correlates
with testosterone recovery.
30,31
A recentlypublished
prospective trial analyzed the BMD declines of
56 patients on IADT without metastatic disease.
32
Patients hadDEXAscans at baseline and at the start
of on- and off-treatment periods. Testosterone and
PSA levels weremeasuredmonthly throughout the
studyperiod. Thefindingsof this trialdemonstrated
significant heterogeneity of DEXA findings but
supported a decline in spine and hipBMD after the
first ADT cycle and an increase in spine BMD after
thefirst off-treatment cycle. Additionally, change in
both spine and hip BMD positively correlatedwith
testosterone levels. One post-traumatic fracture
was sustained in a patientwithnormal BMD after a
median 5.5 years follow up. This phase II trial was
underpowered for the study of BMD and fractures,
but does support the hypothesis that IADT may
attenuate ADT-related bone loss and perhaps
resultant fractures. Because testosterone recovery
and off-treatment intervals are greatest when IADT
is applied for non-metastatic low risk disease, if
ADT is tobeemployedat all, thisbeneficial effect on
bone healthmay be particularly significant in these
patients. However, IADTmay result inan increase in
skeletal-related events inmetastatic patients should
treatment not be resumed early enough. Ultimately,
bone health in the ADT population may be more
readily improved by basic interventions such as
periodicDEXAscans,mitigatingaggravating life-style
behaviors, calcium andvitaminD supplementation,
and treating osteoporotic or osteopenic patients,
all of which are largely underutilized by surveyed
Canadianpractitioners.
33
AlthoughADT promotes cardiovascular disease,
11
conflictingevidenceexistsforitseffectsoncardiovascular
death.
34
The use of GnRH antagonists instead of
agonists may have a beneficial impact on 1 year
cardiovascular events.
35
Highqualitydataare lacking
tosupport theeffectof IADToncardiovascularhealth.
InadverseeventreportingforpublishedphaseIIItrials,
cardiovascular events did not significantly differ; but
thesetrialswereunderpoweredfortheseoutcomesand
did not describe cardiovascular risk demographics of
includedpatients. Inparticular, both the SWOG 9346
andPR7trialsdidnotfinddifferences incardiovascular
events.
21,22
In theSEUG9901 trial,
20
therewere107/462
(23.2%) cardiovasculardeaths in the IADTarmversus
122/456 (26.8%) in theCADT arm, but this difference
was not significant. Benefits of IADT on other long
term effects ofADT,
11
likemood, cognition,metabolic
syndrome, acute kidney injury,
36
anemia, and stroke
arealsouncertain.
Summary and clinical protocol
Survival-related outcomes for IADT have been
compared to CADT in a number of recent phase
III trials. Local therapy or active surveillance are
the standards of care for patients withM0 prostate
cancer,
14
while watchful waiting with deferredADT
is appropriate for select patients with reduced life
expectancy. IfearlyprimaryADT is tobeadministered
due to higher risk prostate cancer in a patient with
a reduced life expectancy, caution is warranted in
administering IADT. Higher risk prostate cancer
33
DasonETAL.
