©TheCanadian Journal ofUrology™: International Supplement, April 2014
with ahazard ratio for deathwith IADTof 1.10 (90%
CI 0.99-1.23). Prostate cancer accounted for 73% of
deaths in the CADT group and 80% of deaths in the
IADT group. This trial was designed such that a
median survival decrease of 7 months in the IADT
groupwasconsidered inferior. Thisrequired theupper
limitof the90%confidence interval tobe less than1.20
for non-inferiority, a condition that was not reached.
Because the lower limit of the confidence interval
included 1.0, IADT was not significantly inferior to
CADT. Thismakes the trial statistically inconclusive,
withneither thenon-inferioritynor inferiorityof IADT
beingdemonstrated.
The SWOG 9346 trial performed a number of
stratifications—the most interesting of which was
extensive (disease in ribs, longbones,visceralorgans)
versus minimal disease (disease confined to spine,
pelvic bones or lymph nodes). Survival with IADT
versus CADTwas 4.9 years versus 4.4 years (HR of
1.02, 95%CI 0.85-1.22) in theextensivediseasegroup.
However inpatientswith limiteddisease, survivalwas
5.4years in the IADTgroupand6.9years in theCADT
group (HRof 1.19, 95%CI 0.98-1.43). Althoughagain
statistically inconclusive—thesefindingssuggest that
caution iswarranted inadministering IADT for those
withminimalmetastaticdisease.
Smallerstudieswith lowprostatecancermortality,
mixed populations, less rigorous methodology, and
shorter follow up have generally demonstrated
equivalencyof IADTandCADT. Since thepublication
ofSWOG9346, these trialsmaybeviewedasbeing less
significant andmay therefore serveonly to confound
ameta-analysis.
6,23-26
In summary, SWOG 9346was a high quality non-
inferiority trialon IADTversusCADT inpatientswith
metastaticdiseasewhichwasstatistically inconclusive.
IADTwasn’t found to be non-inferior to CADT; but
conversely, CADTwas not superior to IADT. Given
theseinconclusivefindings,CADTremainsthestandard
of care in treatmentofpatientswithmetastaticdisease.
Castration related symptoms and health
relatedquality-of-life
Improvement in ADT-related symptomatology
correlates with recovery of testosterone during off-
treatment cycleswhich isdependent on age, baseline
testosterone,numberofADTcycles, ethnicity, and the
duration of induction period and length of the off-
treatmentperiod.
27
DuringADT, routine testosterone
measurement is currently recommended to evaluate
ADT effectiveness
28
and diagnose progression to
CRPC. It is also important to measure testosterone
during IADT todocument returnof gonadal function
and assesswhether IADT is providing actual clinical
benefit. If testosterone and symptomatic benefits
are not recovered after the initial off-treatment
cycles, they are less likely to return in shorter later
cycles.
26
Understandingwhich patients will recover
testosterone during the off-treatment periods is
important in thedecision to select IADT, particularly
when employing IADT formetastatic disease, where
off-treatment time isshorter (53% inSWOG9346
22
trial
versus 73% in thePR7
21
trial).
Phase III studies of IADThave confirmedpatient-
reported improvement incastrationrelatedsymptoms
during off-treatment periods as testosterone rises.
Overall,studyresultshaveshown thaterectilefunction
and libidoconsistently improvedduringoff-treatment
periods. Hot flushes, fatigue, and headaches are
also found to improve during off-treatment periods.
Results concerning overall HRQOL improvements,
generally measured in these trials by the multi-
domain EORTC QLQ-30 questionnaire, were mixed
and may relate to differences in measurement time
points and in particular, blinding. Additionally,
HRQOLmeasurement was performed with metrics
not validated in this population. Unfortunately,
differences in the methodology of collecting and
reportingsymptomandHRQOL-relateddataamongst
phase III trials generally precludedmeta-analysis of
these outcomes, except for a meta-analysis of three
smaller trials that reported reporting that the risk of
hot flushesduring IADT is lower thanwithCADT.
12
In the SWOG 9346 trial,
22
patients in the IADT
group received therapy for 47% of their ADT
course. Reporting of HRQOL outcomes was at 3, 9
and 15 months after randomization; thereby only
encompassing the first cycle off therapy. For this
trial,HRQOLwasdivided intofivedomains—erectile
dysfunction (ED), libido, vitality, mental health
and physical functioning. Mental health, ED, and
libidowere improved at 3 and 9months, vitalitywas
improved at 9months only andphysical functioning
was improved at 9 and 15months. This equalization
ofHRQOLscoresover time is inkeepingwith the fact
thatby the timeof the15monthanalysis,78%ofmen in
the IADTgrouphad resumed therapy, supporting the
HRQOLbenefitof IADTduringoff-treatmentperiods.
HRQOLmeasurement in this trialwas limitedbya lack
of blindingand the fact that that testosteronewasnot
measured and correlated toHRQOL scores.
In the PR7 study,
21
35% of patients had recovery
of testosterone to pretreatment levels and 79% had
a level of at least 5 nmol/L (144 ng/dL) by 2 years
after completing the first period of treatment. Cox
32
Intermittent androgen deprivation therapy for prostate cancer: translating randomized controlled trials into
clinical practice
