©TheCanadian Journal ofUrology™: International Supplement, April 2014
and pathologic outcomes. A recent meta-analysis
examined10studiescomparingradicalprostatectomy
alone to neoadjuvant ADT followed by radical
prostatectomy.
21
Overall, patients generally had T1-
T3diseasewithandwithout evidenceof lymphnode
involvement, although themajorityofpatientsacross
the studies were T1 and T2. Three of ten studies
usedanLHRHagonist alone, and seven studiesused
CAB. Overall survivalwasnot significantlydifferent
between the two groups. Studies did demonstrate
reducedpositivemarginrates (p<0.00001), improved
ratesoforganconfinement (p<0.0001)anddecreased
lymph-node invasion (p < 0.02) when compared to
radical prostatectomy alone. Longer durations (6 or
8months) ofneoadjuvantADTversus shorterones (3
months) improved pathologic outcomes. Currently,
neoadjuvantADT isnotrecommendedpriortosurgery.
In theadjuvant settingafter radicalprostatectomy,
Messing et al looked at 98menwith positive pelvic
lymph nodes found at time of surgery. These
patients were randomized to either immediateADT
or observation. After amedian followup 11.9 years,
improvements in overall survival, cancer-specific
survival and progression-free survival were noted
in patients who received immediate lifelong ADT.
22
Conversely, Iversen et al noted that in men with
localized disease, adjuvant ADT (bicalutamide 150
mg daily) after primary therapy demonstrated no
additional benefit over those who received primary
therapy alone.
23
SWOG S9921 randomized 983men
with high risk features at prostatectomy (any of the
following: Gleason ≥ 8, preoperative PSA > 15 ng/
mL, stageT3borgreater,N1disease, positivemargin,
orGleason7plusPSA>10ng/mL) toeitheradjuvant
ADT (goserelin plus bicalutamide) or adjuvantADT
plus mitoxantrone chemotherapy. Final treatment
comparisons are not due to be reported until 2017.
24
For now, standard of care remains adjuvant RT in
patients with these high risk features after radical
prostatectomy. Basedon theMessingdata, however,
adjuvant ADT does show benefit in patients with
positive lymphnodes at timeof surgery.
22
Withregardstopatientsreceivingprimaryradiation
therapy, there are a multitude of studies examining
patient selection (low versus intermediate versus
high risk disease), duration of therapy (6 months
versus3years), timingof therapy (neoadjuvantversus
adjuvant). Bolla et al first demonstrated benefit to
adjuvantADT for3years inmenundergoingprimary
radiation therapy.
25
The most recent follow up
data shows a striking difference in overall survival
between thosewho received radiation alone (39.8%)
versus radiation plusADT (58.1%). Themajority of
patientshadT3disease, and thecombination therapy
arm overall survival hazard ratio was 0.60 (95% CI
0.45-0.80, p=0.0004).
26
Other important studieshave
clarified other important points: adjuvant ADT does
not benefit patientswith low risk, localizeddisease;
27
intermediate risk localized prostate cancer patients
dowellwith shorter durationofADT (4-6months);
28
and,highriskpatientsbenefit from longer treatment (3
years).
29
Anotherstudyshowednodifferencebetween
progression-free survival in patients undergoing
radiotherapy who received neoadjuvant versus
adjuvantADT.
30
Continuous versus intermittentADT
Another strategyofADTadministration comes in the
formof“drugholidays”whereinpatientsallowserum
testosterone or PSA levels to recover and then repeat
administration. Thebasis for such treatment evolved
from the idea that if the time hormone-sensitive
prostate cancer spent in an androgen-deficient state
weredrawnout, the time tocastrationresistantdisease
couldbeprolonged, improvingpatientoutcomes.
31
In
vitromodels further showed that hormone-sensitive
cellsundergo repeatedboutsof apoptosis in response
to cyclic androgen deprivation.
32
Mouse models
furtherdemonstratedthatthiscyclicactivityprolonged
the time toacastrationresistantdiseasestate.
33,34
Other
hypothesized benefits include improved quality-
of-life, improved costs, and fewer adverse events
associatedwithADT.
Aphase III trial was conducted that randomized
menwhohadpreviouslyundergoneprimary therapy
(radical prostatectomy or radiotherapy) to either
continuous ADT (LHRH agonist with concomitant
non-steroidal antiandrogen) or intermittent ADT (8
month treatment cycles, non-treatment cycle began
after 8 months if there was no evidence of disease
progression and PSAwas < 4 ng/mL). On-therapy
cycle resumedwhen the PSA rose to 10 ng/mL. The
primary endpoint was overall survival. A total of
1,386 patients were randomized. The hazard ratio
for death in the intermittent armwas 1.03 (95% CI
0.86-1.23), indicating no significant advantage. With
regards tonon-inferiorityof the intermittent strategy,
the p valuewas 0.01.
35
Although non-inferior, many
questions with regards to intermittent ADT remain
unanswered with respect to treatment schedules
(PSA-based, calendar-based, or testosterone-based)
andquality-of-lifeoutcomes.
A second trial byHussain et al recently reported
results in 2013, randomizing men with newly
diagnosed, metastatic, hormone-sensitive prostate
16
Traditional androgen ablation approaches to advancedprostate cancer: new insights
