©TheCanadian Journal ofUrology™: International Supplement, April 2014
cancer to either continuous or intermittent therapy.
36
Intermittent dosing schedule was similar except
the PSA-based schedule was set at 20 ng/mL
before restarting ADT (or above 10 ng/mL at the
investigator’s discretion). Total time spent on
protocol was 19 and 17 months for the intermittent
andcontinuousarms, respectively. Patients receiving
intermittent therapy spent 47% of time on ADT.
Median overall survival was 5.7 years (intermittent)
versus 6.4years (continuous) after enrollment,witha
hazard ratio for death in the intermittent arm of 1.10
(90%CI0.99-1.23). Withrespect tonon-inferiority, the
study couldnot rule out a 20% chance of greater risk
of death with intermittent therapy. This study did
demonstrate intermittent therapypatientsexperienced
better erectile function andmental health (p < 0.001
andp=0.003, respectively) atmonth3butnot at later
timepoints.
More such trials to answer questions of different
schedulesareneeded to fullyelucidate themeaningof
thesetwolargerandomizedcontrolledtrials. Infact,one
study thatexamineddifferentdosingschedulednoted
testosterone-baseddosingcarriedasignificantly lower
risk of PSAprogression (hazard ratio 0.65; p < 0.02)
as compared to continuousdosing.
37
Disadvantages of LHRH agonists
AlthoughLHRHagonistshavebeenextremelysuccessful
in treating various prostate cancer disease states, they
dopossess some disadvantages and side effects. With
regards todisadvantages, LHRH agonistswill initially
causestimulationof theanteriorpituitary, leading toan
initial burst of LH release and subsequent testosterone
flare in all patients. For about 10%, this clinical flare
phenomenoncanmanifestitselfsymptomaticallyasacute
spinal cord compression, ureteral/urethral obstruction,
or bone pain. LHRH analogues take about 2-4weeks
to reach castrate levels of testosterone (defined as a
serum testosterone<50ng/dL). Clinicalmanifestation
of testosterone flare can be avoided by adding a non-
steroidal antiandrogen that blocks downstreamAR
activityduring thefirst 4-6weeks.
40
The antiandrogen
doesnotblock the initialflare in testosterone,but rather
blocks signaling activity via AR. Beyond the initial
flare phenomenon, there is evidence to suggest that
microsurgesoccurwithrepeatadministrationsofLHRH
agonists inasmallproportion (around6%)ofpatients.
41
Furthermore, not all patients treated with LHRH
agonistswillachieveacastratelevelofserumtestosterone
of<50ng/dL(3.5%-17%).
41-44
Thedefinitionofcastrate
levels of serum testosterone remains hotly debated.
The current definition of 50 ng/dL is based on the
lower limit of detection for a double-dilution isotope
technique to determine testosterone levels that is no
longer performed.
45
Current liquid chromatography/
tandemmass spectrometry (LC/MS-MS) assays have
amuch lower limit of detection anddemonstrate that
themeanserum testosterone levelachievedwitheither
surgical or medical ADT approaches 15 ng/dL.
42
As
such, expertshaveargued that the cut off bemoved to
20ng/dL.
8
If thisdefinitionwereused,up to13%-37%
of patients onLHRH agonist therapymight not have
truly castrate levelsof serum testosterone.
46-48
Therearesuggestionsfromsomeseriesthat inability
to achieve or maintain castrate levels of testosterone
confer patients worse outcomes in terms of overall
survival.Moroteetalexaminedmenwithnon-metastatic
prostate cancer receivingLHRH agonist. Inmenwho
experienced a breakthrough testosterone > 32 ng/dL
duringnormal 3monthchecks,meanprogression-free
survivalwasonly88monthsversus137months inmen
whomaintained serum testosterone levels<32ng/dL
(p<0.003).
49
Another retrospective study found those
withhigher levelsofserum testosteroneafter6months
of ADT had a 1.33-fold increase in cancer-specific
mortality.
50
Alargeretrospectivereviewof2196patients
receiving radiotherapy with LHRH agonists showed
no difference in biochemical-free survival between
thosewho experienced anybreakthrough> 50ng/dL
(73.1%) versus thosewhodidnot (62%, p=0.09). The
subgroup of men who experienced a breakthrough
between32ng/dLand50ng/dLdidshowasignificant
difference inbiochemical-freesurvival (p=0.048). The
authorsnotethatpatientswhobrokethrough50ng/dL
were more likely to have an antiandrogen added to
their regimen as opposed to those who experienced
more mild breakthroughs between 32 ng/dL and
50ng/dL. Theauthorsnote“thesebreakthroughswere
less pronounced and, therefore, either unrecognized
or presumed to be of lesser importance,” perhaps
explaining thesedata.
51
LHRHagonist usehas alsobeennoted to result in
increasedriskofmetabolicsideeffectssuchasdiabetes
and osteoporosis in addition to increased risk of
cardiovasculareventsandstroke.
52-54
Assuch, in2010,
theU.S.FoodandDrugAdministrationmandated that
warnings be added toLHRH agonist labels.
55
LHRH antagonists
To address some of these shortcomings, antagonists
of LHRH receptors have been developed and have
emerged from phase III clinical trials. This class
of medications has the advantage of immediate
downregulation of the anterior pituitary andwould
17
RoveandCrawford
