using TTh in men with CaP. These results confrm
prior reports oF a low rate oF recurrent CaP in men
who receive TTh.
We observed a slight increase in PSA in men on
TTh with high risk CaP, consistent with prior
studies showing slight increases in PSA For several
months aFter TTh initiation in hypogonadal men. In
a randomized, controlled trial oF TTh in 44 men
Marks et al noted this PSA increase in the treatment
and placebo groups.
14
In a study oF 75 hypogonadal
men with or without PIN treated with TTh slight
PSA increases were observed in the PIN positive and
negative groups with only 1 CaP case Found in the
PIN positive group aFter 1 year oF TTh.
15
Supplementary
table
2
(http://jurology.com/
)
shows the literature on TTh in men with CaP.
Previous studies oF the eFfcacy and saFety oF TTh
aFter RT For CaP in a total oF 69 men demonstrated
no BCR and no PSA increases.
8
e
11
In 2007 Sarosdy
evaluated 31 men with CaP treated with brachy-
therapy Followed by TTh.
11
There was a transient
increase in PSA in 1 patient during a median oF
5 years. Subsequently Morales et al evaluated 5
hypogonadal men with localized CaP treated with
EBRT and TTh, and also Found a transient increase
in PSA in 1.
10
Pastuszak et al evaluated a cohort oF
13 men with localized CaP treated with EBRT or
brachytherapy and TTh.
8
The men were Followed a
median oF 2.5 years and only 1 had a transient PSA
increase. In 2014 Balbontin et al reported a series oF
20 men with CaP treated with brachytherapy Fol-
lowed by TTh who were Followed a median oF 2.5
years.
9
They observed a decrease in PSA in the
cohort From 0.07 to 0.01 ng/ml.
Studies in men treated with RP have similarly
demonstrated low rates oF CaP recurrence or pro-
gression with minimal changes in mean PSA at
Followup as long as 12 years.
4
e
6
A retrospective re-
view oF 103 hypogonadal men on TTh and 49 non-
hypogonadal men with a history oF CaP treated with
RP showed a small, statistically signifcant increase
in PSA in the hypogonadal cohort on TTh.
6
There
was lower BCR in that group during the 28-month
Followup compared with that in an untreated com-
parison group. Overall in men treated with RP the
existing literature reveals that CaP recurrences
were reported in only 4 oF 177 patients (2%)
(supplementary table 2, http://jurology.com/
). This
value is lower than published rates oF 6% to 9%
3 years aFter RP and 14% at 5 years.
4,5,7,16
In
addition, even in a study oF 13 hypogonadal men
with CaP who were on TTh and active surveillance
no clinical progression was observed during a me-
dian 2.5 years oF Followup.
12
In our cohort 6 oF 98 (6%) men met BCR criteria.
Notably 3 men with suspected BCR originally un-
derwent brachytherapy with PSA peaking and
subsequently decreasing (table 2). Rather than
representing BCR, this may have been a post-
brachytherapy PSA bounce and was unlikely to be
a direct eFFect oF TTh. When examining outcomes in
the high risk subgroup, 2 oF 11 men (18.2%) met
BCR criteria. Previously reported CaP recurrence
rates Following RT in men who did not undergo TTh
range From 13% to 65% with high risk disease in less
than 10% oF these cohorts.
17,18
ZeleFsky et al Found
that For tumors treated with conFormal radiation
5-year BCR was 35% to 65% among men with a
Gleason sum oF greater than 6 depending on tumor
stage and baseline PSA.
19
Similarly ┬▒ukunaga-
Johnson et al reported 66% 5-year BCR aFter RT
in patients with Gl 8-10 disease and 40% BCR
2 years aFter RT.
20
It is reassuring that rates oF CaP
recurrence in the current study were lower than
reported recurrence rates aFter RT without TTh.
However, we cannot draw defnitive conclusions on
the saFety oF TTh in this setting due to the study
limited sample size, retrospective nature, overall
short Followup and absent eugonadal control group.
The long-standing concern regarding TTh in men
with CaP originated with the seminal 1941 study oF
Huggins and Hodges, which demonstrated regres-
sion oF metastatic CaP Following castration or es-
trogen administration.
21
This led to the androgen
dependent model oF CaP. Although it has been
interpreted to suggest that increasing serum T is
deleterious, this view is not supported by modern
evidence. In a large prospective study in 3,886 men
with CaP and 6,448 age matched controls the CaP
risk was unrelated to the serum androgen concen-
tration.
22
In the placebo arm oF the REDUCE
(Reduction by Dutasteride oF Prostate Cancer
Events) trial in 3,255 men in which participants
underwent prostate biopsies at years 2 and 4 the
CaP risk was also unrelated to the serum T or
dihydrotestosterone concentration.
23
In a meta-
analysis oF 22 randomized, placebo controlled tri-
als in a total oF 2,351 men who were studied up to
36 months the group on T were at no greater risk For
CaP than the men on placebo.
24
The apparent paradox between the prostate eF-
Fects oF ADT and the Failure to identiFy an increased
CaP risk in men with higher serum androgens is
explained by the saturation model, which describes
a fnite ability oF androgens to stimulate CaP
growth.
25
The saturation point appears to be
approximately 250 ng/dl based on evidence From the
TriUS (Testim
├ĺ
Registry in the United States)
trial
26
and a placebo controlled study oF T gel.
27
In
each study PSA increases were Found in men with
baseline T less than 250 ng/dl but not in men with T
greater than 250 ng/dl. A saturation curve was
similarly Found by Rastrelli et al in their population
oF 2,967 men in whom maximal PSA was achieved at
1274
TESTOSTERONE THERAPY AFTER RADIATION THERAPY FOR PROSTATE CANCER