Re: Tadalafil for Prevention of Erectile Dysfunction After
Radiotherapy for Prostate Cancer: The Radiation Therapy
Oncology Group [0831] Randomized Clinical Trial
Pisansky TM, Pugh SL, Greenberg RE, et al.
JAMA 2014;311:1300–7
Experts’ summary:
Pisansky et al. are to be commended for their double-blind,
76-site international study examining the use of daily tadalafil
to evaluate the recovery of erectile function after radiation
therapy for prostate cancer (PCa). Men undergoing either
external-beam radiation therapy (EBRT) or brachytherapy
were enrolled and randomized to either the phosphodiesterase
type 5 inhibitor (PDE5-I) tadalafil (5 mg) or placebo. In total,
112 men received tadalafil and 109 received placebos for
24 consecutive weeks commencing 7 d after initiation of radia-
tion treatment. The primary end point was unaided erectile
function 28–30 wk after radiation therapy (4–6 wk following
cessation of the randomized medication). Erectile function was
retained to similar degrees in the study arms at both 6 mo and
12 mo, with no significant differences observed in any sub-
domain of the International Index of Erectile Function.
Experts’ comments:
As with all studies examining erectile function after treatment
for PCa, difficulties are evident in patient selection, given
patients’ preoperative sexual and urinary function as well as
PCa stage and grade, surgery performed, patient adherence to
treatment, and/or amount of radiation administered. Pisansky
et al. have valiantly tried to control for a large number of
variables; however, they were forced to acknowledge several
limitations including substantial patient attrition. Neverthe-
less, the results are interesting and worthy of discussion.
Following treatment, be it surgery or radiation, there is an
immediate insult to erectile function that evokes a continu-
ous decline beyond 1 yr after therapy
. Such ongoing and
progressive damage is the result of a combination of vascular,
neural, and endothelial damage that contributes to periph-
eral nerve damage, corporal hypoxia, and fibrosis due to
persistent flaccidity [1,2]. As demonstrated in human and
rodent models, surgical changes after prostatectomy are
decreased with the use of peri- and postoperative daily
Padma-Nathan et al. performed the first randomized,
placebo-controlled clinical trial that found daily sildenafil
contributed to significant improvements in erectile func-
tion after prostatectomy
. This was followed by numer-
ous studies (reviewed by Al Shaiji et al.
) that highlighted
the benefits of PDE5-Is, alprostadil, the vacuum erection
device (VED), MUSE, intracorporal injection, and combina-
tions thereof in postprostatectomy penile rehabilitation.
However, until the recent papers by Pisansky et al. and
Zelefsky et al.
, no significant studies had been conducted
examining rehabilitation in patients receiving brachyther-
apy or EBRT. Although translating the evidence gained from
the postprostatectomy literature to EBRT is possible, it is
important to consider that the potential mechanisms of
cavernous nerve injury during surgery are different from
those obtained during radiotherapy. Use of PDE5-Is results
in cavernous nerve regeneration following crush injury, as
happens during surgery. However, since the exact nature of
injury following EBRT remains unclear, PDE5-Is may not
have the similar beneficial effects on the cavernous nerves.
Traditionally, elderly men were offered radiotherapy
versus younger men who were offered surgery. As such,
studies into the outcomes of penile rehabilitation following
EBRT were not previously conducted because it was
hypothesized that results would be affected by the
differences in patient age and preoperative function. The
advent of intensity-modulated radiation therapy and
computer-based targeting of the prostate has allowed
younger men to seriously consider EBRT as their primary
form of PCa treatment. Presumably, this would lead to
younger men with improved pretreatment erectile function
being offered EBRT. In this vein, the cohort studied by
Pisansky et al. had a median age of 63 yr, with 68% of the
study population under the age of 65 yr. Given that Pisansky
et al. found that age was the only factor associated with
overall worsening of sexual function over time, this variable
appears to play a significant role in sexual function
outcomes, given these conditions.
PDE5-Is have always been considered the foundation of
many penile rehabilitation protocols. When considering
dosages, Pisansky et al. administered PDE5-Is for 24 wk
(6 mo), a time course that effectively captures declines at
both peak (approximately 2 mo) and plateau (approximately
6–24 mo) in the Sexual Score of the Expanded Prostate
Cancer Index, as documented by Sanda et al.
after EBRT
and brachytherapy. Although it is unclear whether treatment
for a longer duration could have made a difference in the
recovery of erections in the study by Pisansky et al., men in
future studies should be treated for
12 mo to minimize
corporal fibrosis and optimize penile oxygenation through-
out the period of penile hypoxia following EBRT.
Another factor to consider is that Pisansky et al. used
only one agent in their rehabilitation protocol. Although
compliance with PDE5-I use may have contributed to the
high rates of patient attrition in the study by Pisansky et al.,
a multimodality approach (ie, combined PDE5-I, ICI, MUSE,
and VED) may prove to be the most successful, even in men
with radiotherapy. This would be due not only to the
variable effects on penile physiology, decreased fibrosis and
oxygenation, but also to the simple fact that such an intense
regiment would serve to self-select those men who are the
most dedicated in continuing the process.
Conflicts of interest:
Larry I. Lipshultz is a clinical trials participant,
consultant, and speaker for Auxilium and Endo. The other authors have
nothing to disclose.
Pinkawa M, Gagel B, Piroth MD, et al. Erectile dysfunction after
external beam radiotherapy for prostate cancer. Eur Urol 2009;55:
Al Shaiji TA, Chb M, Brock G. Should penile rehabilitation become
the norm following radical prostatectomy? Can Urol Assoc J 2009;
EUROPEAN UROLOGY 66 (2014) 593–598