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

[1]

. 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

tadalafil

[2]

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

[3]

. This was followed by numer-

ous studies (reviewed by Al Shaiji et al.

[2]

) 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.

[4]

, 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.

[5]

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.

References

[1]

Pinkawa M, Gagel B, Piroth MD, et al. Erectile dysfunction after

external beam radiotherapy for prostate cancer. Eur Urol 2009;55:

227–36.

[2]

Al Shaiji TA, Chb M, Brock G. Should penile rehabilitation become

the norm following radical prostatectomy? Can Urol Assoc J 2009;

3:50–3.

EUROPEAN UROLOGY 66 (2014) 593–598

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