E U R O P E A N U R O L O G Y 6 3 ( 2 0 1 3 ) 5 0 4 – 5 0 5

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Platinum Priority – EditorialReferring to the article published on pp. 496–503 of this issue

OnabotulinumtoxinA in Benign Prostatic Hyperplasia

Prokar Dasgupta *

Medical Research Council (MRC) Centre for Transplantation, Department of Urology, Guy’s Hospital, King’s College London, London, UK

It is not often that the most poisonous substance known to

man, in the right doses, becomes a magic cure for many

varied conditions. The last 15 yr have been very exciting for

botulinum toxicologists, particularly in the management of

the overactive bladder (OAB). Having been used on a

named-patient basis as a second-line treatment for

neurogenic detrusor overactivity (NDO) [1], onabotulinum-

toxinA has received a license for this purpose in a number of

countries. A similar license for idiopathic detrusor overac-

tivity (IDO) is surely not far away and this will truly be a

landmark.

A recent, randomised, double blind, placebo controlled

trial compared oral anticholinergics (solifencin and tros-

pium) to onabotulinumtoxinA in women with idioathic

urgency incontinence [2]. While the reduction in frequency

was similar between groups, complete resolution of urgency

incontinence was more likely in the onabotulinumtoxinA

group. These patients also had less dry mouth, but more

transient retention and urinary tract infections [2].

It is not surprising that the prostate would prove to be

another target organ for investigating the effects of

onabotulinumtoxinA, being close to the bladder and

becoming a problematic gland in so many older men.

Herein lies the difference: We urologists have learned the

hard way that, for benign prostatic hyperplasia (BPH), what

may look promising today may not be durable in the future.

We have seen numerous minimally invasive challengers to

transurethral resection of the prostate (TURP) come and go;

technologies and their supporting companies either flourish

or vanish into oblivion.

A role for onabotulinumtoxinA in BPH was proposed

following the increasing evidence that the pathophysiology

of this disorder might relate to neural dysregulation within

the prostate. The prostatic epithelium receives cholinergic

DOI of original article: http://dx.doi.org/10.1016/j.eururo.2012.10.005.* Medical Research Council Centre for Transplantation, King’s College LondFax: +44 (0)20 71886787.E-mail address: prokarurol@gmail.com.

0302-2838/$ – see back matter # 2012 European Association of Urology. Phttp://dx.doi.org/10.1016/j.eururo.2012.10.051

innervation and the stroma receives predominantly norad-

renergic innervation. Doggweiler et al., in 1998, were perhaps

the first to investigate the role of botulinum toxin in BPH [3].

They examined the effect of intraprostatic injection in 30 rats

and reported that a 5-U dose resulted in a 44% reduction in

prostate weight. A further reduction was obtained with serial

injections of 2 U or 3 U of the toxin, resulting in a 73%

reduction in prostate weight. Histologic analysis revealed

selective denervation of the prostate, with apoptosis and

generalised atrophy of the gland. These results were

reproduced in a randomised, controlled study in a canine

model, showing prostatic atrophy and increased apoptosis,

thus providing the impetus for human clinical trials [3].

Maria et al. [4] conducted a randomised, placebo-

controlled trial of onabotulinumtoxinA in 30 men with

BPH, and noted that injection with 200 U reduced the

prostatic volume by one-half at 1 mo and by one-third at

2 mo. The benefit was most notable in patients with larger

prostates. However, the effect was not limited solely to large

prostates, as Chuang et al. [5] reported therapeutic benefit in

a smaller group of 16 men with BPH refractory to treatment

with an a blocker and with prostate volumes of <30 ml.

This issue of the Platinum Journal reports the largest,

randomised, international trial of onabotulinumtoxinA in

BPH comparing placebo versus 100-U, 200-U, and 300-U

doses [6]. The follow-up extends to 72 wk, which is a

reflection of previous lessons learned about durability of

therapies for BPH. Significant improvements from baseline

in International Prostate Symptom Score (IPSS), maximum

flow rate, and total prostate and transitional-zone volumes

occurred in all groups at 12 wk with no intergroup

differences. The placebo effect (normal saline in this study)

was pronounced. In a post hoc analysis, not originally

planned, a significant reduction in IPSS versus placebo was

on, Guy’s Hospital, London SE1 9RT, UK. Tel. +44 (0)20 71886796;

ublished by Elsevier B.V. All rights reserved.

E U R O P E A N U R O L O G Y 6 3 ( 2 0 1 3 ) 5 0 4 – 5 0 5 505

observed in the 200-U arm in patients who had previously

used a blockers [6]. This synegistic effect will have to be

confirmed or refuted in a separate trial, which may also

include men treated with 5a-reductase inhibitors or

combination therapy. As evidence emerges about the role

of phosphodiesterase type 5 inhibitors in BPH, patients on

these agents could also form another arm of such a study.

There appear to have been a couple of protocol

amendments that are subsequently discussed as limitations

[6]. First, after 63 patients, the route of injection was

changed from transperineal to transrectal. Second, the

volume of injections was changed from 20% of the total

prostate volume to 12%, which amounted to a total of

4–9 ml. All three routes—transrectal, transperineal, and

transurethral—have previously been reported in the litera-

ture and perhaps a standardisation of technique and

injected volume should have been agreed on across sites

prior to the start of the study.

Based on these results, it is unlikely that onabotulinum-

toxinA will be a viable alternative to existing and emerging

oral medications for patients with moderate lower urinary

tract symptoms secondary to BPH. Furthermore, it failed to

show promise in unfit patients with urinary retention who

underwent a trial of voiding without catheterisation. The

improvements in flow rate with onabotulinumtoxinA are

modest and unlikely to replace TURP or laser prostatectomy

in those needing surgery. Thus, what seemed promising in

smaller initial studies has suffered at the hands of the

placebo/saline effect.

This is a good example of adherence to the Innovation,

Development, Exploration, Assessment, Long-term follow-up

(IDEAL) principles. I congratulate the authors and the

manufacturers for boldly reporting a negative study.

Conflicts of interest: The author acknowledges support from the UK

Department of Health via the National Institute for Health Research

(NIHR) comprehensive Biomedical Research Centre award to Guy’s & St

Thomas’ NHS Foundation Trust in partnership with King’s College

London and King’s College Hospital NHS Foundation Trust. He also

acknowledges support from the MRC Centre for Transplantation and

King’s Health Partners.

References

[1] Kalsi V, Apostolidis A, Gonzales G, Elneil S, Dasgupta P, Fowler CJ.

Early effect on the overactive bladder symptoms following botu-

linum neurotoxin type A injections for detrusor overactivity. Eur

Urol 2008;54:181–7.

[2] Visco AG, Brubaker L, Richter HE, et al. Anticholinergic therapy vs.

onabotulinumtoxinA for urgency urinary incontinence. N Engl J

Med 2012;367:1803–13.

[3] Goldstraw MA, Kirby RS, Dasgupta P. The role of botulinum toxin in

benign prostatic hyperplasia. BJU Int 2006;98:1147–8.

[4] Maria G, Brisinda G, Civello IM, Bentivoglio AR, Sganga G, Albanese A.

Relief by botulinum toxin of voiding dysfunction due to benign

prostatic hyperplasia: results of a randomized, placebo-controlled

study. Urology 2003;62:259–64.

[5] Chuang YC, Chiang PH, Huang CC, Yoshimura N, Chancellor MB.

Botulinum toxin type A improves benign prostatic hyperplasia

symptoms in patients with small prostates. Urology 2005;66:

775–9.

[6] Marberger M, Chartier-Kastler E, Egerdie B, et al. A randomized

double-blind placebo-controlled phase 2 dose-ranging study of

onabotulinumtoxinA in men with benign prostatic hyperplasia.

Eur Urol 2013;63:496–503.