Sustained beneficial effects of intraprostatic botulinum toxin type A on lower urinary tract symptoms and quality of life in men with benign prostatic hyperplasia
Michael B. Chancellor, Suite 700 Kaufmann Building, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA. e-mail: firstname.lastname@example.org
To present a comprehensive experience with intraprostatic botulinum toxin-type A (BoNT-A) injection in men with symptomatic benign prostatic hyperplasia (BPH) and to assess the efficacy on lower urinary tract symptoms (LUTS) and quality of life (QoL).
PATIENTS AND METHODS
In all, 41 men (mean age 69.1 years, sd 7.1 ) with an International Prostate Symptom Score of ≥ 8, peak flow rate of <12 mL/s, and who were refractory to medical treatment were injected with BoNT-A (Botox®, Allergan, Inc., CA, USA) at 100 U (21 men, for prostate volume <30 mL) or 200 U (20, for prostate volume >30 mL) into the prostate transperineally under transrectal ultrasonography guidance. Study exclusion criteria were confirmed or suspected malignancy, previous pelvic surgery or trauma and previous invasive treatment for BPH. The clinical effects were evaluated at baseline and at 1, 3 and 6 months after treatment.
There were no significant local or systemic side-effects in any men. LUTS and QoL indices improved by >30% in 31 of the 41 men (76%), and four of five men with urinary retention for >1 month could void spontaneously at 1 week to 1 month after the BoNT-A injection. In 12 of 41 men (29%) there was no change in prostate volume, yet seven of these men still had a >30% improvement in maximum flow rate, LUTS and QoL. The efficacy was sustained at 12 months.
BoNT-A injected into the prostate is safe and effective for men with symptomatic BPH. The mechanisms of relief of symptoms might not depend totally on the volume shrinkage; the inhibitory effect on the smooth muscle tone and aberrant sensory function might also be important.
Botulinum toxin A
quality of life
maximum urinary flow rate.
BPH is one of the most common conditions affecting aged men. The fundamental aspects of the disease include interactions between prostatic hyperplasia, BOO and LUTS . LUTS associated with BPH include voiding symptoms and storage symptoms, and the degree to which the LUTS bothers the patient and impairs quality of life (QoL) is the key factor for seeking treatment by a urologist.
α1-adrenoceptor antagonists and 5α-reductase inhibitors are the most common therapies used to treat BPH [2,3]. However, both types of drug need daily administration, and some men stop treatment because of side-effects such as postural hypotension, retrograde ejaculation, and impotence. TURP is used when there is no response to medical treatment or when there are BPH-related complications, but concerns have been raised about its safety . Minimally invasive therapies for BPH have been developed for those who respond poorly to medical treatment and are unwilling to have a TURP , or who are at high risk.
The human prostate is innervated by cholinergic and adrenergic efferents, both of which have trophic effects on the prostate glands [4,5]. In addition, the adrenergic innervation is involved in the fibromuscular contraction of prostate and the dynamic component of BPH.
Botulinum toxin type A (BoNT-A), which inhibits acetylcholine release at the presynaptic cholinergic junction, has been injected into the bladder and urethra to treat various voiding dysfunctions . Recent studies showed that BoNT-A can also inhibit other neurotransmitters, including noradrenaline and sensory neurotransmitters [7,8,9]. In the present report, we assessed the safety and efficacy of a single injection of BoNT-A into the prostate to treat LUTS in men with BPH.
PATIENTS AND METHODS
The study was conducted at Chang Gung Memorial Hospital Kaohsiung with the approval of the Institutional Review Board. Informed consent was obtained from all patients. In all, 41 men with symptomatic BPH (mean age 69.1 years, sd 7.1) were enrolled. The men had a complete urological assessment before treatment, including serum PSA level, TRUS and urine analysis. All had an IPSS of ≥ 8, a peak urinary flow rate (Qmax) of <12 mL/s, and history of inadequate response or failure to tolerate α-adrenergic blockers and/or 5α-reductase inhibitors. All had a benign DRE and a PSA level of <4 ng/mL, or a PSA level of 4–10 ng/mL but with a biopsy that showed no malignancy. Study exclusion criteria were confirmed or suspected malignancy, previous pelvic surgery or trauma, and previous invasive treatment for BPH.
Sedation was given i.v. for the first 20 cases, but subsequent procedures were done with no anaesthesia. BoNT-A (Botox®, Allergan, Inc., CA, USA) at 100 U (21 men, for a prostate volume of <30 mL) or 200 U (20 men, for a prostate volume of >30 mL) was injected into the prostate transperineally under TRUS guidance (Figs 1 and 2); 100 U of BoNT-A was dissolved in 4 mL of saline immediately before treatment. One or two injections of equal volume (2 mL) into each lobe of the prostate were given according to the prostate size. Briefly, a 21-G 15- or 20-cm needle was placed in the adapter of the transrectal linear 7.5 MHz endosonic multiplane transducer (Bruel and Kjaer, type 8551); the needle was inserted during transverse scanning and advanced until its tip appeared as a bright spot at the prostate  (Fig. 3). The scanning plane was changed to longitudinal, and the needle was further introduced and confirmed to be within the prostate. Urethral catheter drainage was not used after the procedure, except for men with a chronic indwelling urethral catheter. The men were evaluated before and after treatment for IPSS (0–35), QoL indices (0–6, indicating increasing severity of symptoms and low QoL), Qmax, postvoid residual urine volume detected by ultrasonography, and prostate volume, and the results were evaluated at 1, 3, and 6 months after the procedure. Some men were still willing to attend a follow-up every 3 months thereafter. Quantitative data are expressed as the mean (sem), and statistical comparisons were by Student’s paired t-test, with P < 0.05 considered to indicate statistical significance.
Neither systemic complications, such as respiratory depression or hyposthenia, nor local complications, e.g. gross haematuria, UTI, urinary retention or urethral stricture, occurred after BoNT-A injection. The injection method was safe and simple, and no patient needed narcotic analgesics after the injection. All 41 men had a complete follow-up at 1 month; at 3 months, five men were lost to follow-up; two did not reach the 3-month assessment and three did not respond to treatment. At 6 months, another three men were lost to follow-up. At 12 months, 24 men with a good response to treatment were still being followed.
At 1 month, 31 of 41 men (76%) had a >30% improvement in LUTS and QoL indices. In men treated with 100 U BoNT-A, the mean prostate volume, IPSS, QoL indices were reduced by 15%, 48% and 46%, respectively (all P < 0.001; Table 1), and Qmax was increased by 62% (P < 0.001). The residual urine volume decreased by 44% but this was not statistically significant (P = 0.3); 14 of the 21 men did not have a residual urine volume >60 mL before BoNT-A injection. In men treated with 200 U BoNT-A, the mean prostate volume, symptom score, QoL indices and residual urine volume were reduced by 15%, 51%, 51% (all P < 0.001), and 72% (P = 0.02) respectively (Table 1), and Qmax was increased by 47% (P < 0.001).
Table 1. The baseline characteristics and results at 1, 3, 6 and 12 months in men with BPH treated with 100 or 200 U BoNT-A
|100 U BoNT-A|
| Number of men|| 21||21||19||18||13|
| IPSS|| 18.7 (1.3)|| 9.8 (1.3)*|| 8.1 (1.6)*|| 7.3 (2.0)*|| 9.0 (2.4)*|
| QoL score|| 3.9 (0.3)|| 2.1 (0.3)*|| 2.0 (0.2)*|| 1.4 (0.3)*|| 1.8 (0.4)*|
| Qmax, mL/s|| 7.9 (0.6)||12.0 (0.8)*||12.7 (1.5)*||12.7 (1.1)*||13.4 (0.8)*|
| Residual urine, mL|| 64.2 (23.0)||35.7 (4.4)||24.1 (4.8)*||38.5 (8.4)||40.0 (11.5)|
| Prostate volume, mL|| 21.1 (1.1)||18.0 (1.1)*||18.0 (1.0)*||17.5 (0.9)*||17.0 (1.6)*|
|200 U BoNT-A|
| Number of men|| 20||20||17||15|| 11|
| IPSS|| 19.3 (1.2)|| 9.5 (2.0)*|| 8.3 (2.0)*|| 5.2 (1.1)*|| 8.3 (1.9)*|
| QoL score|| 4.1 (0.2)|| 2.0 (0.3)*|| 2.2 (0.4)*|| 1.8 (0.2)*|| 2.4 (0.6)*|
| Qmax, mL/s|| 7.0 (1.1)||10.3 (1.1)*|| 9.8 (1.1)*|| 11.9 (0.9)*|| 11.1 (0.9)*|
| Residual urine, mL|| 161.7 (48.1)||45.2 (8.2)*||37.6 (5.9)*||45.5 (0.9)*||93.6 (36.1)|
| Prostate volume, mL|| 54.3 (4.7)||46.3 (3.7)*||45.0 (4.2)*||45.3 (4.1)*||47.2 (4.0)*|
The effects of BoNT-A injection appeared maximal at ≈ 1 week after treatment and were maintained at 3 and 6 months. Four of five men with urinary retention for >1 month could void spontaneously from 1 week to 1 month after injection; 12 of 41 men (29%) had no change of prostate volume, but seven of these 12 had a >30% improvement in Qmax, LUTS and QoL.
BPH is common in ageing men, and the goal of therapy is to reduce the associated LUTS and improve QoL. With a dose of 100 or 200 U of BoNT-A injected into the prostate, 31 of 41 men had >30% improvement in LUTS and QoL indices. The effect was prompt, and was maintained for >6 months.
The causes of BPH are unknown, but excessive cellular growth (static component) and fibromuscular contraction (dynamic component) are the main components . The static component is under parasympathetic control and regulated by androgen, while the stromal smooth muscle is sympathetically influenced. The parasympathetic cholinergic innervation of the prostate has an important effect on growth and secretion of the prostate epithelium, while the sympathetic noradrenergic innervation is implicated in smooth muscle contraction and as a cause of BOO accompanying BPH [1,4,5]. In addition, adrenergic neurotransmitters stimulate epidermal growth factor in the prostate, which has been linked to BPH .
Conversely, denervation might reduce the trophic effect and cause glandular atrophy. Sectioning the hypogastric nerve in a rat model causes ipsilateral ventral lobe atrophy , and Chuang et al. reported that chemical denervation using BoNT-A causes down-regulation of α1A-adrenergic receptors, in addition to prostate gland atrophy and apoptosis. Thus, inhibition of acetylcholine and noradrenaline release by BoNT-A might alter the neural control of the prostate and have therapeutic benefits on both the static component and dynamic components of the prostate.
In 2003, Maria et al. reported on intraprostatic BoNT-A injection in men with voiding dysfunction due to BPH. Thirteen of 15 men treated had symptomatic improvement; AUA symptom scores improved from 23.2 to 8.0 (65%), Qmax increased from 8.1 to 16.8 mL/s and prostate volumes decreased from 52.6 to 16.8 mL. Kuo ; reported on 10 men with benign prostatic obstruction (video-urodynamically confirmed) who received a Botox injection (200 U in 20 mL saline) into 10 sites of the transitional zone of the prostate via cystoscopy; the Qmax increased from 7.6 to 9.9 mL/s and the prostate volume decreased from 65.6 to 49.5 mL.
In the present study, in men treated with 200 U of BoNT-A, the prostate volume was reduced from 54.3 to 46.3 mL (15%) and Qmax increased from 7.0 to 10.3 mL/s (47%). In men treated with 100 U BoNT-A, the prostate volume was reduced from 21.1 to 18.0 mL (15%) and Qmax increased from 7.9 to 12.0 mL/s (62%). It appears that intraprostatic BoNT-A injection is effective to a varying degree in relieving the symptoms of BPH. Furthermore, four of five men with urinary retention for >1 month could void spontaneously at 1 week to 1 month after BoNT-A. This result was similar to Kuo’s report of 80% with excellent results in men with chronic urinary retention. Thus prostate injection with BoNT-A seems to be effective for men with benign prostatic obstruction and urinary retention.
BoNT-A induces prostate apoptosis and reduces prostate volume in animals and human [10,13,16]. Interestingly, 12 of 41 men (29%) had no change in prostate volume, yet seven of these still had a >30% improvement in Qmax, LUTS and QoL. The ratio of epithelium to smooth muscle in BPH can vary substantially, from 1 : 3 to 4 : 1 . Thus no one type of drug therapy is expected to be effective in all cases; e.g. a prostate with a large proportion of glandular component might respond to a 5α-reductase inhibitor and reduce in volume, but those with a large proportion of smooth muscle component might respond to α-adrenergic blockers and decrease intraprostatic muscle tone.
The increase in Qmax and improvement of LUTS in seven men with no reduction of prostate volume supports the hypothesis that BoNT-A affects the dynamic component of BPH. A previous study in a capsaicin-induced prostatitis model in rats indicated that intraprostatic BoNT-A injection reduced prostate pain and inflammatory reactions , thus another potential mechanism for BoNT-A effects on reducing LUTS might be through a sensory mechanism.
The present study has some limitations. First, it lacks a placebo control group. However, Maria et al. in a double-blind placebo-controlled study excluded the placebo effect in comparison with BoNT-A. Second, no comparison was made between 100 U and 200 U; this series is too small for this comparison. Further study to assess the dose–response effect, dilution effect, and durability is in progress. Intraprostatic injection therapy for BPH has been used for >100 years with various results from many injectable agents . Most injectants cause coagulative necrosis, followed by shrinkage of prostatic volume and improvements in voiding dysfunction. Previous studies using alcohol for chemo-ablation of prostate tissue were effective in relieving LUTS in men with BPH, but temporary Foley catheter drainage was needed due to focal inflammation and tissue swelling . However, in men treated with BoNT-A, no additional Foley catheter drainage was needed. BoNT-A can be injected into the prostate using transperineal, transurethral or transrectal approaches, depending on the preferences of individual urologists [10,14,15,21]. The transurethral route needs cystoscopy under anaesthesia, but transperineal or transrectal approaches can be used without even local anaesthesia. We prefer transperineal injection under TRUS guidance, to permit definitive visualization of each injection into the prostate.
The transperineal route can be used with no anaesthesia and can avoid the potential complication of UTI by the transurethral or transrectal route. Therapeutic doses have been reported of 100–300 U Botox in different volumes varying of 4–20 mL [10,14,15,21,22]. Different doses, dilution volumes, routes of administration and prostate component might lead to different results . It appears that intraprostatic BoNT-A injection is effective to different degrees in relieving LUTS and improving QoL in men with BPH. To our knowledge there has been no report of local or systemic complications with prostate BoNT-A injection. However, a long-term follow-up is needed to confirm its safety regarding the risk of developing prostate cancer; however, intraprostatic BoNT-A injection induces apoptosis in animals and humans, which might have an anticancer effect.
In conclusion, BoNT-A injected into the prostate is safe and effective for men with symptomatic BPH. The mechanisms of relieving LUTS might not depend only on the volume shrinkage; inhibitory effects on smooth muscle tone and aberrant sensory function might be important. Further evaluations of histology, molecular biology, dose–response characteristics and cost-effectiveness are needed to establish the mechanism and confirm the beneficial effect of BoNT-A.
CONFLICT OF INTEREST
Y.-C. Chuang and M. Chancellor are consultants for Allergan.
The authors report on the positive and sustaining effect (1 year, 24/41 patients) of injection with BoNT-A into the prostate using a transperineal ultrasonography-guided technique.
To our knowledge, this is the sixth published peer-reviewed paper reporting on clinical human use of BoNT-A for treating LUTS and/or acute urinary retention related to BPH (references 10, 14, 15, 21, 22). This paper is one more advocating that BoNT-A might represent a promising treatment of one highly prevalent condition, i.e. symptomatic BPH! However, many questions await proper answers and it is crucial for future investigations to evaluate: sexual function, including erectile function and ejaculation; tolerability of the best route for intraprostatic injection; the best location for intraprostatic injection (bladder neck, transitional zone), etc. According to the principles of evidence-based medicine, the most important issue is probably an accurate evaluation of the placebo effect and the best dosing regimen for the long-term effect, to avoid too many re-injections. The dose is still debatable and published reports are for 100–300 Units BoNT, with variable dilutions. It was fully discussed by the authors and future international double-blind, randomized placebo-controlled studies will be of great interest to start to answer to these questions. Indeed, because BoNT-A intraprostatic therapy might compete with the available pharmacotherapy for treating symptomatic BPH/LUTS, the design of clinical trials evaluating its efficacy, safety and tolerability profile must follow the same rules. No medical therapy has been able to reach the efficacy (according to IPSS and Qmax) that BoNT-A seems to provide. The aim in the next 10 years will be to investigate the place of this treatment (alternative to available oral medical therapies and/or to TURP?), the role of re-injections, effect on prostatic tissue (prevention or risk of prostate carcinoma?) and mechanism of action (efferent and/or afferent denervation, apoptosis, etc.).
The authors must be congratulated in reporting such a preliminary study, giving some hints of the design of mandatory future phase IIA and/or B placebo-controlled multicentre studies. It is also recommended to carefully follow treated patients to determine the natural history and long-term effect of intraprostatic BoNT-A (2 and 5 years) both on symptoms and PSA level. Such early groups will help to determine the role of intraprostatic BoNT-A injection in the options for treating symptomatic BPH. So far the preliminary clinical BPH studies have only been conducted with Botox and not with the other registered BoNT-A types, which will each deserve specific evaluation.
Emmanuel Chartier-Kastler, MD, PhD, FEBU, Professor of Urology, Hôpital de la Pitié-Salpêtrière, Paris, France