REVIEW URRENT C OPINION
Intraprostatic injections for lower urinary tract symptoms treatment Karl-Erik Andersson a,b
Purpose of review The purpose of this study is to review and discuss recently published (2013–2014) experimental and clinical studies of intraprostatic injection therapy as an alternative treatment of lower urinary tract symptoms (LUTS). Recent findings Recent focus has been on intraprostatic injection of botulinum toxin both with regard to mechanism of action and efficacy. In contrast to the promising findings in several previous studies, a recent large, randomized, placebo-controlled trial found no differences between onabotulinumtoxin A treatment and placebo. There is little new information on the use of anhydrous ethanol and agents such as NX-1207 and PRX302, which previously have been reported to have promising effects. Summary Intraprostatic injection of different agents as a minimally invasive surgical therapy for LUTS associated with benign prostatic hyperplasia seems attractive and may have a potential as a treatment alternative, but so far, available results are not convincing. Further studies on the mechanisms of action of novel agents, and controlled clinical trials documenting their efficacy and side-effects when injected into the prostate are needed before their place in the treatment of benign prostatic hyperplasia/LUTS can be properly assessed. Keywords benign prostatic hyperplasia, botulinum toxin, ethanol, male lower urinary tract symptoms, NX-1207, PRX302
INTRODUCTION The management of male lower urinary tract symptoms (LUTS) is still a challenge [1]. Despite a number of new drug treatments, no significant increase in efficacy has been achieved with oral drug monotherapy, and the gains of different combinations have been modest, even if better tolerance to treatment may be obtained [2–4]. When pharmacological therapy fails, surgical treatments are usually considered. Many minimally invasive alternatives have been employed, but the majority of these therapies have failed to achieve the same efficacy as, for example, transurethral resection of the prostate, and have not always been well documented. Intraprostatic injections of different agents to induce prostate involution and symptom relief have recently attracted renewed interest, mostly because of positive reports on the effects of botulinum toxin (BoNT) [5–7,8 ,9]. Most recent developments have focused on the use of BoNT, and below, some of these studies will be discussed. A short summary of previous experiences &&
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of intraprostatic injections of anhydrous ethanol, NX-1207 and PRX302, has also been included.
RATIONALE FOR INTRAPROSTATIC INJECTION The pathophysiology of male LUTS is generally considered to be multifactorial. Even if changes in the bladder and its afferent nerves have been regarded as a main contributor to storage symptoms [10], it cannot be excluded that the prostate is
a
Institute for Regenerative Medicine, Wake Forest University School of Medicine, Department of Urology, Wake Forest Baptist Medical Center, Winston Salem, North Carolina, USA and bAarhus Institute for Advanced Sciences, Aarhus University, Aarhus, Denmark Correspondence to Karl-Erik Andersson, MD, PhD, AIAS, Aarhus Institute of Advanced Studies Aarhus University, Høegh-GuldbergsGade 6B, Building 1632, 8000 Aarhus C, Denmark. e-mail: Karl-Erik.Andersson@ med.lu.se Curr Opin Urol 2015, 25:12–18 DOI:10.1097/MOU.0000000000000122 Volume 25 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Injections for lower urinary tract symptoms treatment Andersson
KEY POINTS Treatment of male LUTS is still a challenge. Since the pathophysiology of LUTS, including that of the overactive bladder syndrome, is multifactorial, use of intraprostatic agents acting on more than one target may be required. Intraprostatic treatment with different agents is an attractive approach, as both the static and dynamic components of bladder outflow obstruction can be influenced leading to reduced prostate volume and decreased afferent activity in prostatic nerves. As the prostate is only one possible site for the generation of LUTS, complete resolution of symptoms may not always be obtained by intraprostatic injections. Current agents used for intraprostatic treatment (anhydrous ethanol, botulinum toxin, NX-1207, PRX302) have limitations, and controlled clinical trials documenting their efficacy and side-effects are needed before their place in the treatment of benign prostatic hyperplasia (BPH)/LUTS can be properly assessed.
involved in the generation of both storage and voiding symptoms [11]. Hyperplastic changes in the prostate caused by inflammation may be able to generate both increased afferent activity and consequent storage symptoms, and increased prostate size and voiding symptoms. An intervention that eliminates both afferent activity from the prostate and reduces its size should therefore be expected to be clinically useful, provided that it is well tolerated. It should be emphasized that intraprostatic injection of agents may not only have direct or indirect effects on prostate afferent nerves but can also by inducing tissue necrosis or by apoptosis reduce prostate volume and remove mechanical obstruction due to an enlarged gland.
AGENTS FOR INTRAPROSTATIC INJECTION There are several recent reviews discussing intraprostatic injections and agents used for treatment of LUTS/BPH [5–7,8 ,9]. The main agents used have been BoNT, anhydrous ethanol, NX-1207 and PRX302. The focus will be only on recent studies &&
Botulinum toxin Most recent investigations on intraprostatic injection treatment have focused on BoNT. Mechanism(s) of action BoNT is produced by Clostridium botulinum and comprises seven sero-subtypes, of which subtype A
(BoNT-A), which has the longest duration of action, is clinically the most relevant. The detailed mechanisms of action of BoNT, in general [12,13], and with particular respect to the LUTS [14] have recently been reviewed. In the nerve, terminal BoNT inactivates the attachment proteins (the SNARE complex, including SNAP 25, synaptobrevin and syntaxin) needed for transmitter release. BoNT-A cleaves SNAP 25, and in striated muscle, this leads to paralysis by inhibition of acetylcholine (ACh) release from cholinergic motor nerve endings. In the human bladder, SNAP-25 expression has been shown in parasympathetic, sympathetic and sensory fibres [14], which means that BoNT has the potential to inhibit release not only of ACh (and ATP) from cholinergic nerves but also of noradrenaline from adrenergic, and various peptides (e.g. calcitonin gene-related peptide and substance P) from sensory fibres. In addition, SNARE proteins are expressed in the urothelium, and BoNT-A can bind to these targets and inhibit ATP release [15]. It can be assumed that similar targets and mechanisms as in the bladder can be found in the prostate. The prostate is innervated by a rich supply of mixed autonomic postganglionic neurons [16 ]. The prostatic stroma contains an abundance of short noradrenergic nerves, consistent with the role of adrenergic nerves mediating contraction of the prostatic smooth muscle. Adrenergic nerves are absent from the prostatic glandular epithelium, and motor nerves travel posterolaterally outside the prostatic capsule, giving off branches that ramify within the gland [17–19]. In addition to mediating contraction, adrenergic innervation plays a role in the growth of the prostate. Cholinergic innervation is found in both the stromal and glandular epithelial regions of the human prostate [16 ]. Despite muscarinic receptors being located primarily in the glandular epithelium, they may play a direct role in postjunctional contraction in the prostate. Available evidence suggests that in the prostate, BoNT-A, by action on the motor part of the myogenic (release of contractant transmitters) and on the sensory (release of sensory transmitters) activation pathways, can decrease both contraction of prostatic smooth muscle and afferent nervous activity, thereby decreasing both voiding and storage symptoms. Even if the exact mechanisms of action of intraprostatic BoNT-A have not been established, recent investigations in the rat, dog and human prostate have revealed that the toxin can produce a decrease in prostate volume [14,20]. Although necrosis of the gland at the places of BoNT-A injection could explain the rapid volume reduction, transrectal ultrasound examination of the glands, performed in different studies [6], was unable to detect signs of
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&
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Male lower urinary tract symptoms
cavitation that indirectly could suggest the presence of necrosis. It was suggested that the decreased prostate volume could be more appropriately related to the widespread apoptosis detected in the gland after BoNT-A administration. An increase in TUNEL staining in acinar and stromal cells, and in immunolabelling for proapoptotic proteins, such as caspase 3 and BAX, has been reported and prostate apoptosis has been suggested to be dependent on sympathetic nerve impairment and consequent decrease of the adrenergic stimulation of the gland [14]. Experimentally, it has been shown that BoNT may also have anti-inflammatory effects and can downregulate the expression of a1A-adrenoreceptors within the prostate [6]. The translational importance of these findings is unclear.
Clinical experiences The effects of intraprostatic injection of BoNT for treatment of LUTS/BPH have been studied in many open-labelled investigations (see [5,6]). Significant improvements [International Prostate Symptom Score (IPSS) and maximum flow rate (Qmax)] have been found in most studies, but also a reduction in prostate volume. The duration of the effects of treatment has been variable, ranging from 3 to 30 months [5]. In patients with urinary retention before BoNTA injections, most men could void spontaneously within 1 month [5]. In a phase II randomized controlled trial (RCT), Crawford et al. [21] explored the effects of 100 and 300 units of onabotulinumtoxin A in 134 men with clinically diagnosed BPH. Assessments were made at 3 months (131 patients) and at 12 months (108 patients) and 108 assessed at 12 months. With both doses and at both time points, the AUA symptom index decreased and Qmax increased. The authors found that the study passed predetermined criteria for treatment efficacy and safety, and suggested that a randomized trial against placebo should be performed. As the results of these studies were promising, the outcome of a recent RCT against placebo was somewhat surprising. Marberger et al. [22 ] performed the largest multicentre study on intraprostatic BoNT to date in 374 men with benign prostatic enlargement (BPE). The efficacy of three doses of onabotulinumtoxin A (100, 200 and 300 U), given transperineally or transurethrally, versus placebo was explored. Even if significant improvements from baseline in IPSS, Qmax, total prostate volume (TPV), transition zone volume (TZV) were observed for all groups, including placebo, at week 12, there was no significant differences between the onabotulinumtoxin A groups and placebo, except a &&
14
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significant improvement in IPSS in a subgroup of prior a-blocker users injected with the onabotulinumtoxin A 200 IU dose. The high placebo response, that is a reduction in IPPS of 26% and an improvement in Qmax of 24% was surprising, considering that in the only other placebocontrolled study published [23], patients who received placebo (physiological saline), the symptom score and serum PSA concentration were not significantly changed compared with the baseline values, and the values at assessments at 1 and 2 months. The contradictory results may have different explanations. The most conspicuous difference was the large placebo effect in the study by Marberger et al. [22 ], which implies difficulties in detection of differences between the compared groups. The study by Maria et al. [23] suffered from low recruitment (32 patients), was performed in a single institution and combined two parameters for the primary outcome (AUA symptom score and Qmax, assessed at 1 and 2 months), whereas the study by Marberger et al. [22 ] was large, multicentre, had a change from baseline of IPSS at 12 weeks as primary efficacy end point and did not report adequate blinding. Furthermore, the investigators changed the route of administration while recruitment in the trial was still evolving. Another source of heterogeneity in these studies was the use of different inclusion criteria. Few important adverse effects have been reported after intraprostatic injection of the neurotoxin in doses ranging between 100 and 300 U. The main reported complications after treatment included urinary tract infection, pelvic pain, urinary retention, macroscopic haematuria and hematospermia [21,22 ]. Some serious adverse events were reported in the series of Crawford et al. [21], including three cases of urosepsis. Intraprostatic injection of BoNT-A seems devoid of sexual adverse events. Silva et al. [24] studied 16 sexually active men aged more than 60 years with BPH/BPE, refractory to standard medical therapy, who received 200 U of BoNT-A intraprostatically by the transrectal route. They concluded that ‘intraprostatic injection of BoNT/A in patients with BPE does not impair erectile, orgasmic or ejaculatory functions and does not change libido’. Even if the outcome of largest RCT against placebo performed so far was disappointing, it cannot be denied that the theoretical rationale for use of intraprostatic BoNT is attractive. It is a quick, minimally invasive treatment alternative with low morbidity for patients who are refractory to medical treatment or are in urinary retention. However, as suggested by the EAU guidelines [25 ], further trials &&
&&
&&
&&
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Injections for lower urinary tract symptoms treatment Andersson
with a large number of patients, and with randomization against saline injections, drugs, transurethral resection of the prostate or other minimally invasive treatments, systematic evaluation of different doses, and long-term follow-up, seems necessary for adequate final assessment of this treatment modality.
Ethanol Ethanol injection is one of the most investigated intraprostatic therapies, but despite undoubted efficacy in some patients, it has not reached a wide acceptance as a treatment of LUTS/BPH. Thus, it was not included as a treatment alternative in the updated AUA Guidelines on the Management of Benign Prostatic Hyperplasia [26], and in the EAU Guidelines on the Treatment and Follow-up of Nonneurogenic Male Lower Urinary Tract Symptoms Including Benign Prostatic Obstruction, it was classified among ‘emerging operations’ [25 ]. Despite that this approach has been studied for more than a decade, in both animal experiments and clinical trials, no randomized controlled clinical trial (RTC) seems to be available. The mechanism of action appears to be that ethanol causes inflammation, coagulative necrosis with protein denaturation and cell membrane lysis, and, finally, sloughing of prostatic tissue resulting in cavity formation [27]. However, it is conceivable that ethanol also destroys afferent nerves conveying sensory information. Promising results have been reported, but also variability in clinical outcomes [6]. The majority of trials have demonstrated a significant reduction in symptoms and postvoid residual volume as well as a significant improvement in Qmax and quality of life (QoL); prostate volume also decreased significantly in the majority of studies [6]. Among recent studies, Li et al. [28] evaluated the efficacy and safety of ultrasound-guided transrectal ethanol injection in 70 BPH in patients with high-risk comorbidities who showed poor oral drug efficacy and were medically fragile or unwilling to undergo operative therapy. The patients received ultrasound-guided transrectal ethanol injection and were followed up at 1, 3, 6, 12 and 24 months post-treatment. Volume and disease of the prostate were observed, and IPSS, QoL, Qmax and post-void residual (PVR) were determined. It was found that the volume of the prostatic inner gland was reduced after a month of treatment and had decreased significantly (P < 0.001) by 16.3% at 24 months post-treatment. Qmax also increased significantly from 4.73.1 ml/s pretreatment to 15.33.2 ml/s post-treatment. IPSS increased from 9.8 þ 2.4 to 29.3 þ 6.7 points pretreatment. PVR dropped from 130.8 þ 71.5 to 25 þ 12.0 ml &&
post-treatment. Prostate volume was positively correlated with PVR, IPSS and QoL and was negatively correlated with Qmax. Interestingly, QoL was reported to decrease from 5.3 þ 1.7 points pretreatment to 1.9 þ 0.7 points post-treatment; how QoL was assessed was not described, but in the discussion, the change was reported as an improvement. In the study, the investigators injected different volumes of ethanol. The first 36 received a volume of more than 30% of the prostate size, and among these, four developed complications such as cystitis induced by liquefaction necrosis of the prostate and urinary tract injury with severe pain. One-third of the patients experienced burning sensation, pain and micturition sensation. In the latter part of the study (34 patients), the injected dose was limited to 25% of the inner gland volume. In these patients, no severe complications were encountered and only one patient reported mild pain. The authors concluded that ultrasound-guided transrectal ethanol injections showed good efficacy with few complications for the treatment of patients with BPH and other high-risk comorbidities. A similar conclusion was reached by Arslan et al. [29], who investigated 52 patients, 32 of them regarded as operation anaesthesia risks. They had an average preoperative IPPS score of 22.6, Qmax 6.4 ml/s, Qaverage 3.3 ml/s, prostate volume 49.3 ml and PVR 160.1 ml. The injected ethanol volumes were adjusted to prostate size and varied between 6 and 16 ml. At follow-up at 24 months, the average IPPS score had decreased to 12.8 and prostate volume to 38.8 ml; Qmax and Q-average increased to 9.7 and 71.1 ml/s, respectively, and PVR to 68 ml. There were no major complications related to the ethanol injections. The duration of the effect of intraprostatic ethanol varies. In most studies, the durability of clinical effects beyond 1 year seems poor. One trial with a mean follow-up of 3 years showed a retreatment rate of 41% [30], but more positive long-term results have been reported [31,32]. Results obtained 54 months after transurethral ethanol prostate ablation in 56 men with BPH/LUTS, all being medically high-risk patients with multiple comorbidities, have been reported [32]. Data on IPSS, prostate-specific antigen (PSA), prostate volume (transrectal ultrasound), Qmax and postvoid residual were collected. The responses in 73% of the patients were considered sufficient, while the remaining 23% showed an insufficient response and needed an alternative treatment. A positive effect of intraprostatic ethanol has been documented in many studies. The approach has been used as a treatment alternative not only in patients with moderate-to-severe LUTS secondary to
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Male lower urinary tract symptoms
BPO but also in high-risk patients with significant comorbidities, or in patients unwilling to undergo an operative procedure. However, the EAU guidelines [25 ] consider that in the absence of RTCs, intraprostatic ethanol injections should be regarded as experimental procedures and only used within the frames of clinical trials. &&
NX-1207 NX-1207 is a ‘new therapeutic protein of proprietary composition with selective pro-apoptotic properties’ [33,34], which is under investigation for the treatment of LUTS associated with BPH. Preclinical and clinical information is scarce, mostly published in abstract form, and not yet in the peer-reviewed literature. According to available information, intraprostatic injection of the drug in rats led to a 40–47% reduction in prostate volume compared with control animals, starting at 72 h and persisting through 12 months. Similar results were seen in dogs [33,34]. In humans, the drug is injected directly into the transitional zone of the prostate as a single administration to induce focal cell loss in prostate tissue through apoptosis, leading to nonregressive prostate shrinkage and both short and long-term symptomatic improvement. Two US Phase II trials have been performed [33,34]. One of them was a multicentre, randomized, noninferiority study involving 32 clinical sites with 85 individuals and two dose ranges (2.5 and 0.125 mg) and an active open-label comparator (finasteride). Individuals and investigators on NX-1207 were double-blind as to dosage. The primary endpoint was a change in AUA Symptom Index at 90 and 180 days for a single injection of NX-1207 as compared with finasteride on a noninferiority basis. Inclusion criteria included an AUA symptom score of more than 15, diminished peak urine flow (
Intraprostatic injections for lower urinary tract symptoms treatment Karl-Erik Andersson a,b
Purpose of review The purpose of this study is to review and discuss recently published (2013–2014) experimental and clinical studies of intraprostatic injection therapy as an alternative treatment of lower urinary tract symptoms (LUTS). Recent findings Recent focus has been on intraprostatic injection of botulinum toxin both with regard to mechanism of action and efficacy. In contrast to the promising findings in several previous studies, a recent large, randomized, placebo-controlled trial found no differences between onabotulinumtoxin A treatment and placebo. There is little new information on the use of anhydrous ethanol and agents such as NX-1207 and PRX302, which previously have been reported to have promising effects. Summary Intraprostatic injection of different agents as a minimally invasive surgical therapy for LUTS associated with benign prostatic hyperplasia seems attractive and may have a potential as a treatment alternative, but so far, available results are not convincing. Further studies on the mechanisms of action of novel agents, and controlled clinical trials documenting their efficacy and side-effects when injected into the prostate are needed before their place in the treatment of benign prostatic hyperplasia/LUTS can be properly assessed. Keywords benign prostatic hyperplasia, botulinum toxin, ethanol, male lower urinary tract symptoms, NX-1207, PRX302
INTRODUCTION The management of male lower urinary tract symptoms (LUTS) is still a challenge [1]. Despite a number of new drug treatments, no significant increase in efficacy has been achieved with oral drug monotherapy, and the gains of different combinations have been modest, even if better tolerance to treatment may be obtained [2–4]. When pharmacological therapy fails, surgical treatments are usually considered. Many minimally invasive alternatives have been employed, but the majority of these therapies have failed to achieve the same efficacy as, for example, transurethral resection of the prostate, and have not always been well documented. Intraprostatic injections of different agents to induce prostate involution and symptom relief have recently attracted renewed interest, mostly because of positive reports on the effects of botulinum toxin (BoNT) [5–7,8 ,9]. Most recent developments have focused on the use of BoNT, and below, some of these studies will be discussed. A short summary of previous experiences &&
www.co-urology.com
of intraprostatic injections of anhydrous ethanol, NX-1207 and PRX302, has also been included.
RATIONALE FOR INTRAPROSTATIC INJECTION The pathophysiology of male LUTS is generally considered to be multifactorial. Even if changes in the bladder and its afferent nerves have been regarded as a main contributor to storage symptoms [10], it cannot be excluded that the prostate is
a
Institute for Regenerative Medicine, Wake Forest University School of Medicine, Department of Urology, Wake Forest Baptist Medical Center, Winston Salem, North Carolina, USA and bAarhus Institute for Advanced Sciences, Aarhus University, Aarhus, Denmark Correspondence to Karl-Erik Andersson, MD, PhD, AIAS, Aarhus Institute of Advanced Studies Aarhus University, Høegh-GuldbergsGade 6B, Building 1632, 8000 Aarhus C, Denmark. e-mail: Karl-Erik.Andersson@ med.lu.se Curr Opin Urol 2015, 25:12–18 DOI:10.1097/MOU.0000000000000122 Volume 25 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Injections for lower urinary tract symptoms treatment Andersson
KEY POINTS Treatment of male LUTS is still a challenge. Since the pathophysiology of LUTS, including that of the overactive bladder syndrome, is multifactorial, use of intraprostatic agents acting on more than one target may be required. Intraprostatic treatment with different agents is an attractive approach, as both the static and dynamic components of bladder outflow obstruction can be influenced leading to reduced prostate volume and decreased afferent activity in prostatic nerves. As the prostate is only one possible site for the generation of LUTS, complete resolution of symptoms may not always be obtained by intraprostatic injections. Current agents used for intraprostatic treatment (anhydrous ethanol, botulinum toxin, NX-1207, PRX302) have limitations, and controlled clinical trials documenting their efficacy and side-effects are needed before their place in the treatment of benign prostatic hyperplasia (BPH)/LUTS can be properly assessed.
involved in the generation of both storage and voiding symptoms [11]. Hyperplastic changes in the prostate caused by inflammation may be able to generate both increased afferent activity and consequent storage symptoms, and increased prostate size and voiding symptoms. An intervention that eliminates both afferent activity from the prostate and reduces its size should therefore be expected to be clinically useful, provided that it is well tolerated. It should be emphasized that intraprostatic injection of agents may not only have direct or indirect effects on prostate afferent nerves but can also by inducing tissue necrosis or by apoptosis reduce prostate volume and remove mechanical obstruction due to an enlarged gland.
AGENTS FOR INTRAPROSTATIC INJECTION There are several recent reviews discussing intraprostatic injections and agents used for treatment of LUTS/BPH [5–7,8 ,9]. The main agents used have been BoNT, anhydrous ethanol, NX-1207 and PRX302. The focus will be only on recent studies &&
Botulinum toxin Most recent investigations on intraprostatic injection treatment have focused on BoNT. Mechanism(s) of action BoNT is produced by Clostridium botulinum and comprises seven sero-subtypes, of which subtype A
(BoNT-A), which has the longest duration of action, is clinically the most relevant. The detailed mechanisms of action of BoNT, in general [12,13], and with particular respect to the LUTS [14] have recently been reviewed. In the nerve, terminal BoNT inactivates the attachment proteins (the SNARE complex, including SNAP 25, synaptobrevin and syntaxin) needed for transmitter release. BoNT-A cleaves SNAP 25, and in striated muscle, this leads to paralysis by inhibition of acetylcholine (ACh) release from cholinergic motor nerve endings. In the human bladder, SNAP-25 expression has been shown in parasympathetic, sympathetic and sensory fibres [14], which means that BoNT has the potential to inhibit release not only of ACh (and ATP) from cholinergic nerves but also of noradrenaline from adrenergic, and various peptides (e.g. calcitonin gene-related peptide and substance P) from sensory fibres. In addition, SNARE proteins are expressed in the urothelium, and BoNT-A can bind to these targets and inhibit ATP release [15]. It can be assumed that similar targets and mechanisms as in the bladder can be found in the prostate. The prostate is innervated by a rich supply of mixed autonomic postganglionic neurons [16 ]. The prostatic stroma contains an abundance of short noradrenergic nerves, consistent with the role of adrenergic nerves mediating contraction of the prostatic smooth muscle. Adrenergic nerves are absent from the prostatic glandular epithelium, and motor nerves travel posterolaterally outside the prostatic capsule, giving off branches that ramify within the gland [17–19]. In addition to mediating contraction, adrenergic innervation plays a role in the growth of the prostate. Cholinergic innervation is found in both the stromal and glandular epithelial regions of the human prostate [16 ]. Despite muscarinic receptors being located primarily in the glandular epithelium, they may play a direct role in postjunctional contraction in the prostate. Available evidence suggests that in the prostate, BoNT-A, by action on the motor part of the myogenic (release of contractant transmitters) and on the sensory (release of sensory transmitters) activation pathways, can decrease both contraction of prostatic smooth muscle and afferent nervous activity, thereby decreasing both voiding and storage symptoms. Even if the exact mechanisms of action of intraprostatic BoNT-A have not been established, recent investigations in the rat, dog and human prostate have revealed that the toxin can produce a decrease in prostate volume [14,20]. Although necrosis of the gland at the places of BoNT-A injection could explain the rapid volume reduction, transrectal ultrasound examination of the glands, performed in different studies [6], was unable to detect signs of
0963-0643 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
www.co-urology.com
13
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Male lower urinary tract symptoms
cavitation that indirectly could suggest the presence of necrosis. It was suggested that the decreased prostate volume could be more appropriately related to the widespread apoptosis detected in the gland after BoNT-A administration. An increase in TUNEL staining in acinar and stromal cells, and in immunolabelling for proapoptotic proteins, such as caspase 3 and BAX, has been reported and prostate apoptosis has been suggested to be dependent on sympathetic nerve impairment and consequent decrease of the adrenergic stimulation of the gland [14]. Experimentally, it has been shown that BoNT may also have anti-inflammatory effects and can downregulate the expression of a1A-adrenoreceptors within the prostate [6]. The translational importance of these findings is unclear.
Clinical experiences The effects of intraprostatic injection of BoNT for treatment of LUTS/BPH have been studied in many open-labelled investigations (see [5,6]). Significant improvements [International Prostate Symptom Score (IPSS) and maximum flow rate (Qmax)] have been found in most studies, but also a reduction in prostate volume. The duration of the effects of treatment has been variable, ranging from 3 to 30 months [5]. In patients with urinary retention before BoNTA injections, most men could void spontaneously within 1 month [5]. In a phase II randomized controlled trial (RCT), Crawford et al. [21] explored the effects of 100 and 300 units of onabotulinumtoxin A in 134 men with clinically diagnosed BPH. Assessments were made at 3 months (131 patients) and at 12 months (108 patients) and 108 assessed at 12 months. With both doses and at both time points, the AUA symptom index decreased and Qmax increased. The authors found that the study passed predetermined criteria for treatment efficacy and safety, and suggested that a randomized trial against placebo should be performed. As the results of these studies were promising, the outcome of a recent RCT against placebo was somewhat surprising. Marberger et al. [22 ] performed the largest multicentre study on intraprostatic BoNT to date in 374 men with benign prostatic enlargement (BPE). The efficacy of three doses of onabotulinumtoxin A (100, 200 and 300 U), given transperineally or transurethrally, versus placebo was explored. Even if significant improvements from baseline in IPSS, Qmax, total prostate volume (TPV), transition zone volume (TZV) were observed for all groups, including placebo, at week 12, there was no significant differences between the onabotulinumtoxin A groups and placebo, except a &&
14
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significant improvement in IPSS in a subgroup of prior a-blocker users injected with the onabotulinumtoxin A 200 IU dose. The high placebo response, that is a reduction in IPPS of 26% and an improvement in Qmax of 24% was surprising, considering that in the only other placebocontrolled study published [23], patients who received placebo (physiological saline), the symptom score and serum PSA concentration were not significantly changed compared with the baseline values, and the values at assessments at 1 and 2 months. The contradictory results may have different explanations. The most conspicuous difference was the large placebo effect in the study by Marberger et al. [22 ], which implies difficulties in detection of differences between the compared groups. The study by Maria et al. [23] suffered from low recruitment (32 patients), was performed in a single institution and combined two parameters for the primary outcome (AUA symptom score and Qmax, assessed at 1 and 2 months), whereas the study by Marberger et al. [22 ] was large, multicentre, had a change from baseline of IPSS at 12 weeks as primary efficacy end point and did not report adequate blinding. Furthermore, the investigators changed the route of administration while recruitment in the trial was still evolving. Another source of heterogeneity in these studies was the use of different inclusion criteria. Few important adverse effects have been reported after intraprostatic injection of the neurotoxin in doses ranging between 100 and 300 U. The main reported complications after treatment included urinary tract infection, pelvic pain, urinary retention, macroscopic haematuria and hematospermia [21,22 ]. Some serious adverse events were reported in the series of Crawford et al. [21], including three cases of urosepsis. Intraprostatic injection of BoNT-A seems devoid of sexual adverse events. Silva et al. [24] studied 16 sexually active men aged more than 60 years with BPH/BPE, refractory to standard medical therapy, who received 200 U of BoNT-A intraprostatically by the transrectal route. They concluded that ‘intraprostatic injection of BoNT/A in patients with BPE does not impair erectile, orgasmic or ejaculatory functions and does not change libido’. Even if the outcome of largest RCT against placebo performed so far was disappointing, it cannot be denied that the theoretical rationale for use of intraprostatic BoNT is attractive. It is a quick, minimally invasive treatment alternative with low morbidity for patients who are refractory to medical treatment or are in urinary retention. However, as suggested by the EAU guidelines [25 ], further trials &&
&&
&&
&&
Volume 25 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Injections for lower urinary tract symptoms treatment Andersson
with a large number of patients, and with randomization against saline injections, drugs, transurethral resection of the prostate or other minimally invasive treatments, systematic evaluation of different doses, and long-term follow-up, seems necessary for adequate final assessment of this treatment modality.
Ethanol Ethanol injection is one of the most investigated intraprostatic therapies, but despite undoubted efficacy in some patients, it has not reached a wide acceptance as a treatment of LUTS/BPH. Thus, it was not included as a treatment alternative in the updated AUA Guidelines on the Management of Benign Prostatic Hyperplasia [26], and in the EAU Guidelines on the Treatment and Follow-up of Nonneurogenic Male Lower Urinary Tract Symptoms Including Benign Prostatic Obstruction, it was classified among ‘emerging operations’ [25 ]. Despite that this approach has been studied for more than a decade, in both animal experiments and clinical trials, no randomized controlled clinical trial (RTC) seems to be available. The mechanism of action appears to be that ethanol causes inflammation, coagulative necrosis with protein denaturation and cell membrane lysis, and, finally, sloughing of prostatic tissue resulting in cavity formation [27]. However, it is conceivable that ethanol also destroys afferent nerves conveying sensory information. Promising results have been reported, but also variability in clinical outcomes [6]. The majority of trials have demonstrated a significant reduction in symptoms and postvoid residual volume as well as a significant improvement in Qmax and quality of life (QoL); prostate volume also decreased significantly in the majority of studies [6]. Among recent studies, Li et al. [28] evaluated the efficacy and safety of ultrasound-guided transrectal ethanol injection in 70 BPH in patients with high-risk comorbidities who showed poor oral drug efficacy and were medically fragile or unwilling to undergo operative therapy. The patients received ultrasound-guided transrectal ethanol injection and were followed up at 1, 3, 6, 12 and 24 months post-treatment. Volume and disease of the prostate were observed, and IPSS, QoL, Qmax and post-void residual (PVR) were determined. It was found that the volume of the prostatic inner gland was reduced after a month of treatment and had decreased significantly (P < 0.001) by 16.3% at 24 months post-treatment. Qmax also increased significantly from 4.73.1 ml/s pretreatment to 15.33.2 ml/s post-treatment. IPSS increased from 9.8 þ 2.4 to 29.3 þ 6.7 points pretreatment. PVR dropped from 130.8 þ 71.5 to 25 þ 12.0 ml &&
post-treatment. Prostate volume was positively correlated with PVR, IPSS and QoL and was negatively correlated with Qmax. Interestingly, QoL was reported to decrease from 5.3 þ 1.7 points pretreatment to 1.9 þ 0.7 points post-treatment; how QoL was assessed was not described, but in the discussion, the change was reported as an improvement. In the study, the investigators injected different volumes of ethanol. The first 36 received a volume of more than 30% of the prostate size, and among these, four developed complications such as cystitis induced by liquefaction necrosis of the prostate and urinary tract injury with severe pain. One-third of the patients experienced burning sensation, pain and micturition sensation. In the latter part of the study (34 patients), the injected dose was limited to 25% of the inner gland volume. In these patients, no severe complications were encountered and only one patient reported mild pain. The authors concluded that ultrasound-guided transrectal ethanol injections showed good efficacy with few complications for the treatment of patients with BPH and other high-risk comorbidities. A similar conclusion was reached by Arslan et al. [29], who investigated 52 patients, 32 of them regarded as operation anaesthesia risks. They had an average preoperative IPPS score of 22.6, Qmax 6.4 ml/s, Qaverage 3.3 ml/s, prostate volume 49.3 ml and PVR 160.1 ml. The injected ethanol volumes were adjusted to prostate size and varied between 6 and 16 ml. At follow-up at 24 months, the average IPPS score had decreased to 12.8 and prostate volume to 38.8 ml; Qmax and Q-average increased to 9.7 and 71.1 ml/s, respectively, and PVR to 68 ml. There were no major complications related to the ethanol injections. The duration of the effect of intraprostatic ethanol varies. In most studies, the durability of clinical effects beyond 1 year seems poor. One trial with a mean follow-up of 3 years showed a retreatment rate of 41% [30], but more positive long-term results have been reported [31,32]. Results obtained 54 months after transurethral ethanol prostate ablation in 56 men with BPH/LUTS, all being medically high-risk patients with multiple comorbidities, have been reported [32]. Data on IPSS, prostate-specific antigen (PSA), prostate volume (transrectal ultrasound), Qmax and postvoid residual were collected. The responses in 73% of the patients were considered sufficient, while the remaining 23% showed an insufficient response and needed an alternative treatment. A positive effect of intraprostatic ethanol has been documented in many studies. The approach has been used as a treatment alternative not only in patients with moderate-to-severe LUTS secondary to
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Male lower urinary tract symptoms
BPO but also in high-risk patients with significant comorbidities, or in patients unwilling to undergo an operative procedure. However, the EAU guidelines [25 ] consider that in the absence of RTCs, intraprostatic ethanol injections should be regarded as experimental procedures and only used within the frames of clinical trials. &&
NX-1207 NX-1207 is a ‘new therapeutic protein of proprietary composition with selective pro-apoptotic properties’ [33,34], which is under investigation for the treatment of LUTS associated with BPH. Preclinical and clinical information is scarce, mostly published in abstract form, and not yet in the peer-reviewed literature. According to available information, intraprostatic injection of the drug in rats led to a 40–47% reduction in prostate volume compared with control animals, starting at 72 h and persisting through 12 months. Similar results were seen in dogs [33,34]. In humans, the drug is injected directly into the transitional zone of the prostate as a single administration to induce focal cell loss in prostate tissue through apoptosis, leading to nonregressive prostate shrinkage and both short and long-term symptomatic improvement. Two US Phase II trials have been performed [33,34]. One of them was a multicentre, randomized, noninferiority study involving 32 clinical sites with 85 individuals and two dose ranges (2.5 and 0.125 mg) and an active open-label comparator (finasteride). Individuals and investigators on NX-1207 were double-blind as to dosage. The primary endpoint was a change in AUA Symptom Index at 90 and 180 days for a single injection of NX-1207 as compared with finasteride on a noninferiority basis. Inclusion criteria included an AUA symptom score of more than 15, diminished peak urine flow (
