The management of male lower urinary tract symptoms (LUTS) is still a challenge . 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 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 , it cannot be excluded that the prostate is involved in the generation of both storage and voiding symptoms . 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/benign prostatic hyperplasia (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
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  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 , 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 . 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 , was unable to detect signs of 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 . Experimentally, it has been shown that BoNT may also have anti-inflammatory effects and can downregulate the expression of α1A-adrenoreceptors within the prostate . The translational importance of these findings is unclear.
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 . In patients with urinary retention before BoNTA injections, most men could void spontaneously within 1 month . In a phase II randomized controlled trial (RCT), Crawford et al. 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 significant improvement in IPSS in a subgroup of prior α-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 placebo-controlled study published , 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. 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., including three cases of urosepsis. Intraprostatic injection of BoNT-A seems devoid of sexual adverse events. Silva et al. 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 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 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 , 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 . However, it is conceivable that ethanol also destroys afferent nerves conveying sensory information.
Promising results have been reported, but also variability in clinical outcomes . 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 . Among recent studies, Li et al. 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 4.7±3.1 ml/s pretreatment to 15.3±3.2 ml/s post-treatment. IPSS increased from 9.8 + 2.4 to 29.3 + 6.7 points pretreatment. PVR dropped from 130.8 + 71.5 to 25 + 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 + 1.7 points pretreatment to 1.9 + 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., 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, Q-average 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% , 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 . 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 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 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 (<15 ml/s) and a prostate size of more than 30 and less than 70 mg. The mean AUA symptom score improvement after 90 days in the intent-to-treat group was 9.71 points for 2.5 mg NX-1207 (n = 48) versus 4.13 points for finasteride (n = 24) (P = 0.001) and 4.29 for 0.125 mg NX-1207 (n = 7) (P = 0.034). The 180-day results were also positive (NX-1207 2.5 mg noninferior to open-label finasteride). No significant changes in serum testosterone or serum PSA levels in the NX-1207 cohorts were observed. There were no reported adverse effects on sexual function.
According to ClinicalTrials.gov (https://clinicaltrials.gov/, accessed 7 August 2014), one US multicentre, double-blind, placebo-controlled Phase III study has been completed, but final outcome data have not yet been published. Another phase III trial is still recruiting. Further studies of the effects of NX-1207 in BPH patients seem to be ongoing (‘active but not recruiting’). The results of such studies are needed to assess whether or not this therapeutic principle is a useful addition to the current treatment alternatives.
PRX302 is a PSA-activated protoxin [35,36]. It is a modification of native proaerolysin (a channel-forming bacterial protoxin that binds to cell-surface receptors and then is activated by proteases). In human and monkey prostates, which produce PSA, PRX302 is active, whereas it was inactive in the non-PSA producing dog prostate. Injected into the prostates of cynomolgus monkeys, a single dose of PRX302 produced an extensive but organ-confined damage, with no damage to neighbouring organs and no general morbidity .
In men with moderate to severe BPH, refractory, intolerant or unwilling to undergo medical therapies for BPH, the safety and efficacy of PRX302 was evaluated . The patients had an IPSS of more than 12, a QoL score of more than 3 and prostate volumes between 30 and 80 g. Fifteen patients were enrolled in phase 1 studies, and 18 patients entered phase 2 studies. Patients received intraprostatic injection of PRX302 into the right and left transition zone via a transperineal approach in an office-based setting. Phase 1 individuals received increasing concentrations of PRX302 at a fixed volume; phase 2 individuals received increasing volumes per deposit at a fixed concentration. IPSS, QoL, prostate volume, Qmax, International Index of Erectile Function, serum PSA levels, pharmacokinetics and adverse events were recorded at 30, 60, 90, 180, 270 and 360 days after treatment. Sixty percent of men in the phase 1 study and 64% of men in the phase 2 study treated with PRX302 had more than 30% improvement compared with baseline in IPSS out to day 360. Patients also experienced an improvement in QoL and a reduction in prostate volume out to day 360. Patients receiving more than 1 ml of PRX302 per deposit had the best response overall. Adverse events were mild to moderate and transient in nature, and there were no deleterious effects on erectile function. The major study limitation was the small sample size. The promising safety profile and evidence of efficacy in the majority of treated individuals in these phase 1 and 2 studies supported further study of PRX302. Such a study was performed by Elhilali et al.[38▪▪] who conducted a phase IIb double-blind safety and efficacy evaluation of intraprostatic injection of PRX302 in a total of 92 patients with IPSS of 15 or greater, peak urine flow 12 ml or less per second and prostate volume 30–100 ml. The patients were randomized 2 : 1 to a single ultrasound-guided intraprostatic injection of PRX302 versus vehicle (placebo). Injection was 20% of prostate volume and 0.6 μg PRX302 per g prostate. Peak urine flow was determined by a blinded reviewer. The primary dataset of efficacy evaluable patients (73) was analysed using last observation carried forward. PRX302 treatment resulted in an approximate nine-point reduction in IPSS and 3 ml per second increase in peak urine flow that were statistically significant changes from baseline compared with vehicle. Efficacy was sustained for 12 months. Early withdrawal for other benign prostatic hyperplasia treatment was more common for patients in the vehicle group. Relative to vehicle, PRX302 apparent toxicity was mild, transient and limited to local discomfort/pain and irritative urinary symptoms occurring in the first few days, with no effect on erectile function.
As both the safety and safety profile of PRX302 seem favourable, further evaluation is warranted in longer term, larger, phase III studies. According to ClinicalTrials.gov (https://clinicaltrials.gov/, accessed 7 August 2014), a phase III trial ‘Randomized, Double-Blind, Vehicle-Controlled, Multicenter Safety and Efficacy Study of Intraprostatic PRX302 for LUTS BPH (PLUS-1)’ is still recruiting patients.
Agents injected intraprostatically have the potential to affect both the static and dynamic component of BPH, reducing prostatic size and related voiding symptoms, and decreasing afferent nerve activity and storage symptoms. In general, the therapy seems to be well tolerated and may be suited for patients unfit for, or unwilling to undergo, surgery, and in whom medical therapy has been unsuccessful. Even if anhydrous ethanol has been used for a long time, there are no RCTs making it possible to assess its efficacy against placebo, and the EAU guidelines recommend that this treatment should be used only within the frames of clinical trials. The many promising reports with BoNT-A should be balanced against the negative outcome of a recent large placebo-controlled RCT that was unable to show any difference versus placebo. Studies on novel principles such as NX-1207 and PRX302 have shown promising results in the few studies published, and some investigations are still ongoing. It should be kept in mind that the prostate is only one contributor to male LUTS, and to what extent changes in the bladder may be responsible for the symptoms may vary individually. Until further large RCTs, which so far are scarce, have been performed, and the results published, the place of agents for intraprostatic injection as a therapy for LUTS remains to be established.
Conflicts of interest
The author is a consultant/member of Advisory Board of Allergan, Astellas, Ferring.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
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