REVIEW URRENT C OPINION
What’s truly minimally invasive in benign prostatic hyperplasia surgery? Amanda Chung and Henry H. Woo
Purpose of review There continues to be a strong interest in the novel minimally invasive therapies for lower urinary tract symptoms due to benign prostatic hyperplasia (BPH). There has been an emergence of new approaches, particularly with mechanical approaches such as the Urolift and new agents suitable for intraprostatic injection. Our purpose is to review the recent literature regarding the safety and efficacy of these therapies, and introduce a number of promising experimental therapies. Recent findings The Urolift device has shown safety and efficacy for BPH treatment in phase III clinical trials, with the advantage of a local anaesthetic outpatient procedure, no catheter, and no sexual dysfunction. Intraprostatic injection of botulinum toxin or ethanol has provided mixed results and need further well designed studies. NX-1207 and PRX302 are newer injectable agents under clinical trial. Several novel therapies such as Rezum, Histotripsy, and Aquablation have no published efficacy and safety data available. Summary Urolift appears to be a well tolerated and effective minimally invasive treatment for lower urinary tract symptoms due to BPH in men who wish to preserve sexual function or who are not suitable for invasive surgery. Further studies will confirm the currently mixed results regarding intraprostatic botulinum toxin or ethanol injections. Rezum, Histotripsy, and Aquablation are experimental treatments under investigation. Keywords benign prostatic hyperplasia, injections, lower urinary tract symptoms, minimally invasive surgical procedures
INTRODUCTION Over the last 2 decades, there has been a strong interest in the minimally invasive surgical therapies for lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). More recently, there has been particular interest in mechanical devices, such as the Urolift for the prostatic urethral lift (PUL) procedure, and intraprostatic injections of various agents. Injectable agents have included ethanol and botulinum toxin, but newer agents under investigation such as NX-1207 and PRX302 are generating much interest. Particularly, novel minimally invasive approaches include water vapour tissue destruction using Rezum technology, mechanical treatments such as Histotripsy, and combination modality treatment such as Aquablation. Our purpose is to review the recent literature on the safety and efficacy of these novel therapies as well as introduce several promising experimental therapies under investigation. The focus of this review will be to discuss these newer minimally invasive approaches, given that treatments that have been commercially available for www.co-urology.com
many years have already been well covered in the systematic reviews or meta-analyses. The key features of each minimally invasive treatment are outlined in Table 1.
NEW MINIMALLY INVASIVE SURGICAL TREATMENTS Intraprostatic injections Injection therapy, using the transperineal, transrectal, and transurethral routes for delivery of various active compounds, has not been very widely used. Sydney Adventist Hospital Clinical School, University of Sydney, Sydney, New South Wales, Australia Correspondence to Assistant Professor Henry H. Woo, Sydney Adventist Hospital Clinical School, University of Sydney, P.O. Box 5017, Wahroonga, Sydney, NSW 2076, Australia. Tel: +61 2 9473 8765; fax: +61 2 9473 8969; e-mail: [email protected] Curr Opin Urol 2014, 24:36–41 DOI:10.1097/MOU.0000000000000006 Volume 24 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Benign prostatic hyperplasia surgery Chung and Woo
KEY POINTS The prostatic urethral lift procedure (Urolift) has shown safety and efficacy in the treatment of LUTS due to BPH in phase III clinical trials, with the preservation of sexual function. Intraprostatic injections of botulinum toxin mixed results. Further well designed studies are needed. Novel intraprostatic injection agents include NX-1207 and PRX302, and are undergoing clinical trials. The most recently marketed prostatic urethral stent is the Allium stent, for which clinical publications (in English) are awaited. Novel experimental technologies include Rezum (water vapour and steam), Histotripsy, and Aquablation, and are under development and clinical investigation.
However, the recent development of several novel and seemingly effective agents (such as botulinum toxin) has attracted new interest in this area.
prostate as a treatment for LUTS due to BPH. Earlier results demonstrated that intraprostatic BTX-A injection induces prostate shrinkage, and 7 of 10 patients experienced improvement in their LUTS within 1 month of treatment [1]. In a nonrandomized, prospective, single-armed cohort study of 64 men, the intraprostatic injection of BTX-A provided clinically significant short-term subjective and objective benefit, and appeared to be a well tolerated and minimally invasive option for standard medication-refractory BPH [2]. Mean International Prostate Symptom Score (IPSS), Qmax, prostate volume, prostate-specific antigen (PSA), and frequency of nocturia improved significantly [3]. However, more recent results are mixed. A large, multicentre, randomized, double-blind, placebocontrolled, phase 2, dose-ranging study (n ¼ 374) showed significant improvements from baseline in IPSS, Qmax, total prostate volume (TPV), and transitional zone volume (TZV) for a variety of BTX-A dosage groups (100 U, 200 U, and 300 U), as well as the placebo group, at week 12 (P < 0.001), with no significant differences between BTX-A and placebo [4 ,5]. The incidence of adverse events was similar across the treatment groups. Most adverse events were related to the procedure, and no serious adverse events were considered related to the study &
Intraprostatic botulinum toxin injection Onabotulinum toxin A (BTX-A) can be injected via the transperineal or transrectal route into the
Table 1. Summary of minimal-invasive surgeries and key features
Technology
a
Local Outpatient Routine Commercially anaesthesia treatment catheterization available? possible? possible? essential? Clinical trial dataa
Adverse events
Intraprostatic botulinum Yes toxin injection
Yes
Yes
No
Phase 2 trial completed and published.
Not significant
Intraprostatic ethanol injection
Yes
Yes
Yes
No
Phase 2 trial completed and published.
Infrequent but catastrophic bladder necrosis reported
Intraprostatic NX-1207 No injection
Yes
Yes
No
Phase 2 trial completed Not significant and published. Phase 3 trial in progress.
Intraprostatic PRX302 injection
No
Yes
Yes
No
Phase 2 trial completed and published.
Not significant
Urolift
Yes
Yes
Yes
No
Phase 3 trial completed and published.
Not significant
Urolume stent
Yes
Yes
Yes
No
Phase 3 trial completed and published.
Migration/explantation
Memokath stent
Yes
Yes
Yes
No
Phase 3 trial completed and published
Migration/explantation
Allium stent
Yes
Yes
Yes
No
None published
Unknown
Rezum
No
Yes
Yes
No
None published
Postprocedure acute urinary retention in 50%
Histotripsy
No
Unknown
Unknown
Unknown
Pilot study in progress.
Unknown
Aquablation
No
Unknown
Unknown
Unknown
Pilot study in progress.
Unknown
English language publications on PubMed.
0963-0643 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-urology.com
37
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Benign prostatic hyperplasia
drug. Prostatitis occurred in 2.1% of patients and resolved with medical treatment. One patient in the 300 U group discontinued the study because of prostatitis, one patient in the 200 U group discontinued because of death due to a traffic accident, and two patients from the placebo group discontinued because of urinary hesitancy/nocturia and urinary retention. There was no significant change in the International Index of Erectile Function (IIEF) scores, vital signs, physical examination, or laboratory evaluations. In an exploratory post hoc analysis, a significant reduction in IPSS versus placebo was observed with BTX-A 200 U in prior alpha-blocker users (n ¼ 180) at week 12 [4 ]. Although further investigation is needed in prospective well designed studies to verify this post hoc analysis result, the results to this point in time have failed to meet the expectations. &
Intraprostatic ethanol injection Anhydrous ethanol is one of the most extensively studied injected agents [6]. Transurethral ethanol ablation of the prostate has been reported to be well tolerated and cost-effective. One study reported that 6–13.5 ml ethanol was endoscopically injected at 4–8 sites in the prostate of 30 men. The shortterm (3 months) outcomes were satisfactory and acceptable with significant (P < 0.05) improvements in IPSS (mean 18.43 2.38 to 6.80 1.34), Qmax (mean 7.33 1.19 to 16.31 1.69), and post void residual (PVR) (mean 54.16 30.93 to 17.01 9.59). The prostate size decreased significantly from a mean of 44.66 (9.52) preoperatively to 32.46 (7.78) postoperatively. Postoperative complications included haematuria, urinary retention, and urinary tract infection, but there was no retrograde ejaculation reported [7 ]. A major concern of this treatment has been the potential for inadvertent proximal injection into the bladder wall, which can give rise to catastrophic bladder necrosis [8]. &
Other agents for intraprostatic injection Other agents such as NX-1207 and PRX302 have been reported to have promising effects [6]. NX-1207 (Nymox Pharmaceutical Co., Hasbrouck Heights, New Jersey, USA) is a protein with selective proapoptotic properties which induce focal cell loss in prostatic tissue, leading to prostate volume reduction. It is administered by injection into the periurethral transitional zone of the prostate under transrectal ultrasound (TRUS) guidance, in an outpatient setting without the need for anaesthesia or routine catheterization. In a few trials, NX-1207 has demonstrated symptomatic improvement better than some currently approved 38
www.co-urology.com
BPH medications. To date, there have been no significant safety issues [9]. Larger, pivotal, multicentre phase III trials have completed enrollment, and results are expected in early 2014, to further report on the efficacy, safety, and tolerability for this minimally invasive treatment for BPH. PRX302 (generic name: topsalysin) (Sophiris Bio Corp., San Diego, California, USA; formerly Protox Therapeutics) is a PSA-activated, modified, poreforming protein (proaerolysin), which can be transperineally injected into the transition zone of the prostate under TRUS guidance, to reduce prostate volumes and improve LUTS due to BPH, in an outpatient setting. A total of 60% of men in phase 1 studies (n ¼ 15) and 64% of men in phase 2 studies (n ¼ 18) treated with PRX302 had at least 30% improvement compared to baseline in IPSS, QoL, and prostate volumes, which was sustained at 360 days’ follow-up. Adverse events were mild-tomoderate and transient in nature, with no erectile dysfunction [10]. In a larger, randomized, phase IIb, double-blind study of 92 patients, the PRX302 injection volume administered was 20% of prostate volume and 0.6 g PRX302 per gram of prostate. There was clinically meaningful and statistically significant improvement in IPSS (by about 9 points) and Qmax (by 3 m/s) compared with placebo, and efficacy was sustained for 12 months. PRX302 apparent toxicity was mild, transient, and limited to local discomfort or pain and irritative urinary symptoms occurring in the initial few days, with no adverse effect on erectile function. Larger phase III trials are being initiated in 2013 [11]. In conclusion, further larger controlled clinical trials documenting the efficacy and side-effects of the various intraprostatic injectable agents are needed before their place in the treatment of LUTS due to BPH can be adequately determined.
Mechanical devices The concept of using a mechanical device to ‘hold open’ the prostatic urethral lumen has been previously performed by prostatic urethral stents which can be either temporary (such as Urolume) or permanent/nonepithelializing (such as Memokath). The PUL device provides a novel method of ‘holding open’ the prostatic urethra to treat LUTS due to BPH. Prostatic urethral lift (Urolift) The PUL procedure is a novel minimally invasive treatment for symptomatic BPH which aims to mechanically open the prostatic urethra by using permanent tensioning sutures positioned from the urethra to the outer fibrous capsule, to separate the Volume 24 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Benign prostatic hyperplasia surgery Chung and Woo
encroaching prostatic lobes (Fig. 1). No ablation or resection of prostatic tissue is performed. The PUL procedure using the Urolift (NeoTract Inc., Pleasanton, California, USA) implants have been shown to achieve rapid and clinically meaningful improvement in LUTS that are durable to at least 2 years [12]. The first, randomized controlled blinded trial demonstrated a reduction in American Urological Association Symptom Index from baseline by 4 points at 2 weeks, 11 points by 3 months, and this reduction remained stable to 1 year. The reported Qmax improvement (4 m/s) was both clinically and statistically significant [13 ]. The reported advantages of PUL include a low complication profile, preservation of ejaculatory and erectile function, and minimal to no catheter requirement [14,15]. It has also been successfully performed under local anaesthesia in the outpatient setting [16]. A comprehensive literature review found that although PUL seems to offer a better IPSS improvement when compared to medical therapy, the result is inferior when compared with surgical therapy [17]. It is the opinion of the authors that PUL has a valuable role in the group of patients who are refractory or unsuitable for medical therapy, and who are either unfit for more invasive surgical therapies (perhaps older patients) or in whom preservation of ejaculatory or erectile function is important (such as in younger patients). &&
Prostatic stents Prostatic stents can be classified as permanent (such as the Urolume) or temporary/nonepithelializing (such as the Memokath and Allium stents). Permanent (Urolume) The long-term results evaluating the treatment of BPH using the Urolume endourethral prosthesis (American Medical Systems, Minnetonka, Minnesota, USA) was published in 2004. In selected patients, the Urolume is a minimally invasive treatment option. However, over 12 years, 29 (47%)
stents were removed. Early stent explantation was primarily a result of poor case selection or stent malposition and migration. Late stent explantation was for symptom progression [18]. There have been no significant recent publications regarding this device in the last 12–18 months. Temporary and nonepithelializing A systematic review of the published reports regarding the safety, effectiveness, and durability of a selfexpanding metallic prostatic stent (Memokath, Engineers & Doctors Association Ltd., Denmark) in patients with BPH who are unfit for surgery was published in 2006. It concluded that the Memokath stent can provide an effective treatment for BPH in men at high operative risk; it also appears to be well tolerated, but inadequate follow-up does not allow firm conclusions on stent durability [19]. No recent large studies have been published regarding the Memokath in the last 12–18 months. The most recently marketed stent is the Allium stent. This is a temporary self-expanding nitinol wire stent that is structured as a triangular skeleton which is completely covered by a biocompatible polymer (Fig. 2). The novel triangular structure potentially enables better conformation to the prostatic lumen, whereas the polymer coating prevents tissue ingrowth and aids in subsequent removal. No English language publications on experience with this stent as a treatment for prostatic obstruction have been identified on literature search. Intuitively, the stent is unlikely to have adverse events additional to previous stent technology, although clinical data are awaited.
Other minimally invasive technologies Other novel minimally invasive procedures include Rezum, Histotripsy, and Aquablation. Rezum The Rezum System (NxThera, Maple Grove, Minnesota, USA) is a novel transurethral therapy
FIGURE 1. The prostatic urethral lift is a mechanical approach achieved by transurethrally deploying a needle beyond the prostate capsule (a) and delivering suture-based implants that are placed under tension (b and c) which mechanically retract the prostatic lobes (d). Reproduced by courtesy of Neotract Inc. (for images). 0963-0643 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-urology.com
39
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Benign prostatic hyperplasia
safety and efficacy of the Vortx Rx Histotripsy BPH Device (HistoSonics Inc., Ann Arbor, Michigan, USA) have commenced in the USA and Canada – both commenced recruiting individuals in 2013 and these first-in-man study results are awaited (clinical trial ID NCT01775488 at ClinicalTrials.gov).
FIGURE 2. The Allium stent is a temporary self-expanding nitinol wire stent which is covered in a biocompatible copolymer. Reproduced by courtesy of Allium Medical Solutions Ltd (for images).
for BPH which utilizes targeted controlled water vapour (steam) to create necrotic lesion within the prostate, and is intended to be performed in an outpatient setting under local anaesthesia. Combined results of a 15 patient first-in-man dose-ranging trial and a 15 patient Rezum I (pilot) study were presented at the 2013 European Association of Urology Congress. The Rezum System was reported to achieve effective, rapid, controlled, prostatic ablation with a procedure time of less than 5 min, clinically relevant improvements in IPSS, QoL, Qmax, and PVR at 6 months, and without reports of urinary incontinence, erectile dysfunction, or ejaculatory dysfunction as a consequence of treatment [20]. Further studies are obviously warranted. Histotripsy Histotripsy is an extracorporeal therapeutic ultrasound technology, in which high-amplitude acoustic energy is applied to the targeted tissue to achieve acoustic cavitation. Ultrasound pressure changes form microbubbles in tissues and the energetic microbubbles fragment the tissue, causing cell destruction. Studies have shown the feasibility, safety, and effectiveness of histotripsy tissue homogenization and debulking of the prostate in the canine model. A recent study in a canine model examined the susceptibility of critical periprostatic structures to cavitation injury in the event of histotripsy mistargeting. Direct targeting of the bladder trigone with supratherapeutic histotripsy as a ‘worst-case, destructive testing’ scenario failed to induce significant tissue damage or clinical complication [21]. Two trials in humans to assess the initial 40
www.co-urology.com
Aquablation The Procept Aquablation System (Procept Biorobotics Corp., Redwood Shores, California, USA) is a newly developed technology under trial for the treatment of BPH. Aquablation involves a transurethral procedure which delivers a high-pressure water jet that fractionates tissue without thermal injury. A dedicated surgical laser (the AquabeamTM) was delivered through the column of water to coagulate tissue and effect haemostasis. A pilot study commenced recruiting patients in 2013 (clinical trial ID ACTRN12613000167763 at Australian New Zealand Clinical Trials Registry).
CONCLUSION The Urolift device for PUL has shown safety and efficacy for the treatment of BPH in phase III clinical trials, with the advantage of an outpatient procedure under local anaesthesia, no catheter requirement, and no sexual dysfunction. Further studies will confirm the currently mixed results regarding intraprostatic botulinum toxin and ethanol injections. Other than possibly ethanol ablation, these treatments appear to be truly minimally invasive with minimal significant morbidity. Newer injectable agents such as NX-1207 and PRX302 are under clinical trial. Several novel technologies such as Rezum, Histotripsy, and Aquablation are experimental and under clinical investigation. Acknowledgements None. Conflicts of interest Disclosures: A.C. has no disclosures. H.W. has stock holding and was formerly a consultant to Neotract.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Yokoyama T, Yamamoto Y, Suzuki T, et al. Intraprostatic botulinum neurotoxin type a injection for benign prostatic hyperplasia: preliminary results with a newly purified neurotoxin. Acta Med Okayama 2012; 66:291–297. 2. Sacco E, Bientinesi R, Marangi F, et al. Patient-reported outcomes in men with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with intraprostatic OnabotulinumtoxinA: 3-month results of a prospective single-armed cohort study. BJU Int 2012; 110:E837–E844.
Volume 24 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Benign prostatic hyperplasia surgery Chung and Woo 3. Hamidi Madani A, Enshaei A, Heidarzadeh A, et al. Transurethral intraprostatic Botulinum toxin-A injection: a novel treatment for BPH refractory to current medical therapy in poor surgical candidates. World J Urol 2013; 31:235– 239. 4. 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. A multicentre, double-blind, randomized, placebo-controlled trial which demonstrated reductions in LUTS and BPH symptoms in all groups, including placebo, with no significant between group differences owing to a large placebo effect from the injectable therapy. 5. Seth J, Khan MS, Dasgupta P, Sahai A. Botulinum toxin – what urologic uses does the data support? Curr Urol Rep 2013; 14:227–234. 6. Andersson KE. Treatment of lower urinary tract symptoms: agents for intraprostatic injection. Scand J Urol 2013; 47:83–90. 7. Faruque MS, Alam MK, Ullah MA, et al. Evaluation of transurethral ethanol & ablation of prostate for symptomatic benign prostatic hyperplasia. Mymensingh Med J 2012; 21:265–269. Transurethral ethanol ablation of prostate appears to be well tolerated and costeffective for the treatment of LUTS and BPH in the short term (3 months). 8. Grise P, Plante M, Palmer J, et al. Evaluation of the transurethral ethanol ablation of the prostate (TEAP) for symptomatic benign prostatic hyperplasia (BPH): a European multi-center evaluation. Eur Urol 2004; 46: 496–502. 9. Shore N, Cowan B. The potential for NX-1207 in benign prostatic hyperplasia: an update for clinicians. Ther Adv Chronic Dis 2011; 2:377–383. 10. Chevalier S, Cury FL, Scarlata E, et al. Endoscopic vascular targeted photodynamic therapy with the photosensitizer TOOKAD(R) soluble (WST11) for benign prostatic hyperplasia in the pre-clinical dog model. J Urol 2013; 190:1946–1953. 11. Elhilali M, Pommerville P, Yocum R, et al. Prospective, randomized, doubleblind, vehicle controlled, multicenter phase IIb clinical trial of the pore forming protein PRX302 for targeted treatment of symptomatic benign prostatic hyperplasia. J Urol 2013; 189:1421–1426.
12. Chin PT, Bolton DM, Jack G, et al. Prostatic urethral lift: two-year results after treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. Urology 2012; 79:5–11. 13. Roehrborn CG, Gange SN, Shore ND, et al. Multi-center randomized con&& trolled blinded study of the prostatic urethral lift for the treatment of LUTS associated with prostate enlargement due to BPH: the L.I.F.T. Study. J Urol 2013. [Epub ahead of print]. doi: 10.1016/j.juro.2013.05.116. The first, multicentre, randomized blinded trial of the Prostatic Urethral Lift (Urolift), which concludes the procedure is reliably performed under local anaesthesia, provides rapid and sustained improvement in symptoms and flow, whilst preserving sexual function. 14. McNicholas TA, Woo HH, Chin PT, et al. Minimally invasive prostatic urethral lift: surgical technique and multinational experience. Eur Urol 2013; 64:292– 299. 15. Woo HH, Bolton DM, Laborde E, et al. Preservation of sexual function with the prostatic urethral lift: a novel treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Sex Med 2012; 9:568–575. 16. Barkin J, Giddens J, Incze P, et al. UroLift system for relief of prostate obstruction under local anesthesia. Can J Urol 2012; 19:6217–6222. 17. Larcher A, Broglia L, Lughezzani G, et al. Urethral lift for benign prostatic hyperplasia: a comprehensive review of the literature. Curr Urol Rep 2013; 14:620–627. 18. Masood S, Djaladat H, Kouriefs C, et al. The 12-year outcome analysis of an endourethral wallstent for treating benign prostatic hyperplasia. BJU Int 2004; 94:1271–1274. 19. Armitage JN, Rashidian A, Cathcart PJ, et al. The thermo-expandable metallic stent for managing benign prostatic hyperplasia: a systematic review. BJU Int 2006; 98:806–810. 20. Dixon C, Rijo Cedano E, Pacik D, et al. Transurethral water vapor therapy for BPH; initial clinical results of the first in man trial and Rezum I pilot study. Eur Urol Suppl 2013; 12:e631. 21. Allam C, Wilkinson JE, Cheng X, et al. Histotripsy effects on the bladder trigone: functional and histologic consequences in the canine model. J Endourol 2013; 27:1267–1271.
0963-0643 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-urology.com
41
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
What’s truly minimally invasive in benign prostatic hyperplasia surgery? Amanda Chung and Henry H. Woo
Purpose of review There continues to be a strong interest in the novel minimally invasive therapies for lower urinary tract symptoms due to benign prostatic hyperplasia (BPH). There has been an emergence of new approaches, particularly with mechanical approaches such as the Urolift and new agents suitable for intraprostatic injection. Our purpose is to review the recent literature regarding the safety and efficacy of these therapies, and introduce a number of promising experimental therapies. Recent findings The Urolift device has shown safety and efficacy for BPH treatment in phase III clinical trials, with the advantage of a local anaesthetic outpatient procedure, no catheter, and no sexual dysfunction. Intraprostatic injection of botulinum toxin or ethanol has provided mixed results and need further well designed studies. NX-1207 and PRX302 are newer injectable agents under clinical trial. Several novel therapies such as Rezum, Histotripsy, and Aquablation have no published efficacy and safety data available. Summary Urolift appears to be a well tolerated and effective minimally invasive treatment for lower urinary tract symptoms due to BPH in men who wish to preserve sexual function or who are not suitable for invasive surgery. Further studies will confirm the currently mixed results regarding intraprostatic botulinum toxin or ethanol injections. Rezum, Histotripsy, and Aquablation are experimental treatments under investigation. Keywords benign prostatic hyperplasia, injections, lower urinary tract symptoms, minimally invasive surgical procedures
INTRODUCTION Over the last 2 decades, there has been a strong interest in the minimally invasive surgical therapies for lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). More recently, there has been particular interest in mechanical devices, such as the Urolift for the prostatic urethral lift (PUL) procedure, and intraprostatic injections of various agents. Injectable agents have included ethanol and botulinum toxin, but newer agents under investigation such as NX-1207 and PRX302 are generating much interest. Particularly, novel minimally invasive approaches include water vapour tissue destruction using Rezum technology, mechanical treatments such as Histotripsy, and combination modality treatment such as Aquablation. Our purpose is to review the recent literature on the safety and efficacy of these novel therapies as well as introduce several promising experimental therapies under investigation. The focus of this review will be to discuss these newer minimally invasive approaches, given that treatments that have been commercially available for www.co-urology.com
many years have already been well covered in the systematic reviews or meta-analyses. The key features of each minimally invasive treatment are outlined in Table 1.
NEW MINIMALLY INVASIVE SURGICAL TREATMENTS Intraprostatic injections Injection therapy, using the transperineal, transrectal, and transurethral routes for delivery of various active compounds, has not been very widely used. Sydney Adventist Hospital Clinical School, University of Sydney, Sydney, New South Wales, Australia Correspondence to Assistant Professor Henry H. Woo, Sydney Adventist Hospital Clinical School, University of Sydney, P.O. Box 5017, Wahroonga, Sydney, NSW 2076, Australia. Tel: +61 2 9473 8765; fax: +61 2 9473 8969; e-mail: [email protected] Curr Opin Urol 2014, 24:36–41 DOI:10.1097/MOU.0000000000000006 Volume 24 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Benign prostatic hyperplasia surgery Chung and Woo
KEY POINTS The prostatic urethral lift procedure (Urolift) has shown safety and efficacy in the treatment of LUTS due to BPH in phase III clinical trials, with the preservation of sexual function. Intraprostatic injections of botulinum toxin mixed results. Further well designed studies are needed. Novel intraprostatic injection agents include NX-1207 and PRX302, and are undergoing clinical trials. The most recently marketed prostatic urethral stent is the Allium stent, for which clinical publications (in English) are awaited. Novel experimental technologies include Rezum (water vapour and steam), Histotripsy, and Aquablation, and are under development and clinical investigation.
However, the recent development of several novel and seemingly effective agents (such as botulinum toxin) has attracted new interest in this area.
prostate as a treatment for LUTS due to BPH. Earlier results demonstrated that intraprostatic BTX-A injection induces prostate shrinkage, and 7 of 10 patients experienced improvement in their LUTS within 1 month of treatment [1]. In a nonrandomized, prospective, single-armed cohort study of 64 men, the intraprostatic injection of BTX-A provided clinically significant short-term subjective and objective benefit, and appeared to be a well tolerated and minimally invasive option for standard medication-refractory BPH [2]. Mean International Prostate Symptom Score (IPSS), Qmax, prostate volume, prostate-specific antigen (PSA), and frequency of nocturia improved significantly [3]. However, more recent results are mixed. A large, multicentre, randomized, double-blind, placebocontrolled, phase 2, dose-ranging study (n ¼ 374) showed significant improvements from baseline in IPSS, Qmax, total prostate volume (TPV), and transitional zone volume (TZV) for a variety of BTX-A dosage groups (100 U, 200 U, and 300 U), as well as the placebo group, at week 12 (P < 0.001), with no significant differences between BTX-A and placebo [4 ,5]. The incidence of adverse events was similar across the treatment groups. Most adverse events were related to the procedure, and no serious adverse events were considered related to the study &
Intraprostatic botulinum toxin injection Onabotulinum toxin A (BTX-A) can be injected via the transperineal or transrectal route into the
Table 1. Summary of minimal-invasive surgeries and key features
Technology
a
Local Outpatient Routine Commercially anaesthesia treatment catheterization available? possible? possible? essential? Clinical trial dataa
Adverse events
Intraprostatic botulinum Yes toxin injection
Yes
Yes
No
Phase 2 trial completed and published.
Not significant
Intraprostatic ethanol injection
Yes
Yes
Yes
No
Phase 2 trial completed and published.
Infrequent but catastrophic bladder necrosis reported
Intraprostatic NX-1207 No injection
Yes
Yes
No
Phase 2 trial completed Not significant and published. Phase 3 trial in progress.
Intraprostatic PRX302 injection
No
Yes
Yes
No
Phase 2 trial completed and published.
Not significant
Urolift
Yes
Yes
Yes
No
Phase 3 trial completed and published.
Not significant
Urolume stent
Yes
Yes
Yes
No
Phase 3 trial completed and published.
Migration/explantation
Memokath stent
Yes
Yes
Yes
No
Phase 3 trial completed and published
Migration/explantation
Allium stent
Yes
Yes
Yes
No
None published
Unknown
Rezum
No
Yes
Yes
No
None published
Postprocedure acute urinary retention in 50%
Histotripsy
No
Unknown
Unknown
Unknown
Pilot study in progress.
Unknown
Aquablation
No
Unknown
Unknown
Unknown
Pilot study in progress.
Unknown
English language publications on PubMed.
0963-0643 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-urology.com
37
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Benign prostatic hyperplasia
drug. Prostatitis occurred in 2.1% of patients and resolved with medical treatment. One patient in the 300 U group discontinued the study because of prostatitis, one patient in the 200 U group discontinued because of death due to a traffic accident, and two patients from the placebo group discontinued because of urinary hesitancy/nocturia and urinary retention. There was no significant change in the International Index of Erectile Function (IIEF) scores, vital signs, physical examination, or laboratory evaluations. In an exploratory post hoc analysis, a significant reduction in IPSS versus placebo was observed with BTX-A 200 U in prior alpha-blocker users (n ¼ 180) at week 12 [4 ]. Although further investigation is needed in prospective well designed studies to verify this post hoc analysis result, the results to this point in time have failed to meet the expectations. &
Intraprostatic ethanol injection Anhydrous ethanol is one of the most extensively studied injected agents [6]. Transurethral ethanol ablation of the prostate has been reported to be well tolerated and cost-effective. One study reported that 6–13.5 ml ethanol was endoscopically injected at 4–8 sites in the prostate of 30 men. The shortterm (3 months) outcomes were satisfactory and acceptable with significant (P < 0.05) improvements in IPSS (mean 18.43 2.38 to 6.80 1.34), Qmax (mean 7.33 1.19 to 16.31 1.69), and post void residual (PVR) (mean 54.16 30.93 to 17.01 9.59). The prostate size decreased significantly from a mean of 44.66 (9.52) preoperatively to 32.46 (7.78) postoperatively. Postoperative complications included haematuria, urinary retention, and urinary tract infection, but there was no retrograde ejaculation reported [7 ]. A major concern of this treatment has been the potential for inadvertent proximal injection into the bladder wall, which can give rise to catastrophic bladder necrosis [8]. &
Other agents for intraprostatic injection Other agents such as NX-1207 and PRX302 have been reported to have promising effects [6]. NX-1207 (Nymox Pharmaceutical Co., Hasbrouck Heights, New Jersey, USA) is a protein with selective proapoptotic properties which induce focal cell loss in prostatic tissue, leading to prostate volume reduction. It is administered by injection into the periurethral transitional zone of the prostate under transrectal ultrasound (TRUS) guidance, in an outpatient setting without the need for anaesthesia or routine catheterization. In a few trials, NX-1207 has demonstrated symptomatic improvement better than some currently approved 38
www.co-urology.com
BPH medications. To date, there have been no significant safety issues [9]. Larger, pivotal, multicentre phase III trials have completed enrollment, and results are expected in early 2014, to further report on the efficacy, safety, and tolerability for this minimally invasive treatment for BPH. PRX302 (generic name: topsalysin) (Sophiris Bio Corp., San Diego, California, USA; formerly Protox Therapeutics) is a PSA-activated, modified, poreforming protein (proaerolysin), which can be transperineally injected into the transition zone of the prostate under TRUS guidance, to reduce prostate volumes and improve LUTS due to BPH, in an outpatient setting. A total of 60% of men in phase 1 studies (n ¼ 15) and 64% of men in phase 2 studies (n ¼ 18) treated with PRX302 had at least 30% improvement compared to baseline in IPSS, QoL, and prostate volumes, which was sustained at 360 days’ follow-up. Adverse events were mild-tomoderate and transient in nature, with no erectile dysfunction [10]. In a larger, randomized, phase IIb, double-blind study of 92 patients, the PRX302 injection volume administered was 20% of prostate volume and 0.6 g PRX302 per gram of prostate. There was clinically meaningful and statistically significant improvement in IPSS (by about 9 points) and Qmax (by 3 m/s) compared with placebo, and efficacy was sustained for 12 months. PRX302 apparent toxicity was mild, transient, and limited to local discomfort or pain and irritative urinary symptoms occurring in the initial few days, with no adverse effect on erectile function. Larger phase III trials are being initiated in 2013 [11]. In conclusion, further larger controlled clinical trials documenting the efficacy and side-effects of the various intraprostatic injectable agents are needed before their place in the treatment of LUTS due to BPH can be adequately determined.
Mechanical devices The concept of using a mechanical device to ‘hold open’ the prostatic urethral lumen has been previously performed by prostatic urethral stents which can be either temporary (such as Urolume) or permanent/nonepithelializing (such as Memokath). The PUL device provides a novel method of ‘holding open’ the prostatic urethra to treat LUTS due to BPH. Prostatic urethral lift (Urolift) The PUL procedure is a novel minimally invasive treatment for symptomatic BPH which aims to mechanically open the prostatic urethra by using permanent tensioning sutures positioned from the urethra to the outer fibrous capsule, to separate the Volume 24 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Benign prostatic hyperplasia surgery Chung and Woo
encroaching prostatic lobes (Fig. 1). No ablation or resection of prostatic tissue is performed. The PUL procedure using the Urolift (NeoTract Inc., Pleasanton, California, USA) implants have been shown to achieve rapid and clinically meaningful improvement in LUTS that are durable to at least 2 years [12]. The first, randomized controlled blinded trial demonstrated a reduction in American Urological Association Symptom Index from baseline by 4 points at 2 weeks, 11 points by 3 months, and this reduction remained stable to 1 year. The reported Qmax improvement (4 m/s) was both clinically and statistically significant [13 ]. The reported advantages of PUL include a low complication profile, preservation of ejaculatory and erectile function, and minimal to no catheter requirement [14,15]. It has also been successfully performed under local anaesthesia in the outpatient setting [16]. A comprehensive literature review found that although PUL seems to offer a better IPSS improvement when compared to medical therapy, the result is inferior when compared with surgical therapy [17]. It is the opinion of the authors that PUL has a valuable role in the group of patients who are refractory or unsuitable for medical therapy, and who are either unfit for more invasive surgical therapies (perhaps older patients) or in whom preservation of ejaculatory or erectile function is important (such as in younger patients). &&
Prostatic stents Prostatic stents can be classified as permanent (such as the Urolume) or temporary/nonepithelializing (such as the Memokath and Allium stents). Permanent (Urolume) The long-term results evaluating the treatment of BPH using the Urolume endourethral prosthesis (American Medical Systems, Minnetonka, Minnesota, USA) was published in 2004. In selected patients, the Urolume is a minimally invasive treatment option. However, over 12 years, 29 (47%)
stents were removed. Early stent explantation was primarily a result of poor case selection or stent malposition and migration. Late stent explantation was for symptom progression [18]. There have been no significant recent publications regarding this device in the last 12–18 months. Temporary and nonepithelializing A systematic review of the published reports regarding the safety, effectiveness, and durability of a selfexpanding metallic prostatic stent (Memokath, Engineers & Doctors Association Ltd., Denmark) in patients with BPH who are unfit for surgery was published in 2006. It concluded that the Memokath stent can provide an effective treatment for BPH in men at high operative risk; it also appears to be well tolerated, but inadequate follow-up does not allow firm conclusions on stent durability [19]. No recent large studies have been published regarding the Memokath in the last 12–18 months. The most recently marketed stent is the Allium stent. This is a temporary self-expanding nitinol wire stent that is structured as a triangular skeleton which is completely covered by a biocompatible polymer (Fig. 2). The novel triangular structure potentially enables better conformation to the prostatic lumen, whereas the polymer coating prevents tissue ingrowth and aids in subsequent removal. No English language publications on experience with this stent as a treatment for prostatic obstruction have been identified on literature search. Intuitively, the stent is unlikely to have adverse events additional to previous stent technology, although clinical data are awaited.
Other minimally invasive technologies Other novel minimally invasive procedures include Rezum, Histotripsy, and Aquablation. Rezum The Rezum System (NxThera, Maple Grove, Minnesota, USA) is a novel transurethral therapy
FIGURE 1. The prostatic urethral lift is a mechanical approach achieved by transurethrally deploying a needle beyond the prostate capsule (a) and delivering suture-based implants that are placed under tension (b and c) which mechanically retract the prostatic lobes (d). Reproduced by courtesy of Neotract Inc. (for images). 0963-0643 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-urology.com
39
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Benign prostatic hyperplasia
safety and efficacy of the Vortx Rx Histotripsy BPH Device (HistoSonics Inc., Ann Arbor, Michigan, USA) have commenced in the USA and Canada – both commenced recruiting individuals in 2013 and these first-in-man study results are awaited (clinical trial ID NCT01775488 at ClinicalTrials.gov).
FIGURE 2. The Allium stent is a temporary self-expanding nitinol wire stent which is covered in a biocompatible copolymer. Reproduced by courtesy of Allium Medical Solutions Ltd (for images).
for BPH which utilizes targeted controlled water vapour (steam) to create necrotic lesion within the prostate, and is intended to be performed in an outpatient setting under local anaesthesia. Combined results of a 15 patient first-in-man dose-ranging trial and a 15 patient Rezum I (pilot) study were presented at the 2013 European Association of Urology Congress. The Rezum System was reported to achieve effective, rapid, controlled, prostatic ablation with a procedure time of less than 5 min, clinically relevant improvements in IPSS, QoL, Qmax, and PVR at 6 months, and without reports of urinary incontinence, erectile dysfunction, or ejaculatory dysfunction as a consequence of treatment [20]. Further studies are obviously warranted. Histotripsy Histotripsy is an extracorporeal therapeutic ultrasound technology, in which high-amplitude acoustic energy is applied to the targeted tissue to achieve acoustic cavitation. Ultrasound pressure changes form microbubbles in tissues and the energetic microbubbles fragment the tissue, causing cell destruction. Studies have shown the feasibility, safety, and effectiveness of histotripsy tissue homogenization and debulking of the prostate in the canine model. A recent study in a canine model examined the susceptibility of critical periprostatic structures to cavitation injury in the event of histotripsy mistargeting. Direct targeting of the bladder trigone with supratherapeutic histotripsy as a ‘worst-case, destructive testing’ scenario failed to induce significant tissue damage or clinical complication [21]. Two trials in humans to assess the initial 40
www.co-urology.com
Aquablation The Procept Aquablation System (Procept Biorobotics Corp., Redwood Shores, California, USA) is a newly developed technology under trial for the treatment of BPH. Aquablation involves a transurethral procedure which delivers a high-pressure water jet that fractionates tissue without thermal injury. A dedicated surgical laser (the AquabeamTM) was delivered through the column of water to coagulate tissue and effect haemostasis. A pilot study commenced recruiting patients in 2013 (clinical trial ID ACTRN12613000167763 at Australian New Zealand Clinical Trials Registry).
CONCLUSION The Urolift device for PUL has shown safety and efficacy for the treatment of BPH in phase III clinical trials, with the advantage of an outpatient procedure under local anaesthesia, no catheter requirement, and no sexual dysfunction. Further studies will confirm the currently mixed results regarding intraprostatic botulinum toxin and ethanol injections. Other than possibly ethanol ablation, these treatments appear to be truly minimally invasive with minimal significant morbidity. Newer injectable agents such as NX-1207 and PRX302 are under clinical trial. Several novel technologies such as Rezum, Histotripsy, and Aquablation are experimental and under clinical investigation. Acknowledgements None. Conflicts of interest Disclosures: A.C. has no disclosures. H.W. has stock holding and was formerly a consultant to Neotract.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Yokoyama T, Yamamoto Y, Suzuki T, et al. Intraprostatic botulinum neurotoxin type a injection for benign prostatic hyperplasia: preliminary results with a newly purified neurotoxin. Acta Med Okayama 2012; 66:291–297. 2. Sacco E, Bientinesi R, Marangi F, et al. Patient-reported outcomes in men with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with intraprostatic OnabotulinumtoxinA: 3-month results of a prospective single-armed cohort study. BJU Int 2012; 110:E837–E844.
Volume 24 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Benign prostatic hyperplasia surgery Chung and Woo 3. Hamidi Madani A, Enshaei A, Heidarzadeh A, et al. Transurethral intraprostatic Botulinum toxin-A injection: a novel treatment for BPH refractory to current medical therapy in poor surgical candidates. World J Urol 2013; 31:235– 239. 4. 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. A multicentre, double-blind, randomized, placebo-controlled trial which demonstrated reductions in LUTS and BPH symptoms in all groups, including placebo, with no significant between group differences owing to a large placebo effect from the injectable therapy. 5. Seth J, Khan MS, Dasgupta P, Sahai A. Botulinum toxin – what urologic uses does the data support? Curr Urol Rep 2013; 14:227–234. 6. Andersson KE. Treatment of lower urinary tract symptoms: agents for intraprostatic injection. Scand J Urol 2013; 47:83–90. 7. Faruque MS, Alam MK, Ullah MA, et al. Evaluation of transurethral ethanol & ablation of prostate for symptomatic benign prostatic hyperplasia. Mymensingh Med J 2012; 21:265–269. Transurethral ethanol ablation of prostate appears to be well tolerated and costeffective for the treatment of LUTS and BPH in the short term (3 months). 8. Grise P, Plante M, Palmer J, et al. Evaluation of the transurethral ethanol ablation of the prostate (TEAP) for symptomatic benign prostatic hyperplasia (BPH): a European multi-center evaluation. Eur Urol 2004; 46: 496–502. 9. Shore N, Cowan B. The potential for NX-1207 in benign prostatic hyperplasia: an update for clinicians. Ther Adv Chronic Dis 2011; 2:377–383. 10. Chevalier S, Cury FL, Scarlata E, et al. Endoscopic vascular targeted photodynamic therapy with the photosensitizer TOOKAD(R) soluble (WST11) for benign prostatic hyperplasia in the pre-clinical dog model. J Urol 2013; 190:1946–1953. 11. Elhilali M, Pommerville P, Yocum R, et al. Prospective, randomized, doubleblind, vehicle controlled, multicenter phase IIb clinical trial of the pore forming protein PRX302 for targeted treatment of symptomatic benign prostatic hyperplasia. J Urol 2013; 189:1421–1426.
12. Chin PT, Bolton DM, Jack G, et al. Prostatic urethral lift: two-year results after treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. Urology 2012; 79:5–11. 13. Roehrborn CG, Gange SN, Shore ND, et al. Multi-center randomized con&& trolled blinded study of the prostatic urethral lift for the treatment of LUTS associated with prostate enlargement due to BPH: the L.I.F.T. Study. J Urol 2013. [Epub ahead of print]. doi: 10.1016/j.juro.2013.05.116. The first, multicentre, randomized blinded trial of the Prostatic Urethral Lift (Urolift), which concludes the procedure is reliably performed under local anaesthesia, provides rapid and sustained improvement in symptoms and flow, whilst preserving sexual function. 14. McNicholas TA, Woo HH, Chin PT, et al. Minimally invasive prostatic urethral lift: surgical technique and multinational experience. Eur Urol 2013; 64:292– 299. 15. Woo HH, Bolton DM, Laborde E, et al. Preservation of sexual function with the prostatic urethral lift: a novel treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Sex Med 2012; 9:568–575. 16. Barkin J, Giddens J, Incze P, et al. UroLift system for relief of prostate obstruction under local anesthesia. Can J Urol 2012; 19:6217–6222. 17. Larcher A, Broglia L, Lughezzani G, et al. Urethral lift for benign prostatic hyperplasia: a comprehensive review of the literature. Curr Urol Rep 2013; 14:620–627. 18. Masood S, Djaladat H, Kouriefs C, et al. The 12-year outcome analysis of an endourethral wallstent for treating benign prostatic hyperplasia. BJU Int 2004; 94:1271–1274. 19. Armitage JN, Rashidian A, Cathcart PJ, et al. The thermo-expandable metallic stent for managing benign prostatic hyperplasia: a systematic review. BJU Int 2006; 98:806–810. 20. Dixon C, Rijo Cedano E, Pacik D, et al. Transurethral water vapor therapy for BPH; initial clinical results of the first in man trial and Rezum I pilot study. Eur Urol Suppl 2013; 12:e631. 21. Allam C, Wilkinson JE, Cheng X, et al. Histotripsy effects on the bladder trigone: functional and histologic consequences in the canine model. J Endourol 2013; 27:1267–1271.
0963-0643 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-urology.com
41
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
