Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) is a common affliction among older men that can have a significant impact on health-related quality of life. High-risk patients with BPH are defined as over 70 years in age and complicated with heart, brain and other organ diseases ; as such, these patients are at a significant risk of death during surgery. Because advanced age and comorbidity represents contraindications for surgery, it is crucial for treating physicians to identify and carry out the safest and most effective procedure for each of these patients, according to their unique physiological and biological profiles. Conventional treatment modalities such as transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP) or laser coagulation techniques have been declining in numbers in the last few years, whereas other established techniques such as transurethral radiofrequency needle ablation (TUNA), transurethral microwave thermoablation (TUMT), as well as laser vapourization and laser enucleation of the prostate are increasingly adapted [2▪].
Different additional emerging surgical treatment modalities have been presented in the last 12 months. Herein, we present an overview of emerging treatments of BPH and track the continued evolution in BPH surgical therapy.
After its introduction in the late 1980s, prostatic stenting has maintained a role over recent years, but due to the complications experienced with permanent stents, it only gained limited acceptance among urologists. Nevertheless, with the introduction of new stent materials and especially with the ongoing search for an alternative to long-term catheterization, the evaluation of prostatic stents is again work in progress.
Between July 2002 and December 2010, Sakamoto et al. implanted self-expanding nitinol urethral stents in the prostatic urethra of 36 patients. This is a tubular, web-shaped, flexible permanent stent that contracts in cold water and expands after being placed in the urethra at body temperature. Removing it is fairly easy after irrigating the urethra with cold water. The average follow-up period was 24 months. After stent implantation, 34 out of the 36 patients were able to urinate. The average residual urine volume was 24.7 ml (0–250 ml), and the maximal urinary flow rate was 10.7 ml/s (3–24 ml/s). Complications were one bladder tamponade, one stent dislocation and two stones. The authors concluded that therapy with the Memotherm urethral stent is a good option for patients suffering from urinary retention due to BPH not suitable to conventional procedures.
Sertcelik et al.[4▪▪] presented their results by adopting the same urethra stent for prostatic and bulbar stricture. At the end of a 7-year period, 37 out of 47 patients (78.7%) had been treated successfully. Postmicturition dribbling incontinence lasting up to 3 months after stent placement occurred in 68.1% patients, but this was reduced to only seven patients (14.9%) by the 7-year follow-up. There was stress incontinence of various severities in 19.2% patients at the 1-year follow-up. These patients were those who had stenosed urethral segments adjacent to the external sphincter. At the long-term follow-up, less than 10% of the patients had stress incontinence complaints [4▪▪].
Kotsar et al.[5▪] developed a new biocompatible biodegradable indomethacin-eluting urethral stent in order to reduce restenosis due to hyperplasia of the mucosa or scarring typically caused by bare metal prostatic stents.
Indomethacin is a well known NSAID that inhibits prostaglandin synthesis. The authors could demonstrate that indomethacin-eluting biodegradable urethral stents are highly biocompatible, and the new drug-releasing property does not remarkably affect the degradation time of these stents in vitro. Epithelial polyposis can be potentially reduced by drug-eluting stents, but further clinical studies are needed to evaluate whether it is possible to prevent urethral stricture formation with drug-eluting stents [5▪].
PROSTATIC URETHRAL LIFT PROCEDURE
Chin et al.[7▪] treated a total of 64 men, in a multicentre trial, with moderate to severe symptomatic BPH. The treatment consisted of transurethral delivery of small implants to secure the prostatic lobes in an open condition, thereby reducing obstruction of the urethral lumen.
The transurethral prostatic urethral lift was performed with the patient under local (n = 26) or general (n = 40) anaesthesia according to physician and patient preference. Local anaesthesia was typically coupled with light sedation and achieved either through urethral instillation of lidocaine jelly or an intraprostatic block. The implantation procedures were completed using a delivery device to compress a prostatic lateral lobe in an anterolateral direction towards the capsule and advance a spring-actuated, 19-gauge, 33-mm needle through the prostatic lobe and capsule. Multiple implants, typically 4 (range 2–9), were delivered.
The effectiveness, including International Prostate Symptom Score (IPSS), quality of life, BPH Impact Index and peak urethral flow rate were assessed at time intervals. The IPSS was reduced 42% at 2 weeks, 49% at 6 months and 42% at 2 years in evaluable patients. The peak flow rate improved by at least 30% (2.4 ml/s) at all intervals compared with baseline. The average postvoiding residual (PVR) urine volume was stable from baseline through the follow-up period.
The cystoscopic follow-up examination in 22 patients 6 months after the prostatic urethral lift revealed no evidence of encrustation, infection or other abnormalities. Overall, TURP, photoselective vaporization of the prostate or repeat prostatic urethral lift was conducted on 20% (13 out of 64) of patients in the 2-year follow-up period owing to failure to respond to the initial treatment.
The same study group could demonstrate that there was no evidence of degradation in sexual function after treatment for LUTS with the prostatic urethral lift procedure. Erectile function, as measured by Sexual Health Inventory for Men, was slightly increased at all time points as compared with baseline. No patient reported retrograde ejaculation at any follow-up visit .
INTRAPROSTATIC INJECTION OF BOTULINUM TOXIN
Botulinum neurotoxin type A (BoNTA) is the strongest biologic toxin known to humans . Nonetheless, human innovation was able to transform this strong poison into a treatment modality for a large variety of diseases .
Recently, the human use of BoNTA was extended to the treatment of BPH and BPH-related LUTS [9,10▪▪,11].
The mechanisms through which BoNTA is able to reduce prostate volume are, however, still unclear. At this moment, it is known that BoNTA induces apoptosis both in the epithelial and stromal cellular components of the prostate [10▪▪,11–13] and that the contractile response of the dog prostate tissue to phenylephrine or electrical stimulation was dose-dependently reduced by BoNTA .
In a recent clinical trial, 10 patients with LUTS suggestive of BPH who had responded poorly to medical therapy for at least 6 months and were poor surgical candidates received different doses of transurethral Botulinum-A injection on the basis of their prostate volume . The prostate volume, prostatic-specific antigen (PSA), Qmax, IPSS, PVR and frequency of nocturia were evaluated and compared before and after treatment.
The mean IPSS was 24.50 and 13.40 before and after the treatment, respectively (P < 0.001). The mean prostate volume was decreased from 41.50 to 30.40 ml (P < 0.001). The Qmax was increased from 7.87 to 16.19 ml/s (P < 0.001). The mean PSA was 3.12 and 1.71 ng/ml before and after the treatment, respectively (P < 0.001). The mean PVR was 75.6 and 63.50 ml before and after the treatment, respectively (P = 0.096). The mean number of nocturia was decreased from 4.1 to 2.4 (P < 0.001).
The authors concluded that transurethral intraprostatic injection of Botulinum-A may be an effective and well tolerated treatment for symptomatic BPH in selected patients whose medical treatment has faced failure and are poor surgical candidates.
In another prospective, nonrandomized clinical study , patients received transperineal injection of 200 U BTX-A in the transition zone, under transrectal ultrasonographic guidance.
The outcome assessment was performed at 3 months and included a patient-reported outcomes questionnaire with questions on patient global impression of improvement, satisfaction and efficacy. Patients reported a mean reduction of 49% in IPSS, which decreased from 19.7 to 10 (P < 0.001), and a mean reduction of 44% in IPSS health-related quality of life item score, which decreased from 4.17 to 2.3 (P < 0.001). There was a 33% increase in maximum urinary flow rate (P < 0.001) and an 80% reduction in PVR (P < 0.001). In all, 36 (56%) patients had a subjective improvement in LUTS, 43 (67%) reported satisfaction with the treatment and 44 (68%) judged the treatment as effective. In all, 50 (79%) patients would repeat the same treatment under the same circumstances, while 54 (84%) would recommend the treatment to another person with the same diagnosis.
Silva et al.[17▪▪] were the first to evaluate the consequences on male sexual function of intraprostatic injection of BoNTA as a treatment for BPH. Although BoNTA is effective in decreasing symptoms of BPH, neuronal impairment caused by the neurotoxin might affect emission/ejaculation. The authors included 16 sexually active men aged more than 60 years with BPH, IPSS of at least 8 and a maximum urinary flow rate Qmax of less than 15 ml/s refractory to standard medical therapy.
The mean age was 73 years. The international index of erectile function-5 score was 16.5 at baseline, 15.7 at 1 month, 16.6 at 3 months and 15.7 ± 5 at 6 months. The score for ejaculatory/orgasmic function remained fairly constant from baseline to the sixth month. The sexual desire score also remained little changed from baseline (5.9) to month 6 (6.1). Total serum testosterone, luteinizing hormone (LH), follicle-stimulating hormone and prolactin did not change during the study.
Intraprostatic injection of BoNTA in patients with BPH did not impair erectile, orgasmic or ejaculatory functions and did not change libido. The male hormonal profile was not altered by BoNTA injection. The authors concluded that this fact facilitates the acceptance of BoNTA as a treatment for BPH LUTS refractory to standard medical management.
INTRAPROSTATIC INJECTIONS WITH NX-1207
NX-1207 is an investigational drug for treatment of BPH that is currently in phase III, double-blinded, placebo-controlled, multicentre clinical trials in the USA [18▪]. It is a new therapeutic protein with reported apoptotic properties. A 0.25 mg/ml of this protein is administrated as an office-based procedure under local anaesthesia into the periurethral transitional zone of the prostate under TRUS guidance .
A first phase II trial (0014) was a multicentre, randomized, double-blind, placebo-controlled study involving 43 clinical trial sites in the USA [18▪]. A total of 175 men with BPH were enrolled in the study and randomized to receive a single intraprostatic injection of one of three doses of NX-1207 (2.5, 5.0 or 10 mg) or a saline vehicle placebo control.
The primary endpoint was an improvement in American urological association symptom index (AUASI) score after 90 days. All three doses of NX-1207 showed a therapeutic effect at the study's primary endpoint with a mean improvement in AUASI score ranging from 11.0 to 8.7 (5.0 mg; P = 0.08) to 8.1 (10 mg; P = 0.17). Patients receiving NX-1207 had mean prostate glandular volume reduction of 6.8 ml in the transition zone (P < 0.05, compared with placebo).
The second phase II trial (0016) was designed as a multicentre, randomized, noninferiority study involving 32 clinical US centres [18▪]. The 2.5-mg dose of NX-1207 was chosen for comparison with finasteride. The mean AUASI score improvement after 90 days in the intent-to-treat group was 9.71 points for NX-1207 versus 4.13 points for finasteride (P = 0.001).
Preclinical animal toxicology and safety studies showed no evidence of toxicity or other safety concerns for NX-1207 . There were no significant changes in serum testosterone or serum PSA levels in the NX-1207 cohorts and no reported adverse effects on sexual function of the patients in the NX-1207 cohorts [18▪]. Two large phase III trials are ongoing to further confirm efficacy, safety and tollerability for this catheter and anaesthetic-free, clinic-based procedure for the treatment of BPH.
HISTOTRIPSY FRACTIONATION OF PROSTATE TISSUE
Histotripsy is an experimental extracorporeal ultrasound technology that utilizes cavitational mechanisms to produce nonthermal tissue fractionation . Delivery of intense, short (<10 μs) bursts of ultrasound energy generates extreme pressures within the targeted focal volume leading to microbubble formation. Subsequent oscillation, coalescence and collapse of these bubbles mechanically fractionates targeted tissues reducing architectural and cellular structures to a fine slurry of acellular debris. This histotripsy process is markedly different than high-intensity focused ultrasound (HIFU), in which less intense 3–5 s pulses of acoustic energy are used to heat tissues and produce thermal coagulation .
This distinction was demonstrated in an in-vitro porcine kidney model in which acoustic parameters that produced desiccated HIFU lesions resulted in an average tissue temperature of 67.5°C, whereas mechanical tissue disruption (characteristic of histotripsy lesions) appeared to be temperature independent .
Recently, Hempel et al.[23▪] characterized the local effects and systemic response after histotripsy treatment of prostate tissue in an in-vivo canine model showing interesting results for a future clinical application in humans.
Eighteen intact male canines were used in this study. Histotripsy consisted of transabdominally delivery of three-cycle acoustic bursts (4 μs) at a repetition rate of 300 Hz from a 750 kHz, 18-element piezo-composite transducer. Coupling was achieved by placing the therapy apparatus in a bath of degassed water contained in a plastic membrane in direct contact with the shaved abdomen. A diagnostic 8-MHz imaging probe placed through the centre of the therapeutic transducer and aligned with the geometric focus confirmed location of the therapy volume within the prostate. A transrectal imaging probe was subsequently used to monitor cavitational activity during treatment. Histotripsy doses up to 270 000 pulses/cm3 were applied to preplanned treatment volumes of 4 cm3 (n = 11), 2 cm3 (n = 3) or 0.75 cm3 (n = 1) to ensure that the treatment did not extend outside the prostate.
In the 13 patients treated with planned ablation patterns of 1 × 2 cm cross-sectional dimension, the measured cross-sectional cavity area (height × width) was 1.95 cm2. The remnants of a typical acute inflammatory response, seen in prostates harvested 7 days after histotripsy, were replaced by normal histologic evidence of wound healing with minimal fibrosis and urothelialization of the treatment cavity at 28 and 56-day time points. All patients tolerated histotripsy treatments without incident. Observation of vital signs did not reveal any episodes of acute oxygen desaturization, pronounced tachycardia or hypo/hypertensive episodes. The overall average elevation in pain score (scale 0–18) was 0.7 points. An increase in pain score greater than 0.5 points was seen in six patients and returned to within 0.5 points of baseline 1 day after urinary catheter removal in all but two cases. No patients exhibited incontinence, urinary fistula or retention nor was there any evidence of acoustic collateral injury on direct and microscopic examination.
The authors obtained a precise debulking of the prostate confirmed by the presence of a cavity with sharp margins and corners on prostate cross-sections corresponding to the planned histotripsy target volume.
In the last decade, minimally invasive procedures have become increasingly popular options for interventional treatment of BPH, and several new options are showing up in preclinical trials. Nevertheless, we still need to define proofs of additional benefit of nonstandard surgical treatments for BPH and to create a decision scale to individually adapt the ideal surgical therapy for every single patient.
Conflicts of interest
The authors have no conflict of interest nor received any sponsorship or grant. No professional colleague or body has been involved in the preparation of the present article.
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
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 97–98).
1. Fritschi L, Tabrizi J, Leavy J, et al. Risk factors for surgically treated benign prostatic hyperplasia
in Western Australia. Public Health 2007; 121:781–789.
2▪. Malaeb BS, Yu X, McBean AM, et al. National trends in surgical therapy for benign prostatic hyperplasia
in the United States (2000-2008). Urology 2012; 79:1111–1116.
Surgical treatment of BPH continues to change rapidly. There is a big shift towards outpatient/office procedures.
3. Sakamoto H, Matsuda A, Arakaki R, et al. Outcome analysis of the urethral stent (Memotherm). Hinyokika Kiyo 2012; 58:13–16.
4▪▪. Sertcelik MN, Bozkurt IH, Yalcinkaya F, et al. Long-term results of permanent urethral stent Memotherm implantation in the management of recurrent bulbar urethral stenosis. BJU Int 2011; 108:1839–1842.
Memotherm is described as a good treatment option in patients with recurrent urethral stricture of any cause.
5▪. Kotsar A, Nieminen R, Isotalo T, et al. Preclinical evaluation of new indomethacin-eluting biodegradable urethral stent. J Endourol 2012; 26:387–392.
The authors produced and described the results of a new biocompatible, biodegradable, indomethacin-eluting urethral stent in order to reduce restenosis.
6. Mikkonen J, Uurto I, Isotalo T, et al. Drug-eluting bioabsorbable stents – an in vitro study. Acta Biomater 2009; 5:2894–2900.
7▪. 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.
A new, minimal invasive therapy for BPH even under local anaesthesia.
8. 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.
9. Cruz F, Dinis P. Resiniferatoxin and botulinum toxin
type A for treatment of lower urinary tract symptoms. Neurourol Urodyn 2007; 26 (Suppl 6):920–927.
10▪▪. Chartier-Kastler E, Mehnert U, Denys P, et al. Botulinum neurotoxin A for male lower urinary tract symptoms. Curr Opin Urol 2011; 21:13–21.
The most recent findings in basic and clinical research on the use of BoNTA are summarized and comprehensively highlighted.
11. Chuang YC, Chiang PH, Huang CC, et al. Botulinumtoxin typeA improves benign prostatic hyperplasia
symptoms in patients with small prostates. Urology 2005; 66:775–779.
12. Doggweiler R, Zermann DH, Ishigooka M, et al. Botox induced prostatic involution. Prostate 1998; 37:44–50.
13. Silva J, Pinto R, Carvallho T, et al. Mechanisms of prostate atrophy after glandular botulinum neurotoxin type a injection: an experimental study in the rat. Eur Urol 2009; 56:134–140.
14. Lin ATL, Yang AH, Chen K-K. Effects of botulinum toxin
A on the contractile function of dog prostate. Eur Urol 2007; 52:582–589.
15. 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 2012 [Epub ahead of print].
16. 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 [Epub ahead of print].
17▪▪. Silva J, Pinto R, Carvalho T, et al. Intraprostatic botulinum toxin
type A administration: evaluation of the effects on sexual function. BJU Int 2011; 107:1950–1954.
BoNTA in patients with BPH did not impair erectile, orgasmic or ejaculatory functions and did not change libido.
18▪. 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.
The ongoing research of a new drug, with apoptotic properties for intraprostatic administration, is presented.
19. Shore N. NX-1207: a novel investigational drug for the treatment of benign prostatic hyperplasia
. Expert Opin Investig Drugs 2010; 19:305–310.
20. Xu Z, Raghavan M, Hall TL, et al. High speed imaging of bubble clouds generated in pulsed ultrasound cavitational therapy histotripsy. IEEE Trans Ultrason Ferroelectr Freq Control 2007; 54:2091–2093.
21. Lake AM, Hall TL, Kieran K, et al. Histotripsy: minimally invasive technology for prostatic tissue ablation in an in vivo canine model. Urology 2008; 72:682–685.
22. Kieran K, Hall TL, Parsons JE, et al. Refining histotripsy: defining the parameter space for the creation of nonthermal lesions with high intensity pulsed ultrasound of the in vitro kidney. J Urol 2007; 178:672–676.
23▪. Hempel CR, Hall TL, Cain CA, et al. Histotripsy fractionation of prostate tissue: local effects and systemic response in a canine model. J Urol 2011; 185:1484–1489.