An aging population promises to be among the 21st century's prominent global demographic trends. In the USA, the projected increase in the percentage of elderly persons (>65 years) climbs from 12.6% in 2000 to 20% by 2030 . Aging patients’ comorbidities and frailty make anesthesia and lengthy catheterization risky during benign prostate obstruction (BPO) treatment. Increasing evidence shows older patients (>65 years) with higher rates of postoperative cognitive decline (POCD) or dementia following prostate surgery, comparing general to local anesthesia . Quick, alternative treatments, with minimal side-effects and rapid recovery, also may be desired by other patients, as well. In this article, we critically review the safety, effectiveness, and usefulness of ‘anesthesia-free’ interventions. Are they worthwhile?
THERMOTHERAPIES: TRANSURETHRAL MICROWAVE THERMOTHERAPY AND TRANSURETHRAL NEEDLE ABLATION
Transurethral microwave therapy (TUMT) and transurethral needle ablation (TUNA) are minimally invasive thermal treatments which achieve a high degree of evidence and recommendation in the current guidelines [3▪,4]. Both are more common in the USA than Europe, but procedure rates decreased significantly over the last 5–10 years . This decrease may partially stem from the perceptions that TUMT and TUNA lack transurethral resection of the prostate (TURP) long-term efficacy, and increased alternatives like laser vaporization. The value of these procedures is rated lower for extensive capacity of desobstruction and higher retreatment rates compared with TURP. Nonetheless, both procedures may help high-risk patients [3▪]. Only one thermotherapy study has been published in the last 12–18 months. Thus, these statements are primarily based on a Cochrane Review from 2012 for TUMT  and meta-analysis from 2006 for TUNA .
TUMT transmits microwave energy via intraurethral catheter for transurethral prostatic heat application, causing tissue destruction, apoptosis, and α-receptor denervation. This reduces BPO and lower urinary tract symptoms (LUTS). Although one randomized controlled trial (RCT) obtained comparable clinical results 5 years after TUMT and TURP , a Cochrane Review deemed TUMT less effective than TURP in reducing LUTS (65 vs. 77%) and improving Qmax (maximum urine flow; 70 vs. 119%). Side-effects including blood transfusions, retrograde ejaculation, strictures, hematuria, and transurethral resection (TUR) syndrome are generally less frequent with TUMT than TURP. Acute urinary retention, dysuria, and reintervention are more frequent with TUMT .
These published data were generated using different devices, limiting comparability, and newer developments (i.e. transperineal microwave application or transurethral stent after TUMT) were precluded. Additional TUMT investigations are needed of long-term outcomes, device efficacy, and optimal energy settings.
In the USA in 2008, 98.7% of TUMT procedures were performed in the office settings . In 2014, Aagaard et al.[9▪] described local anesthesia protocol for TUMT in high-risk patients with chronic urinary retention (n = 99). They administered 2% lidocaine gel intraurethrally 10 min before Schelin catheter insertion, through which 5–10 ml of carbocain with adrenalin were injected intraprostatically. The Schelin catheter was replaced by a treatment catheter. Median prostate size was 60 ml, median prostate size reduction was 25%, and median treatment time was 15 min. The desired temperature was 50–60°C. Side-effects occurred in 4.8% of patients. Overall, 79% reported quality-of-life (QOL) improvement; 77% were relieved from catheterization, but the initial attempt at catheter removal came 14 days after intervention.
TUNA treatment inserts transurethral needle antennae into the prostate. The adenoma tissue is heated with low-level radiofrequency energy up to 100°C, generating a defined necrosis of 1–2 cm diameter to precipitate BPO reduction and resolution. Along with the outpatient feasibility, low bleeding risk and lack of incontinence or erectile dysfunction are the benefits of TUNA compared with TURP. Meta-analysis of 35 studies (nine comparative and 26 noncomparative) confirmed that TUNA significantly improves International Prostate Symptom Score (IPSS) (50%) and Qmax (70%) compared with baseline. However, delayed side-effects (23% transitory urinary retention after TUNA) and lower desobstruction effect compared with TURP, as well as the higher urinary retention incidence on follow-up (four times higher compared with TURP) and higher retreatment rates (7.4 times higher compared with TURP) are the disadvantages .
TUNA is less effective than TURP, but offers adequate short-term symptom relief and QOL improvement with low postoperative morbidity. Thus, TUNA may be attractive for patients with high symptom indexes but low degrees of obstruction, those wishing to preserve sexual function, or multimorbid elderly patients [3▪,7].
In three studies, TUNA was performed under local anesthesia alone (13% of patients), and in 10 studies under both local anesthesia and sedation (43.5% of patients). Hospitalization for 87% of patients was only a few hours after TUNA therapy. Moderate pain was reported by 0.9% and intense pain by 0.3% of patients . Among general anesthesia-free patients, pain and discomfort occurred in 22–42% and severe pain in 4% of patients [10–12]. In one study, TUNA was interrupted because of intense pain or burning in 23.1% of patients, necessitating perineal local blocks in 7.7% of patients .
MECHANICAL DEVICES: PROSTATIC STENTS AND PROSTATIC URETHRAL LIFT
Stents are tubes placed temporarily or permanently in the prostatic urethra to compress prostatic tissue and open the bladder outlet, in use since the 1980s. Newer prostatic urethral lift devices provide a novel method to open the prostatic urethra mechanically, with the first data published in 2011. Stent insertion occurs on an outpatient basis under regional or topical anesthesia, providing immediate BPO relief, but they require a functioning detrusor [3▪]. Various stent materials exist, including self-retaining spiral stents, malleable stents, and heat-expandable stents. Stents are further classified as permanent (epithelializing) or temporary (nonepithelializing).
A popular epithelializing stent is the UroLume (AMS, Minnetonka, Minnesota, USA) reviewed in 2007 , alongside the Memotherm (Angiomed Gmbh & Co. Medizintechnik KG, Karlsruhe, Germany) [14▪,15]. The best data on nonepithelializing prostatic stents come from a 2006 review of Memokath (Pnn Medical, Kvistgaard, Denmark), a self-thermoexpandable metallic stent . The most recently marketed stent is the Allium stent (Allium Medical, Caesarea Industrial Park South, Israel). This is a temporary self-expanding nitinol wire stent that is structured as a triangular skeleton which is completely covered by a biocompatible polymer. The stent's novel construction is said to enable functional advantages, but study data are lacking to our knowledge. Stents are subject to misplacement, migration, and poor tolerability through LUTS and encrustation. The main adverse events immediately following stent placement include perineal pain or bladder storage symptoms. In a study of catheter-dependent men, 84% voided spontaneously upon UroLume insertion and symptomatic improvement was similar to TURP. However, 16% of patients developed complications, mainly stent migration (37%), requiring UroLume removal within 1 year. Inadequate follow-up prevents conclusions regarding stent durability beyond 1 year . Latest data for the Memotherm prostatic stent in the treatment of bladder outlet obstruction from BPO in patients with high anesthetic risk for surgery was published by Bozkurt et al.[14▪] in 2013. In a cohort of 29 men, treatment was successful in 25 (86%). For the remaining four patients (13.8%), stent migration into the bladder prompted removal of the stents. Marked improvement in residual urine volume, symptom score, QOL index scores, and peak flow rates were observed 1 and 5 years after the procedure.
The Memokath stent offers similar BPO treatment for higher risk patients and appears to be well tolerated. Treatment failure rates were reported between 0 and 48%; however, inadequate follow-up again prevents firm conclusions regarding stent durability . This supports the BPO recommendations for stent consideration only in high-risk patients, as an alternative to transurethral catheterization, as a temporary option for short-term LUTS relief secondary to BPO in patients temporarily unfit for surgery, or after minimally invasive treatment [3▪,4].
Treating stent migration, stent encrustation, or epithelial ingrowth usually requires general anesthesia for removal. Temporary stent removal is eased under local anesthesia by pulling the retrieval suture for complete stent retraction or endoscopically with graspers.
Newer polyurethane stents (e.g. Spanner, AbbeyMoor Medical, Inc, Parkers Prairie, Minnesota, USA, and CoreFlow, ProstaLund Operations AB, Lund, Sweden), similar to the proximal 4–6 cm of a Foley catheter, are being investigated. Advantages may include easier introduction and removal under local anesthesia and diminished urinary tract infections, migration, and encrustation . The third temporary stent types are biodegradable devices made of polyglycolic acid (PGA), but limited data are available .
Prostatic urethral lift (UroLift)
PUL technique is a novel intervention pulling the lateral lobes of the prostate toward the capsule through permanent tensioning. Nonabsorbable monofilament sutures and a nitinol capsular tab are positioned from the urethra to the outer fibrous capsule, separating encroaching prostatic lobes (Fig. 1a–d). This is performed by outpatient cystoscopy with a custom implant delivery device (UroLift System, Neo Tract Inc., Pleasanton, California, USA) under local anesthesia and sedation . Barkin et al. report good toleration of UroLift implantation using this protocol: oral antianxiety and anti-inflammatory medications 30–60 min prior, with lidocaine 2% gel introduction into the urethra 20 min prior to the procedure. Rapid desobstruction with minimal to no catheterization is reported [19▪,20▪].
UroLift is the newest minimally invasive BPO mechanical device marketed. Recent data demonstrate 40% IPSS reduction, 40–50% QOL improvement, and 30% Qmax improvement sustained for 1–2 years [18,20▪,21]. The Luminal Improvement Following Prostatic Tissue Approximation (LIFT) study, the first randomized, controlled, blinded trial of PUL, could improve the American Urological Association (AUA) Symptom Index and the Qmax lasting up to 1 year [22▪▪]. In a multicenter, prospective, cross-over study done in April 2014, Cantwell et al.[23▪] confirmed these results. Advantages of UroLift include preservation of antegrade ejaculation and erectile function and a low complication profile [19▪,20▪,21,22▪▪,23▪,24]. Complications include hematuria, dysuria, and irritation. Uncommon later complications include urinary tract infection and prostatitis.
Various agents have been tested for minimally invasive intraprostatic injection treatment in BPO. The most established agents are ethanol and botulinum toxin A (BTXA). The newest injection substances are NX1207 and PRX302. The recently introduced complete device, the Rezum system, uses steam (hot water vapor).
Intraprostatic ethanol injections
Prostatic ablation using absolute ethanol (dehydrated, 95–98%) injection is a well investigated intraprostatic therapy. Ethanol causes atrophy and ablation of prostatic tissue by inflammation, coagulation necrosis, and protein denaturation, resulting in cavitation and BPO reduction [3▪,25]. Promising results have been reported, albeit with clinical outcome variances.
Andersson's [26▪] recent review of agents for intraprostatic injections summarizes the data for intraprostatic ethanol injections in BPO. The majority of trials demonstrate significant IPSS reduction (40–71%), improved QOL and postvoid residual volume (PVR; up to 99%), Qmax increase (35–155%), and decreased prostate volume [3▪,26▪,27–32].
El-Husseiny and Buchholz  completed a detailed long-term study. Patients were high-risk, multimorbid patients unsuitable for general anesthesia. Procedures were performed under intravenous sedation with local urethral lidocaine jelly introduction and transrectal ultrasonography (TRUS)-guided periprostatic block. Considerable retreatments (41% after 3 years) were reported. Adverse events were uncommon, including perineal and abdominal pain, bladder storage symptoms, hematuria, urinary tract infections, epididymitis, and urinary retention. Some severe adverse events required cystectomy and urinary diversion .
Although a lot of research was done, the mechanism of action, patient selection, and application of ethanol (site and volume protocol) are not well described. It is therefore an expert's opinion that intraprostatic ethanol injections should be regarded as experimental and performed only in trials [3▪]. Despite the rare serious complications and elevated retreatment rate, it may be an option in patients unsuited for general anesthesia.
Intraprostatic botulinum toxin A injections
The described mechanisms of BTXA therapy are not well investigated , but several studies on this LUTS and BPO treatment show promising results. A review of 20 available RCTs or prospective observational studies on the use of BTXA intraprostatic injections  showed IPSS improvement in 13 studies, Qmax increase in 14 studies, and prostate size reduction in 18 studies, with treatment efficacy duration from 3 to 30 months [3▪]. In two recent RCTs [35,36] comparing BTXA dosing, no differences were observed in terms of efficacy, but Crawford et al. concluded that 100 IU may be suggested, with efficacy similar to higher doses at lower costs and side-effect rates.
Disappointingly, the results from the largest placebo-controlled study on the efficacy of different doses of BTXA in men with LUTS and BPO, published in 2013, showed no significant difference between BTXA and placebo in terms of IPSS (41 vs. 13%), QOL, Qmax (33 vs. 13%), and prostate size (14 vs. 7%). However, prostate-specific antigen (PSA) and PVR did decrease significantly by 18% (P = 0.04) and 29% (P = 0.02), respectively, at 12 weeks [37▪▪]. This high placebo response was not seen in the only other placebo-controlled study, by Maria et al., accounting for differences in PSA and PVR in the Marberger study.
Nevertheless, BTXA may promise quick, minimally invasive treatment with low morbidity (dysuria, hematuria, epididymitis, and prostatitis) under local anesthesia . The present conclusion must remain that BTXA data are contradictory. It should be reserved for patients refractory to medical treatment who wish to preserve sexual function or frail patients with urinary retention unsuited to invasive procedures [3▪]. This therapy should not be used routinely pending the results of further trials [39▪].
New intraprostatic drugs: NX1207 AND PRX302
Information for the treatment of LUTS and BPO with these new drugs is scarce, mostly published in abstract form outside of the peer-reviewed literature.
NX1207 is administered via outpatient, ultrasound-guided, transrectal intraprostatic injection. It has selective pro-apoptotic properties, which induce focal prostatic cell loss leading to volume reduction and improved symptoms. In four US clinical phase II trials, NX1207 demonstrated symptomatic improvement better than the current BPH medications without significant safety issues. Larger, phase III trials are ongoing to further confirm the efficacy, safety, and tolerability for NX1207 [40,41].
PRX302 is an inactive precursor of a bacterial cytolytic pore-forming protein (protoxin), which is activated via proteolytic processing by PSA, a glycoprotein enzyme. In phase I and II RCTs to determine safety and efficacy, PRX302 was transperineally injected under local anesthesia into benign prostatic hyperplasia (BPH) patient prostates (n = 32) . A 30% IPSS decrease was observed in 67–73% of patients after 3 months and in 64–67% after 12 months. Patients reported improved QOL and at least 20% prostate volume reduction for up to 1 year. Erectile dysfunction was not reported. Adverse events were mild to moderate and transient in nature. Further investigation is indicated, including the potential development of antibodies after repeated treatment, as both drugs represent proteins.
Other minimally invasive technologies: Rezum: water vapor therapy
The Rezum System (NxThera, Maple Grove, Minnesota, USA) is a novel, transurethral therapy using sterile water vapor to treat BPO. It delivers the targeted thermal energy to the prostatic transition zone. This allows rapid tissue ablation, shorter procedures, and ‘compartmentalization’ to the transition zone.
A cystoscope-like sheath is inserted transurethrally, positioned within the prostatic urethra between the bladder neck and verumontanum. A thin needle is deployed into the prostatic transition zone and an 8–10 s administration of water vapor is delivered, immediately dispersing through hyperplastic tissue interstices. A total of 2–6 administrations, each 8–10 s, are required for 30–80 ml prostates. Upon tissue contact, the vapor condenses, releasing stored thermal energy against the treated tissue cells, denaturing the membranes causing immediate cell death (Fig. 2a–f).
Combined 3-month and 1-year results of a first-in-man dose ranging trial (n = 15), as well as a Rezum I pilot study (n = 15), were presented at the 2013 European Association of Urology Congress and the 2014 American Urological Association Congress. The Rezum system reported rapid, effective, controlled ablation of prostatic tissue with an 8-min mean intervention time. No treatment-related adverse events occurred, but transient retention, mild dysuria, and hematuria were reported.
The IPSS, QOL, and Qmax were improved by −64% (23.2 vs. 8.4), −65% (3.8 vs. 1.3), and +42% (8.4 vs. 11.9 ml/s), respectively, at 3 months, and remained stable throughout 1 year. At 3 months, there was a 26% prostate volume reduction. Urinary incontinence, erectile dysfunction, and ejaculatory dysfunction were not the treatment consequences.
In their Rezum evaluation at the 2014 AUA Congress, Wagrell and Tornblom confirmed these promising data from a single-center, 3-month follow-up (n = 27). Preprocedure analgesia included T-etoricoxib 120 mg, oxycodon hydrochloride 5 mg, and paracetamol 500 mg (2 times). Data regarding intraoperative pain intensity or management were lacking. Mean catheterization was 2.6 days. One week after the procedure, 75% of patients reported ‘excellent’ or ‘good’ treatment and recovery experiences, with 17% reporting ‘average’ experiences.
Initial data suggest favorable outpatient clinical outcomes and safe delivery of water vapor to the prostatic transition zone in BPO. In July 2013, a prospective, controlled, randomized, single-blind clinical trial of patients with BPH was registered in the USA, investigating the safety and efficacy with the Rezum system (www.clinicaltrials.gov Identifier: NCT01912339). This system is currently considered an investigational device.
Over the last two decades, thermotherapies emerged as general anesthesia-free alternatives to TURP, but rates have declined. Current focus is on the newer, minimally invasive options like mechanical devices and intraprostatic injections. For these treatment modalities, good short-term functional results are described. However, few long-term studies are available to evaluate the effectiveness and safety of these methods, and TURP remains comparatively more effective. No truly ‘anesthesia-free’ interventional procedures are currently available, with local anesthesia and sedation still necessary. In most related studies, pain therapy management is only rudimentary or not described, including intraoperative pain analysis of patients.
Conflicts of interest
There are no conflicts of interest.
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
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