In the setting of benign prostatic obstruction related to hyperplasia, novel treatment strategies based on new mini-invasive techniques are currently in development. UroLift implants are the most developed and are recommended by most international Guidelines. Prostatic arterial embolization is currently being evaluated and is still experimental. Finally, botulinic toxin prostatic injections have been thoroughly tested, but phase 3 studies did not show any beneficial effects.
KeywordsBenign prostatic hyperplasia, UroLift, Embolization, Botulinic toxin
Treatment strategies for lower urinary tract symptoms presumably due to benign prostatic hyperplasia (LUTS/BPH) range from conservative treatment to pharmacologic or surgical treatments [ , ]. The latter is usually proposed in men who are still unsatisfied with optimal medical therapy or experience clinical progression or BPH-related complications. A major evolution in surgical techniques was observed with the use of endoscopic laser ablative procedures, photovaporization (PVP), and holmium laser enucleation (HoLEP) being the most achieved techniques in their evaluation [ ]. The use of laser was shown to decrease significantly bleeding-related morbidity, thus allowing shorter hospital stay (as well as ambulatory setting in some centers), as well as a broadening of indications to elderly, frail patients, and those who are under long-term anticoagulation or antithrombotic therapy and who would have not been considered for surgery. Nevertheless, morbidity of surgery remains a major issue, all techniques confounded, as observed in contemporary series [ ], with an overall 1-year morbidity rate of almost 20%, and mortality reported in 0.34%.
In the last few years, new concepts of treatment together with novel surgical techniques have led to new expectations. The aim of this chapter is to address an overview of these strategies, their potential impact in clinical practice, and their state of development.
New Concepts and Objectives
If medical treatment exposes to less side effects than surgical treatment, LUTS improvement expectation is also lower: International Prostatic Symptom Score (IPSS) improves by approximately 6 points with pharmacologic therapy while surgical treatment provides 10 to 15 points improvement [ , ]. Urodynamic improvement is also lower, with an approximate 20%–25% increase in Qmax with alpha-blockers or 5-apha reductase inhibitors alone, and a 3.7 mL/s improvement with combination therapy observed in the MTOPS study [ ]. These improvements are way far from those observed after transurethral resection of the prostate (TURP), with mean improvements in Qmax reported around 120% [ ]. These huge differences, however, may not be of any clinical relevancy if they are not interpreted in the context of the patients’ perception and needs, as well as balanced with the induced morbidity. This kind of reasoning leads to different considerations in the clinical objectives from the patient point of view.
Improvement Required With Surgical Ablative Techniques
These last years, the trend has been to propose alternative surgical ablative techniques to standard TURP to minimize immediate morbidity, especially TURP syndrome and bleeding. The aim, however, was also a noninferiority in symptomatic and urodynamic efficacy.
This point is well illustrated with the evaluation of laser PVP. In the GOLIATH study, evaluating the noninferiority of 180 W PVP (GreenLight XPS) versus monopolar TURP [ ], the primary endpoint was IPSS at 1 year. This endpoint was achieved, and maintained after 24 months [ ]. However, the issue of incomplete tissue removal with PVP has been raised by other groups and considered as a pitfall of the technique. The longest RCT comparing the 120-W HPS laser with transurethral resection of the prostate (TURP) had a follow-up of 36 months and showed indeed a higher re-operation rate after PVP (11% vs. 1.8%; P = .04) [ ]. These mid-term results have to be balanced with the advantages provided by the technique, which is considered the first option for patients under anticoagulation or thrombotic therapy in the latest EAU Guidelines [ ].
Balancing Efficacy and Morbidity
It is challenging to establish what amount of improvement is needed or required for the patient to be satisfied, and to balance these expectations with the risk of complications. From the patient point of view, of course, the improvement required should be weighted with individual co-morbidities, concurrent treatments, and life expectancy. This reflexion leads to the concept of reducing morbidity while accepting lower efficacy ( Fig. 14.1 ).
The evaluation of the novel technique of UroLift implants illustrates quite well this concept. This technique does not allow more than 40% improvement in IPSS or Qmax, but on the other hand does not induce any sexual morbidity, with no reported ejaculatory dysfunction based on the MSHQ-Ej auto-questionnaire [ , ]. Other aspects of quality of life, such as early rehabilitation, absence of hospitalization, are also in favor of the technique.
An attempt to evaluate key aspects of quality of life, all-together summarized in a single score, was proposed with the BPH6 score ( Table 14.1 ) [ ]. This score, which is not validated, includes symptomatic improvement (IPSS), but also continence, sexual adverse events, overall morbidity (Clavien-Dindo score), and delay before complete recovery. Although relevant from the clinician point of view, trying to evaluate these different components in a same measure is however challenging. The main difficulty lies in how to take into account the different outcomes and which of them should be given more credit? The answer is probably different from a patient to another, which illustrates quite well how much the patient has to be involved in the decision process.
|Outcome||Validated Measure||Proposed Nonvalidated Threshold|
|1. Recovery||QOR-VAS||> 70% at 1 month|
|2. LUTS||IPSS||< 30%|
|3. Erectile function||SHIM||Reduction of < 6 points|
|4. Ejaculatory function||MSHQ-EjD||Non “0” response to question 3 (emission of semen)|
|5. Continence||ISI||< 4 points|
|6. Safety||Clavien-Dindo||No adverse event > grade 1|
Pharmacological or Standard Surgical Treatment as Comparator
When accepting a surgical technique allowing lesser functional and urodynamic improvement than standard ablative techniques, clinicians have to consider the best comparator to evaluate the efficacy and cost-effectiveness of such strategy. The development of new mini-invasive techniques raised indeed the issue of their positioning within all the treatment modalities. The concept of “intermediate treatment” was proposed to illustrate the expected results of such strategy in terms of efficacy and morbidity. However, to be considered as intermediate, these techniques would have to be compared with both medical and surgical treatments.
UroLift implants illustrate quite well this new concept, although they have never been compared directly to medical treatment. Potentially, they could be of some value in patients not improved with pharmacological treatments, but would then have to demonstrate their superiority in efficacy to an optimal medical strategy. Also, they could be of some value in patients refusing pharmacological treatment-related side effects, but then would have to demonstrate less morbidity, and be cost-effective, which is challenging. Medical treatment-related side effects were reported to lead to treatment withdrawal in 10%–15% of the patients [ ]. A significant number of them have thus to face surgery as sole option, although they yet decline any ablative surgery because of its morbidity.
A Validated Mini-Invasive Technique: UroLift Implants
The UroLift procedure is a new, minimally invasive procedure based solely on a mechanic compression of prostate lobes, relieving urethral obstruction without any tissue ablation. The procedure consists in placing small suture-based implants in the prostate lobes under cystoscopy. The absence of tissue ablation enables to preserve anatomical structures, with decreased bleeding risk, and no reported sexual side effect.
The procedure may be performed under local anesthesia using urethral lidocaine jelly [ ]. Each implant is delivered using single use delivery device introduced in the prostatic urethra under cystoscopy (Sheath of 20 Fr and endoscope of 2.9 mm 0 degree). The delivery device is positioned against the prostatic lobe under vision, and angled 30 degrees laterally to open the lumen. A 19-gauge needle is then deployed through the prostate lobe all the way to the capsule. The needle is then retracted, leaving the capsular tab of the implant against the capsule. The capsular tab is attached to a polyterephtalate ethylene suture, which is bind to the delivery device. The suture is then tensioned, fixed to the luminal tab, and sectioned. The luminal tab invaginates under the urethral mucosa and is not in contact with urine. Two to four implants per patients are usually necessary for prostate glands 30–60 mL.
The first pilot study was published in 2011 [ ]. The authors evaluated prospectively the safety and efficacy of UroLift implants in 19 patients with bothersome BPH-related symptoms. All procedures were performed without technical difficulty. The mean number of implants delivered was of 3 [ ]. A postoperative bladder catheterization was performed in 11(58%) patients for 12 h. Three patients experienced acute urinary retention after catheter removal and required prolonged catheterization for 3 days. After a 1-month follow-up period, the reported adverse events were mild hematuria in 12 patients during 3 days (median), dysuria in 11 patients during 5 days (median), and urgencies in 9 patients for 28 days (median). Mean IPSS improvement 2 weeks after the procedure was of 37%, with a 40% increase in Qmax. At 12-month follow-up, mean IPPS improvement was of 39%, with 49% increase in Qmax. Cystoscopic controls showed a re-epithelialization of the prostatic urethra without any sign of incrustation. TURP was performed in three patients during the follow-up because of symptoms-related bother. The procedures were uneventful. The subsequent studies published suggested similar results, on more patients [ ]. In 2013, a European retrospective study reported the results of the procedure in 102 men consecutively treated in seven centers across five countries [ ]. Patients were evaluated up to a median follow-up of 1 year postprocedure. Average age, prostate size, and IPSS were 68 years, 48 mL, and 23, respectively. All procedures were completed successfully with a mean of 4.5 implants without serious adverse events. Patients experienced symptom relief by 2 weeks that was sustained to 12 months. Mean IPSS, QOL, and Qmax improved 36%, 39%, and 38% by 2 weeks, and 52%, 53%, and 51% at 12 months ( P < .001), respectively. Adverse events were mild and transient. A total of 6.5% of patients progressed to TURP without complication.
The originality of the technique, and probably its major benefit, is the complete absence of ejaculatory dysfunction. Erectile and ejaculatory functions were evaluated prospectively by Woo et al. [ ] in 64 consecutive patients. The validated questionnaires SHIM and MSHQ-EjD were used at 1, 3, 6, and 12 months after the procedure. The authors reported an improvement in erectile and ejaculatory functions at all time points. The improvement in erectile function was statistically significant at 3 and 12 months, whereas that of ejaculatory function was significant at 1 and 3 months. Ejaculation-related bother (question 4 of MSHQ-EjD) was significantly decreased as compared to baseline at all-time points. The authors concluded that UroLift implants allowed preserving patient’s sexuality.
Since these first pilot studies, two international comparative trials were conducted. The first was a prospective randomized placebo-controlled trial performed in the United States, Canada, and Australia (the LIFT study) [ ]. Men of at least 50 years with IPSS > 12, a maximum flow rate (Qmax) ≤ 12 mL/s, and a prostate 30–80 mL, were randomized 2:1 between UroLift implants and sham. Sham entailed rigid cystoscopy with sounds mimicking the UroLift implants placement. The primary endpoint was superiority of IPSS reduction at 3 months. A total of 206 men were randomized (140 UroLift implants and 66 sham). UroLift implants and sham IPSS were reduced by 11.1 ± 7.67 and 5.9 ± 7.66, respectively ( P = .003), thus meeting the primary endpoint. UroLift implants subjects experienced IPSS reduction from 22.1 baseline to 18.0, 11.0, and 11.1 at 2 weeks, 3 months, and 12 months, respectively ( P < .001). Qmax increased 4.4 mL/s at 3 months and was sustained at 4.0 mL/s at 12 months ( P < .001). Adverse events were typically mild and transient. There was no occurrence of de novo ejaculatory or erectile dysfunction. These first results lead to the FDA approval of the device in the United States. More recently, 3-year results were published [ ]. Average improvements from baseline through 3 years were significant for total IPSS (41.1%), quality of life (48.8%), Qmax (53.1%), and individual IPSS symptoms. There were no de novo, sustained ejaculatory, or erectile dysfunction events and all sexual function assessments showed average stability or improvement after UroLift placement. Fifteen of the 140 patients (10.7%) originally randomized to UroLift required surgical reintervention for treatment failure within the first 3 years [ ]. The second study is a European prospective randomized comparison with TURP, using the BPH-6 score as primary endpoint at 12 months [ ]. A total of 79 men were randomized. Without any surprise, IPSS improvement was significantly higher and Qmax significantly more reduced after TURP. On the other hand, patients treated with UroLift implants recovered more quickly and showed no ejaculatory dysfunction ( Table 14.2 ).
|1 Year||PUL ( n = 44)||TURP ( n = 35)||P Value|
|Composite BPH6 endpoint||52.3%||20.0%||0.005|
|(1) LUTS (≥ 30% IPSS reduction)||72.7%||91.2%||0.05|
|(2) Recovery (≥ 70% VAS @ 1 mo)||81.8%||52.9%||< 0.01|
|(3) Erectile function (< 6 SHIM reduction)||97.4%||93.9%||NS|
|(4) Ejaculatory function (MSHQ-EjD #3 ≠ 0)||100%||60.6%||< 0.01|
|(5) Continence (ISI < 5)||85.0%||75.0%||NS|
|(6) Safety (no Clavien-Dindo II +)||92.7%||78.8%||NS|