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Rezūm Water Vapor Thermal Therapy for Lower Urinary Tract Symptoms Associated With Benign Prostatic Hyperplasia: 4-Year Results From Randomized Controlled Study

Open AccessPublished:January 21, 2019DOI:https://doi.org/10.1016/j.urology.2018.12.041

      Abstract

      Objective

      To report 4-year outcomes of the randomized controlled trial of water vapor thermal therapy for treatment of moderate to severe lower urinary tract symptoms due to benign prostatic hyperplasia.

      Materials and Methods

      Total 188 subjects; 135 men ≥50years old, International Prostate Symptom Score ≥ 13, maximum flow rate (Qmax) ≤15 mL/s and prostate volume 30 to 80 cc treated with Rezūm System thermal therapy were followed 4 years; subset of 53 men who requalified for crossover from control to active treatment were followed 3years.

      Results

      Lower urinary tract symptoms were significantly improved within ≤3 months after thermal therapy and remained consistently durable (International Prostate Symptom Score 47%, quality of life 43%, Qmax 50%, Benign Prostatic Hyperplasia Impact Index 52%) throughout 4years (P <.0001); outcomes were similarly sustained in crossover subjects at 3years. Surgical retreatment rate was 4.4% over 4years. No disturbances in sexual function were reported.

      Conclusion

      The minimally invasive thermal therapy provides effective symptom relief and improved quality of life that remains durable for over 4years. It is applicable to all prostate zones with procedures performed under local anesthesia in an office setting.
      By the seventh decade of life approximately 70% of men have histological evidence of histological stromoglandular hyperplasia, namely benign prostatic hyperplasia (BPH). This hyperplasia is commonly associated with progressive development of voiding and storage related lower urinary tract symptoms (LUTS). Several options exist for BPH management with a significant range of invasiveness, efficacy, and cost. The therapy a patient pursues should rely on careful physical evaluation and informed discussion with his provider. Decision making varies according to severity of symptoms, gland size, anatomical features, and efficacy and safety of the different treatments. Minimally invasive surgical treatments (MISTs), both thermal and mechanical expander options, represent alternative intervention before or after any pharmacotherapy.
      The newest MIST is water vapor thermal therapy using radiofrequency to create thermal energy (Rezūm System, Boston Scientific, Marlborough, MA) in the form of water vapor. This therapy was specifically developed as a platform technology for transurethral energy transfer using the convective properties of water, releasing large amounts of stored thermal energy (540calories/mL H2O) as the vapor contacts prostate tissue and condenses back to water. Thesteam/vapor travels through cellular interstices to a boundary of tissue plane between prostate zones, disrupting cell membranes without discernible temperature gradients within a treatment zone. No thermal effects occur outside the targeted treatment zone.
      • Dixon C.M.
      • Cedano E.R.
      • Mynderse L.A.
      • et al.
      Transurethral convection water vapor as a treatment for lower urinary tract symptomology due to benign prostatic hyperplasia using the Rezūm system: evaluation of acute ablative capabilities in the human prostate.
      • Mynderse L.A.
      • Hanson D.
      • Robb R.A.
      • et al.
      Rezūm system water vapor treatment for lower urinary tract symptoms/benign prostatic hyperplasia: validation of convective thermal energy transfer and characterization with magnetic resonance imaging and 3-dimensional renderings.
      This overcomes the limitations of conductive heat transfer used in other forms of thermotherapy: transurethral needle ablation (TUNA) and transurethral microwave thermotherapy (TUMT). Thermodynamically the latter techniques (TUNA, TUMT) require lengthy treatment time lasting up to an hour with considerable energy disposition to achieve tissue destruction. The Rezūm system has been widely adopted into urology practices in the United States and Europe. Its clinical advantage includes rapid and sustained relief of LUTS and enhanced quality of life without accompanying disturbance of sexual function in men with moderate to severe BPH symptoms.
      • McVary K.T.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Minimally invasive prostate convective water vapor energy (WAVE) ablation: a multicenter, randomized, controlled study for treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia.
      • McVary K.T.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Erectile and ejaculatory function preserved with convective water vapor energy treatment of LUTS secondary to BPH: randomized controlled study.
      • Roehrborn C.G.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Convective water vapor energy (WAVE) ablation therapy: durable two-year results and prospective blinded crossover study for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
      • McVary K.T.
      • Roehrborn C.G.
      Three-year outcomes of the prospective, randomized controlled Rezūm system study: convective radiofrequency thermal therapy for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
      The Rezūm thermal therapy is also distinguished by the ability to treat all prostate zones without restrictions in morphology. This is crucial as intravesical protrusions are now recognized to predict poor outcomes from most pharmacotherapies, as well as the presence of urodynamic obstruction.
      • Rieken M.
      • Presicce F.
      • Autorino R.
      • DE Nunzio C.
      Clinical significance of intravesical prostatic protrusion in the management of benign prostatic enlargement: a systematic review and critical analysis of current evidence.
      We herein present 4-year outcomes of the multicenter, randomized controlled trial (RCT) of water vapor thermal therapy.

      MATERIALS AND METHODS

      Study Protocol

      Men with moderate to severe symptomatic BPH were treated and followed annually for 4years in a prospective, multicenter, double-blind randomized controlled study of the effectiveness and safety of the Rezūm System water vapor thermal therapy. Subjects were enrolled at 15 centers in the United States (Clinicaltrials.gov: NCT01912339). Ethics committees at each participating center approved the protocol; written informed consent was obtained by all subjects. The complete list of inclusion and exclusion criteria has been published in full.
      • McVary K.T.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Minimally invasive prostate convective water vapor energy (WAVE) ablation: a multicenter, randomized, controlled study for treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia.
      Enrollment was limited to men at least 50years of age with an International Prostate Symptom Score (IPSS) ≥13, a prostate volume 30 cc to 80 cc, maximum urinary flow rate (Qmax) of ≤15 mL/s and a measured postvoid residual (PVR) urine <250mL. Excluded from enrollment were men with a PSA >2.5 ng/mL with a free PSA <25% unless prostate cancer was ruled out by biopsy, and those with an active urinary tract infection. TRUS and cystoscopic examinations were conducted before the procedure to determine the prostate size and eligibility for the study. Subjects were first stratified by IPSS severity then randomized 2:1 to thermal therapy with the Rezūm device or sham/control procedure with rigid cystoscopy. Participants were required to undergo a washout and discontinue use of any medications for LUTS/BPH prior to treatment. After unblinding at 3 months, the primary study endpoint, control subjects who elected to proceed were requalified by inclusion criteria and eligible to participate in a crossover study to receive thermal therapy and then followed annually.
      • Roehrborn C.G.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Convective water vapor energy (WAVE) ablation therapy: durable two-year results and prospective blinded crossover study for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
      The thermal procedure was capable of adenoma ablation in all prostate zones those with median lobe or elevated central zone at the bladder neck.

      Statistical Methods

      Randomization was performed with electronic programming prior to treatment using permuted blocks of random sizes stratified by investigational site for allocation to the thermal treatment and control arms. To maintain balance between the randomized arms at each study site, subjects were first stratified by severity of symptoms, with baseline IPSS 13 to 18 (moderate LUTS) and IPSS ≥19 (severe LUTS) to ensure equal distribution in both arms. The study was powered at 80% with 0.025 1-sided type I error for the primary end point of IPSS reduction at 3 months, using a Student's t test on the intent-to-treat populations to compare mean changes in treatment and control arms. Descriptive statistics were used to describe baseline and follow-up values for all variables. Data are presented as the mean ± SD or mean and the percent change and 95% confidence interval. A paired t test was used to calculate P values for each follow-up evaluation compared to baseline.

      Procedures

      Water vapor thermal therapy with the Rezūm System utilizes transurethral endoscopic guidance. Details of this technology and device have been previously reported.
      • McVary K.T.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Minimally invasive prostate convective water vapor energy (WAVE) ablation: a multicenter, randomized, controlled study for treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia.
      • Darson M.F.
      • Alexander E.E.
      • Schiffman Z.J.
      • et al.
      Procedural techniques and multicenter post-market experience using minimally invasive convective radiofrequency thermal therapy with Rezūm system for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
      • Woo H.H.
      • Gonzalez R.R.
      Perspective on the Rezūm system: a minimally invasive treatment strategy for benign prostatic hyperplasia using convective radiofrequency water vapor thermal therapy.
      The primary goal of the procedure is to create continuous, overlapping ablative lesions running parallel to the natural slope of the prostatic urethra, eliminating the tissue interfering with natural function. Confirmation of the contours of the prostate and planned disbursement of thermal lesions is determined at baseline cystoscopy. The handheld delivery device, housing the retractable treatment needle, is a standard 4mm 30° rod lens cystoscope allowing the procedure to be performed under direct cystoscopic visualization; a sterile saline flush irrigation enhances visualization and cools the urethral surface. Water vapor (∼103°C) is delivered in 9-second injections (each 0.5 mL) via a treatment needle with 12 small emitter holes spaced around its tip to allow circumferential dispersion of vapor or steam to create an approximate 1.5 to 2.0 cm lesion. The needle tip is visually positioned and inserted beginning approximately 1cm distal to the bladder neck into the transition and central prostatic adenomas. Intravesical prostatic protrusions and median lobe are injected starting 1cm from the edge of the protrusion. The needle is retracted after each vapor injection and repositioned in 1cm increments distally from the previous point to the prostatic tissue just proximal to the verumontanum. The total number of vapor treatments in each lobe of the prostate is determined by the length of the prostatic urethra and can be customized to the configuration of the hypertrophied gland, which may include the median lobe or enlarged central zone. The sham/control procedure involved rigid cystoscopy with simulated active treatment sounds and shielded visualization of physician and device.

      Study Assessments

      After blinded comparison of the active and sham/control groups for the primary efficacy endpoint at 3 months, outcome assessments were performed by an assessor blinded to knowledge of the procedures. The subjects who received water vapor thermal therapy were followed annually for 4years and assessed for symptom relief (IPSS), quality of life measures (IPSS-QOL, BPH Impact Index), peak urinary flow rate (Qmax), postvoid residual (PVR) volume, voided volume, incontinence (Overactive Bladder Questionnaire-Short Form [OAB-q SF], International Continence Society Male Incontinence Scale questionnaire-Short Form [ICS male IS-SF]), sexual function (International Index of Erectile Function [IIEF-15], Male Sexual Health Questionnaire for Ejaculatory Dysfunction), prostate serum antigen (PSA), and acute and late occurring adverse events. Any subject who received thermal therapy in the initial active treatment arm and crossover study is included in annual follow-up evaluations for 5years. Independent data monitoring and clinical events committees reviewed safety and adjudicated adverse events.

      RESULTS

      A total of 384 men were assessed and 197 eligible by inclusion criteria were enrolled. Randomization assigned 136 subjects to water vapor thermal therapy and 61 to sham/control procedure (Fig.1). Baseline characteristics (mean ± SD) of the active treatment cohort include age of 63 ± 7.1years, prostate volume 45.8 ± 13 cc, IPSS of 22.0 ± 4.8, QOL of 4.4 ± 1.1 and Qmax 9.9 ± 2.2. The mean baseline IPSS and QOL of men with moderate LUTS (IPSS 13-18; n = 37) was 16.3 ± 1.6 and 3.9 ±1.1; for those with severe LUTS (IPSS 19-35; n = 98) was 24.1 ± 3.7 and 4.6 ± 1.0, respectively. The control and crossover subjects had similar characteristics.
      • McVary K.T.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Minimally invasive prostate convective water vapor energy (WAVE) ablation: a multicenter, randomized, controlled study for treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia.
      • Roehrborn C.G.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Convective water vapor energy (WAVE) ablation therapy: durable two-year results and prospective blinded crossover study for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
      All procedures were successfully performed in an office or ambulatory surgery center and completed without perioperative device or procedure-related adverse events. Management of pain and anxiety was based on investigator discretion. Anesthesia was variable: 69% received oral sedation only; 21% had prostate block and 10% intravenous sedation.
      • McVary K.T.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Minimally invasive prostate convective water vapor energy (WAVE) ablation: a multicenter, randomized, controlled study for treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia.
      The total number of vapor injections was a mean 4.7± 1.7 and 1.6 ± 0.7 to the median lobe when present. Thermal therapy procedures were performed on the median lobe/enlarged central zone in 58 of 188 (30.9%) subjects treated in the RCT and crossover studies.
      Figure1.
      Figure1CONSORT (Consolidated Standards of Reporting Trials) diagram of subject disposition in Rezūm water vapor thermal therapy study including the thermal therapy, control and crossover (C) groups. *Subjects retreated with Rezūm procedures were excluded from analysis. ITT, intent to treat analysis; PP, per protocol analysis; TURP, transurethral resection of prostate. (Color version available online.)
      Non-serious adverse events included anticipated events that may develop after rigid cystoscopy; they were infrequent and mild to moderate in severity. The most common included dysuria (16.9%), hematuria (11.8%), frequency and urgency (5.9%), acute urinary retention (3.7%) and urinary tract infection suspected (3.7%); all were treated routinely or resolved without treatment within 3 weeks. One subject had a bladder neck contracture and bladder calculi reported 6 months after the procedure. A second subject had urosepsis after follow up cystoscopy.
      • Roehrborn C.G.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Convective water vapor energy (WAVE) ablation therapy: durable two-year results and prospective blinded crossover study for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
      No late occurring related adverse events or de novo erectile dysfunction were reported.
      The primary and secondary endpoints for the study were met. After unblinding at 3 months IPSS was reduced by 50% compared with 20% for the controls, P <.0001. Details of all outcome measures for the blinded segment of the RCT were previously reported.
      • McVary K.T.
      • Gange S.N.
      • Gittelman M.C.
      • et al.
      Minimally invasive prostate convective water vapor energy (WAVE) ablation: a multicenter, randomized, controlled study for treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia.
      Following randomized comparison through 3 months, water vapor thermal therapy showed significant and durable improvements throughout 4years of follow up (Table1). The mean IPSS improvements from baseline remained consistent fromthe early response at 3 months (49.9%) to years 1 (52.2%), 2(50.7%), 3 (49.7%) and 4 (46.7%). Flowrate improvements were sustained relative to baseline, remaining significant, although slightly attenuated, with an increase of 5.5 ± 6.4mL/s at 1 year to a mean 4.2 ± 5.7mL/s at 4years. Subjects with treated median lobe enlargement had objective and subjective improvements similar to those subjects without an identified median lobe. Baseline severity of symptoms is known to influence treatment outcomes. Men with moderate and severe LUTS had symptomatic relief with similar IPSS improvements at 4years of 46.1% and 46.9% and Qmax of 45% and 51.3%, respectively. QOL and BPH Impact Index remained improved, P <.0001. The profile of improvements in crossover subjects over 3years of follow-up replicates that of the initial RCT thermal therapy group (Fig.2).
      Table1Paired outcomes measures after water vapor thermal therapy from baseline through 48 months
      Outcome MeasureBaseline12 Mos24 Mos36 Mos48 Mos
      IPSS
      Decrease indicates improvement.
      N (paired values)1351211099990
      Baseline22.0 ± 4.821.8 ± 4.821.4 ± 4.521.4 ± 4.621.4 ± 4.4
      Follow-up10.3 ± 6.710.2 ± 6.210.5 ± 6.111.4 ± 7.4
      Change−11.6 ± 7.3−11.2 ± 7.3−11.0 ± 7.1−10.1 ± 7.6
      % Change−52.2−50.7−49.7−46.7
      P value<.0001<.0001<.0001<.0001
      IPSS QoL
      Decrease indicates improvement.
      N (paired values)1351211099990
      Baseline4.4 ± 1.14.4 ± 1.14.3 ± 1.04.3 ± 1.04.3 ± 1.0
      Follow-up2.1 ± 1.52.1 ± 1.42.1 ± 1.32.3 ± 1.5
      Change−2.2 ± 1.6−2.2 ± 1.5−2.2 ± 1.6−2.0 ± 1.7
      % Change−50.1−49.9−48.5−42.9
      P value<.0001<.0001<.0001<.0001
      Qmax (mL/s)
      Increase indicates improvement.
      [voided volume ≥125 mL]
      N (paired values)135112998281
      Baseline9.9 ± 2.210.0 ± 2.210.0 ± 2.29.7 ± 2.19.5 ± 2.2
      Follow-up15.5 ± 6.714.7 ± 6.113.2 ± 4.813.7 ± 5.7
      Change5.5 ± 6.44.8 ± 6.13.5 ± 4.64.2 ± 5.7
      % Change58.552.539.749.5
      P value<.0001<.0001<.0001<.0001
      PVR volume (mL)
      Decrease indicates improvement.
      N (paired values)1351181069389
      Baseline82.4 ± 51.582.5 ± 51.284.9 ± 54.082.7 ± 54.384.4 ± 55.3
      Follow-up78.6 ± 79.984.6 ± 92.054.5 ± 61.875.2 ± 69.7
      Change−3.9 ± 82.7−0.3 ± 85.3−28.2 ± 65.8−9.2 ± 72.2
      % Change50.78.6−21.538.0
      P value.6070.9697<.0001.2319
      Voided volume (mL)
      Increase indicates improvement.
      N (paired values)1351191079789
      Baseline236.6 ± 85.6237.4 ± 87.2236.2 ± 81.3237.0 ± 82.0238.7 ± 83.9
      Follow-up266.3 ± 138.9267.7 ± 123.0230.6 ± 123.3285.2 ± 173.4
      Change28.9 ± 132.731.5 ± 132.3−6.4 ± 132.946.5 ± 159.5
      % Change17.620.92.821.6
      P value.0190.0155.6370.0073
      BPHII
      Decrease indicates improvement.
      N (paired values)1351211099990
      Baseline6.3 ± 2.86.2 ± 2.86.1 ± 2.86.1 ± 2.96.1 ± 2.9
      Follow-up2.3 ± 3.02.3 ± 2.72.4 ± 2.82.6 ± 2.9
      Change−3.9 ± 3.3−3.8 ± 3.1−3.7 ± 3.3−3.5 ± 3.4
      % Change−60.5−61.1−57.3−52.2
      P value<.0001<.0001<.0001<.0001
      IIEF-EF
      Increase indicates improvement.
      N (paired values)9177716358
      Baseline22.7 ± 7.423.3 ± 6.922.9 ± 7.323.1 ± 7.323.2 ± 7.0
      Follow-up23.0 ± 8.421.8 ± 8.721.1 ± 9.220.8 ± 9.6
      Change−0.3 ± 7.5−1.2 ± 7.6−2.0 ± 8.2−2.5 ± 8.7
      % Change3.5−1.0−4.1−7.6
      P value.7054.2019.0602.0333
      MSHQ Function
      Decrease indicates a decline in function.
      N (paired values)9178706456
      Baseline9.3 ± 3.19.6 ± 3.09.6 ± 3.09.8 ± 3.010.0 ± 3.0
      Follow-up9.3 ± 4.09.1 ± 4.48.4 ± 4.58.2 ± 4.6
      Change−0.3 ± 3.5−0.5 ± 4.2−1.4 ± 3.8−1.8 ± 4.4
      % Change0.40.3−13.6−14.2
      P value.4338.3601.0046.0038
      MSHQ Bother
      Decrease indicates improvement.
      N (paired values)9179706456
      Baseline2.2 ± 1.72.2 ± 1.62.2 ± 1.62.1 ± 1.62.1 ± 1.6
      Follow-up1.5 ± 1.51.7 ± 1.71.6 ± 1.52.0 ± 1.7
      Change−0.7 ± 1.8−0.5 ± 1.7−0.5 ± 1.6−0.1 ± 1.8
      % Change−18.4−25.4−18.8−5.7
      P value.0017.0118.0153.6495
      ICS male score
      Decrease indicates improvement.
      N (paired values)1351201099989
      Baseline4.5 ± 2.94.3 ± 2.74.2 ± 2.44.2 ± 2.44.2 ± 2.3
      Follow-up3.0 ± 2.83.0 ± 2.63.1 ± 2.83.2 ± 2.8
      Change−1.2 ± 2.5−1.2 ± 2.6−1.1 ± 2.6−0.9 ± 2.8
      % Change−23.5−19.3−17.9−15.0
      P value<.0001<.0001.0001.0024
      OAB HRQL Score
      Increase indicates improvement.
      N (paired values)1341201069788
      Baseline64.3 ± 19.965.8 ± 18.966.6 ± 18.366.6 ± 18.367.3 ± 17.9
      Follow-up83.7 ± 18.285.6 ± 15.184.8 ± 15.383.0 ± 17.5
      Change17.9 ± 18.618.9 ± 16.918.1 ± 17.515.7 ± 19.3
      % Change48.051.353.539.9
      P value<.0001<.0001<.0001<.0001
      OAB symptom score
      Decrease indicates improvement.
      N (paired values)1351211099990
      Baseline39.6 ± 17.939.0 ± 17.538.2 ± 17.237.9 ± 16.937.9 ± 17.0
      Follow-up20.6 ± 18.420.9 ± 16.622.1 ± 16.323.3 ± 18.1
      Change−18.4 ± 17.8−17.2 ± 14.3−15.8 ± 16.4−14.6 ± 19.3
      % Change−44.7−44.9−39.1−29.8
      P value<.0001<.0001<.0001<.0001
      PSA
      Decrease indicates improvement.
      N (paired values)1351201099886
      Baseline2.1 ± 1.52.1 ± 1.62.1 ± 1.62.0 ± 1.61.9 ± 1.6
      Follow-up1.9 ± 1.61.8 ± 1.61.8 ± 1.71.9 ± 1.8
      Change−0.3 ± 1.0−0.3 ± 1.1−0.2 ± 1.1−0.1 ± 1.1
      % Change−8.5−9.4−1.32.5
      P value.0023.0041.0911.6248
      EjD, ejaculatory dysfunction; HRQL, health related quality of life; ICS, International Continence Society; IIEF-15, International Index of Erectile Function; IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms; MSHQ-EjD, Male Sexual Health Questionnaire for EjD; OAB, overactive bladder; Qmax, peak urinary flow; QOL, quality of life; PVR, postvoid residual urine volume.
      Analysis population includes all treatment arm subjects who underwent treatment with Rezūm System procedure. Only subjects who were sexually active are included for IIEF-EF, MSHQ-EjD Function and Bother evaluations. Data presented as mean ± SD and compared with baseline using paired Student t test.
      low asterisk Decrease indicates improvement.
      Decrease indicates a decline in function.
      Increase indicates improvement.
      Figure2.
      Figure2Outcomes for water vapor thermal therapy over 4years for the initial active treatment arm in the RCT and over 3years for the crossover study subjects including IPSS (A), Qmax (B), QOL (C) and BPH Impact Index (D) Values are means and error bars represent 95% CI. Changes relative to baseline are significant at all time points, P <.0001. BPHII, BPH Impact Index; CI, confidence interval; IPSS, International Prostate Symptom Score; Qmax, peak urinary flow rate; QOL, quality of life; RCT, randomized controlled trial.
      Throughout 4 years, urinary incontinence scores decreased significantly (Table1). Sexual function throughout 2years after treatment shows that erectile function (IIEF) and ejaculatory function (MSHQ-EjD) scores remained unchanged. The ejaculatory bother score improved relative to baseline over 3years, P ≤.05.
      At 4years 90 of 135 (66.7%) subjects were included in the effectiveness analysis per protocol. No study withdrawals were due to procedure or device-related adverse events. Thirty-one of the 45 subjects not included in the analysis had a ≥7 point (range 7-27) improvement in IPSS at the time of study exit. Of the 45 subjects excluded from analysis, 15 were lost to follow-up, 12 withdrew consent (2 with a cancer diagnosis), 7 were censored for use of BPH medications and 4 for use of testosterone at follow-up, 1 missed clinic visit, and 6 underwent a secondary treatment for LUTS (1 open prostatectomy, 3 plasma-button transurethral vaporization of the prostate, and 2 retreated with the Rezūm procedure). At 4years, surgical intervention was performedin 6 of 135 subjects (4.4%) including 4 subjects in whom a median lobe was identified but not treated. Additionally 7 subjects (5.2%) initiated use of alpha blockers within 4years of follow up. No other drugs were used such as anticholinergics, mirabegron, or 5-alpha reductase inhibitors.

      COMMENT

      This 4-year follow-up of a randomized controlled study using water vapor thermal therapy for BPH demonstrates significant durable outcomes for such a minimal invasive procedure. It is noted that subjects with severe urinary symptoms (IPSS 19-35) made up 72.5% of the trial enrollment and that group had an average 50% improvement in both subjective and objective variables. Men with moderate and severe LUTS reported no negative changes in sexual function scores and no de novo erectile dysfunction. The targeted prostate tissue ablation may be applied to all zones of the prostate including an enlarged central zone and median lobe. Patients who underwent a treated median lobe had similar significant improvements to those with no median lobe.
      Retreatment rate is an important evaluation factor of durability. The 4-year surgical retreatment rate was 4.4% after water vapor thermal therapy. However, in the early phase use of this technology some investigators failed to treat an identified median lobe or elevated central zone in 4 subjects leading to subsequent surgeries. This retreatment could possibly have been avoided reducing the retreatment rate to 2.2%. Nevertheless, the 4.4% rate compares favorably at less than half the rate reported for all other MISTs. Thermal ablation devices using conductive heat delivery report surgical retreatment rates of 19.1% for TUNA at 3years
      • Bouza C.
      • López T.
      • Magro A.
      • et al.
      Systematic review and meta-analysis of transurethral needle ablation in symptomatic benign prostatic hyperplasia.
      and 14%-51% at 5 years;
      • Zlotta A.
      • Giannakopoulos X.
      • Maehlum O.
      • et al.
      Long-term evaluation of transurethral needle ablation of the prostate (TUNA) for treatment of symptomatic benign prostatic hyperplasia: clinical outcome up to five years from three centers.
      • Hill B.
      • Belville W.
      • Bruskewitz R.
      • et al.
      Transurethral needle ablation versus transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia: 5-year results of a prospective randomized, multicenter clinical trial.
      • Rosario D.
      • Phillips J.C.
      • Chapple C.R.
      Durability and cost-effectiveness of transurethral needle ablation of the prostate as an alternative to transurethral resection of the prostate when alpha-adrenergic antagonist therapy fails.
      TUMT at 5years is 8.9%-21%.
      • Miller P.D.
      • Kastner C.
      • Ramsey E.W.
      • Parsons K.
      Cooled thermotherapy for the treatment of benign prostatic hyperplasia: durability of results obtained with the Targis System.
      • Mattiasson A.
      • Wagrell L.
      • Schelin S.
      • et al.
      Five-year follow-up of feedback microwave thermotherapy versus TURP for clinical BPH: a prospective randomized multicenter study.
      • Lucarelli G.
      • Battaglia M.
      • Bettocchi C.
      • et al.
      High energy microwave thermotherapy for symptomatic benign prostatic enlargment: predictive parameters of long term outcome.
      • Mynderse L.A.
      • Roehrborn C.G.
      • Partin A.W.
      • et al.
      Results of a 5-year multicenter trial of a new generation cooled high energy transurethral microwave thermal therapy catheter for benign prostatic hyperplasia.
      The prostatic urethral lift procedure has a reported surgical retreatment of 10.6% at 3years and 13.6% at 5years.
      • Roehrborn C.G.
      • Rukstalis D.B.
      • Barkin J.
      Three year results of the prostatic urethral L.I.F.T. study.
      • Roehrborn C.G.
      • Barkin J.
      • Gange S.N.
      • et al.
      Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study.
      The comparison retreatment rate for TURP ranges from 3% to 14.5% after 5years.
      • Rassweiler J.
      • Teber D.
      • Kuntz R.
      • et al.
      Complications of transurethral resection of the prostate (TURP)—incidence, management, and prevention.
      Initiation of BPH oral medication after a minimally invasive procedure also serves as an indication of durability. Following Rezūm thermal therapy at 1, 2, 3, and 4years, the patients that initiated use of the incidence of pharmacotherapy with alpha blockers was 0.7%, 2.2%, 3.7%, and 5.2% of subjects. This compares favorably to other MISTs.
      • Mattiasson A.
      • Wagrell L.
      • Schelin S.
      • et al.
      Five-year follow-up of feedback microwave thermotherapy versus TURP for clinical BPH: a prospective randomized multicenter study.
      • Lucarelli G.
      • Battaglia M.
      • Bettocchi C.
      • et al.
      High energy microwave thermotherapy for symptomatic benign prostatic enlargment: predictive parameters of long term outcome.
      • Mynderse L.A.
      • Roehrborn C.G.
      • Partin A.W.
      • et al.
      Results of a 5-year multicenter trial of a new generation cooled high energy transurethral microwave thermal therapy catheter for benign prostatic hyperplasia.
      ,
      • Roehrborn C.G.
      • Barkin J.
      • Gange S.N.
      • et al.
      Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study.
      The shared experiences with water vapor thermal therapy from community urology practices describe intraoperative techniques that may guide clinicians new to this efficient and versatile MIST and present outcomes after treating older patients and those with larger prostates.
      • Darson M.F.
      • Alexander E.E.
      • Schiffman Z.J.
      • et al.
      Procedural techniques and multicenter post-market experience using minimally invasive convective radiofrequency thermal therapy with Rezūm system for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
      • Cantrill C.H.
      • Zorn K.C.
      • Gonzalez R.R.
      The Rezūm System—a minimally invasive water vapor thermal therapy for obstructive benign prostatic hyperplasia.
      One pitfall of proceeding to treatment without urodynamic study involves ignorance of bladder function, including degree of obstruction, underactive, or overactive bladder contractility—major contributors to the total LUTS complex.
      Symptomatic men with moderate to severe LUTS could consider water vapor thermal therapy as a low-risk, first-line treatment option in lieu of a commitment to lifetime pharmacological management with attendant undesirable side effects and less than sufficient relief of LUTS. The advantage of a one-time only procedure using thermal therapy was assessed after 3years in comparison to continuous daily monotherapy with 2 drug classes (alpha blocker and 5-alpha reductase inhibitor) and combination drug therapy in cohorts from the Medical Therapy of Prostatic Symptoms study matched for prostate volume and IPSS severity.
      • Gupta N.
      • Rogers T.
      • Holland B.
      • et al.
      Three-year treatment outcomes of water vapor thermal therapy (Rezūm System) compared to doxazosin, finasteride and combination drug therapy for men with benign prostatic hyperplasia: cohort data from the Medical Therapy of Prostatic Symptoms (MTOPS) Trial.
      Symptom improvement was significantly greater with thermal therapy than monotherapy but similar to outcomes with a combination drug therapy. Rates of BPH clinical progression over 3years were nearly 5times greater under medical therapy vs a single thermal procedure. All drug treatments typically had significant negative impact on sexual function in contrast to preservation of libido, erectile, and ejaculatory function after thermal therapy.
      • McVary K.T.
      • Rogers T.
      • Mahon J.
      • Gupta N.K.
      Is sexual function better preserved after water vapor thermal therapy or medical therapy for lower urinary tract symptoms due to benign prostatic hyperplasia?.
      There are multiple options for treating LUTS/BPH within the armamentarium of treatments including pharmaceutical agents, surgery, and the newer minimally invasive procedures. As value and quality-based reimbursement programs continue to evolve, cost-effectiveness becomes paramount. The advantages of the Rezūm water vapor thermal therapy compare favorably with other options, and can achieve cost equivalence to combination medical therapy within a few years.
      • Ulchaker J.C.
      • Martinson M.
      Cost-effectiveness analysis of six therapies for the treatment of Lower urinary tract symptoms due to benign prostatic hyperplasia.
      • Gill B.C.
      • Ulchaker J.C.
      Costs of managing benign prostatic hyperplasia in the office and operating room.
      Relative to reimbursement for this procedure, the AMA/CPT Coding Committee announced that Rezūm meets all the stringent requirements for a unique Category I CPT Code. CPT 53854 became effective in January 2019. The Rezūm procedure effects rapid and durable symptom relief, has a good safety profile with preservation of sexual function, and accessibility as an office-based procedure such that it will have appeal and provide benefit to physicians and patients. Of great importance is that this procedure can substantially enhance the QOL in men with moderate to severe LUTS.

      CONCLUSION

      Water vapor thermal therapy represents a new technological approach for thermal ablative reduction of benign prostate adenomas. It provides effective symptom relief and improved QOL that remained durable throughout 4years. The procedure has a minimal physician learning curve and early intervention with this thermal therapy rather than use of pharmaceutical agents or invasive surgery may be an ideal option for men with moderate to severe LUTS at risk for BPH progression.

      Acknowledgments

      The clinical trial was sponsored by NxThera, Inc., Maple Grove, MN. The following clinical investigators and institutions participated in the Rezūm Clinical Study: J. Randolf Beahrs ̶ Metro Urology, Woodbury, MN; Christopher H. Cantrill ̶ Urology San Antonio Research, San Antonio, TX; Barrett E. Cowan ̶ Urology Associates of Denver, Englewood, CO; Steven N. Gange ̶ Western Urologic Clinic, Salt Lake City, UT; Marc C. Gittelman ̶ South Florida Medical Research, Aventura, FL; Kenneth A. Goldberg ̶ Texas Urology, Carrollton, TX; Jed Kaminetsky ̶ Manhattan Medical Research, New York, NY; Richard M. Levin ̶ Chesapeake Urology Research Associates, Towson, MD; Lance A. Mynderse ̶ Mayo Clinic, Rochester, MN; Kalpesh Patel ̶ Arizona Institute of Urology, Tucson, AZ; Michael Rousseau ̶ The Urology Group, Cincinnati, OH; Neal D. Shore ̶ Carolina Urologic Research Center, Myrtle Beach, SC; James C. Ulchaker ̶ Cleveland Clinic, Cleveland, OH; Scientific advisors (investigator training): Thayne R. Larson ̶ Institute of Medical Research, Scottsdale, AZ; Christopher M. Dixon ̶ Lenox Hill Hospital, New York, NY. This study was funded by NxThera, Inc., and the authors would like to thank Elaine K. Orenberg for her assistance and support.

      Appendix. Supplementary materials

      References

        • Dixon C.M.
        • Cedano E.R.
        • Mynderse L.A.
        • et al.
        Transurethral convection water vapor as a treatment for lower urinary tract symptomology due to benign prostatic hyperplasia using the Rezūm system: evaluation of acute ablative capabilities in the human prostate.
        Res Rep Urol. 2015; 7: 13-18https://doi.org/10.2147/RRU.S74040
        • Mynderse L.A.
        • Hanson D.
        • Robb R.A.
        • et al.
        Rezūm system water vapor treatment for lower urinary tract symptoms/benign prostatic hyperplasia: validation of convective thermal energy transfer and characterization with magnetic resonance imaging and 3-dimensional renderings.
        Urology. 2015; 86 (https://doi.org/10.1016/j.urology.2015.03.021): 122-127
        • McVary K.T.
        • Gange S.N.
        • Gittelman M.C.
        • et al.
        Minimally invasive prostate convective water vapor energy (WAVE) ablation: a multicenter, randomized, controlled study for treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia.
        J Urol. 2016; 195: 1529-1538https://doi.org/10.1016/j.juro.2015.10.181
        • McVary K.T.
        • Gange S.N.
        • Gittelman M.C.
        • et al.
        Erectile and ejaculatory function preserved with convective water vapor energy treatment of LUTS secondary to BPH: randomized controlled study.
        J Sex Med. 2016; 13: 924-933https://doi.org/10.1016/j.jsxm.2016.03.372
        • Roehrborn C.G.
        • Gange S.N.
        • Gittelman M.C.
        • et al.
        Convective water vapor energy (WAVE) ablation therapy: durable two-year results and prospective blinded crossover study for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
        J Urol. 2017; 197: 1507-1516https://doi.org/10.1016/j.juro.2016.12.045
        • McVary K.T.
        • Roehrborn C.G.
        Three-year outcomes of the prospective, randomized controlled Rezūm system study: convective radiofrequency thermal therapy for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
        Urology. 2018; 111 (PMID: 29122620): 1-9https://doi.org/10.1016/j.urology.2017.10.023
        • Rieken M.
        • Presicce F.
        • Autorino R.
        • DE Nunzio C.
        Clinical significance of intravesical prostatic protrusion in the management of benign prostatic enlargement: a systematic review and critical analysis of current evidence.
        Minerva Urol Nefrol. 2017; 69 (PMID: 28263050): 548-555https://doi.org/10.23736/S0393-2249.17.02828-4
        • Darson M.F.
        • Alexander E.E.
        • Schiffman Z.J.
        • et al.
        Procedural techniques and multicenter post-market experience using minimally invasive convective radiofrequency thermal therapy with Rezūm system for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
        Res Rep Urol. 2017; 9: 159-168https://doi.org/10.2147/RRU.S143679
        • Woo H.H.
        • Gonzalez R.R.
        Perspective on the Rezūm system: a minimally invasive treatment strategy for benign prostatic hyperplasia using convective radiofrequency water vapor thermal therapy.
        Med Devices (Auckl). 2017; 10: 71-80https://doi.org/10.2147/MDER.S135378
        • Bouza C.
        • López T.
        • Magro A.
        • et al.
        Systematic review and meta-analysis of transurethral needle ablation in symptomatic benign prostatic hyperplasia.
        BMC Urol. 2006; 6: 14https://doi.org/10.1186/1471-2490-6-14
        • Zlotta A.
        • Giannakopoulos X.
        • Maehlum O.
        • et al.
        Long-term evaluation of transurethral needle ablation of the prostate (TUNA) for treatment of symptomatic benign prostatic hyperplasia: clinical outcome up to five years from three centers.
        Eur Urol. 2003; 44: 89-93https://doi.org/10.1016/S0302-2838(03)00218-5
        • Hill B.
        • Belville W.
        • Bruskewitz R.
        • et al.
        Transurethral needle ablation versus transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia: 5-year results of a prospective randomized, multicenter clinical trial.
        J Urol. 2004; 171: 2336-2340https://doi.org/10.1097/01.ju.0000127761.87421.a0
        • Rosario D.
        • Phillips J.C.
        • Chapple C.R.
        Durability and cost-effectiveness of transurethral needle ablation of the prostate as an alternative to transurethral resection of the prostate when alpha-adrenergic antagonist therapy fails.
        J Urol. 2007; 177: 1047-1051https://doi.org/10.1016/j.juro.2006.10.042
        • Miller P.D.
        • Kastner C.
        • Ramsey E.W.
        • Parsons K.
        Cooled thermotherapy for the treatment of benign prostatic hyperplasia: durability of results obtained with the Targis System.
        Urology. 2003; 61 (PMID: 12809888): 1160-1164
        • Mattiasson A.
        • Wagrell L.
        • Schelin S.
        • et al.
        Five-year follow-up of feedback microwave thermotherapy versus TURP for clinical BPH: a prospective randomized multicenter study.
        Urology. 2007; 69 (PMID: 17270624): 91-96
        • Lucarelli G.
        • Battaglia M.
        • Bettocchi C.
        • et al.
        High energy microwave thermotherapy for symptomatic benign prostatic enlargment: predictive parameters of long term outcome.
        Arch Ital Urol Androl. 2011; 83 (PMID: 21826880): 83-87
        • Mynderse L.A.
        • Roehrborn C.G.
        • Partin A.W.
        • et al.
        Results of a 5-year multicenter trial of a new generation cooled high energy transurethral microwave thermal therapy catheter for benign prostatic hyperplasia.
        J Urol. 2011; 185: 1804-1811https://doi.org/10.1016/j.juro.2010.12.054
        • Roehrborn C.G.
        • Rukstalis D.B.
        • Barkin J.
        Three year results of the prostatic urethral L.I.F.T. study.
        Can J Urol. 2015; 22 (PMID: 25858102): 7772-7782
        • Roehrborn C.G.
        • Barkin J.
        • Gange S.N.
        • et al.
        Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study.
        Can J Urol. 2017; 24 (PMID: 28646935): 8802-8813
        • Rassweiler J.
        • Teber D.
        • Kuntz R.
        • et al.
        Complications of transurethral resection of the prostate (TURP)—incidence, management, and prevention.
        Eur Urol. 2006; 50: 969-980https://doi.org/10.1016/j.eururo.2005.12.042
        • Cantrill C.H.
        • Zorn K.C.
        • Gonzalez R.R.
        The Rezūm System—a minimally invasive water vapor thermal therapy for obstructive benign prostatic hyperplasia.
        Can J Urol. 2019; (in press 2019)
        • Gupta N.
        • Rogers T.
        • Holland B.
        • et al.
        Three-year treatment outcomes of water vapor thermal therapy (Rezūm System) compared to doxazosin, finasteride and combination drug therapy for men with benign prostatic hyperplasia: cohort data from the Medical Therapy of Prostatic Symptoms (MTOPS) Trial.
        J Urol. 2018; 200 (PMID: 29499208): 405-413https://doi.org/10.1016/j.juro.2018.02.3088
        • McVary K.T.
        • Rogers T.
        • Mahon J.
        • Gupta N.K.
        Is sexual function better preserved after water vapor thermal therapy or medical therapy for lower urinary tract symptoms due to benign prostatic hyperplasia?.
        J Sex Med. 2018; 15: 1728-1738https://doi.org/10.1016/j.jsxm.2018.10.006
        • Ulchaker J.C.
        • Martinson M.
        Cost-effectiveness analysis of six therapies for the treatment of Lower urinary tract symptoms due to benign prostatic hyperplasia.
        Clinicoecon Outcomes Res. 2018; 11 (eCollection 2018): 29-43https://doi.org/10.2147/CEOR.S148195
        • Gill B.C.
        • Ulchaker J.C.
        Costs of managing benign prostatic hyperplasia in the office and operating room.
        Curr Urol Rep. 2018; 19 (PMID: 30022307): 72https://doi.org/10.1007/s11934-018-0822-z