Water Vapor Thermal Therapy for LUTS/BPH

Language quoted from Centers for Medicare and Medicaid Services (CMS), National Coverage Determinations (NCDs) and coverage provisions in interpretive manuals is italicized throughout the policy. NCDs and coverage provisions in interpretive manuals are not subject to the LCD Review Process (42 CFR 405.860[b] and 42 CFR 426 [Subpart D]). In addition, an administrative law judge may not review an NCD. See Section 1869(f)(1)(A)(i) of the Social Security Act. 

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CMS Publications:

CMS Publication 100-02, Medicare Benefit Policy Manual, Chapter 14, 

10 Coverage of Medical Devices 

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 23, 

30 Services paid under the Medicare Physicians Fee Schedule 

CMS Publication 100-08, Medicare Program Integrity Manual, Chapter 13, 

5.1 Reasonable and necessary provisions in LCDs 

7.1 Evidence supporting LCDs. 

This LCD addresses use of water vapor thermal therapy for the treatment of lower urinary tract symptoms attributable to benign prostatic hyperplasia (LUTS/BPH). 

ONE treatment for LUTS/BPH treatment is covered ONCE in patients with BOTH the following: 

1. Indications including ALL of the following:

   1. Age ≥50

   2. Symptomatic despite maximal medical management including ALL of the following:

      1. International Prostate Symptom Score (IPSS) ≥13

      2. Maximum urinary flow rate (Qmax) of ≤15 mL/s (voided volume greater than 125 cc)

      3. Failure, contraindication or intolerance to at least three months of conventional medical therapy for BPH (e.g., alpha blocker, PDE5 Inhibitor, finasteride/dutasteride)

   3. Prostate volume of 30-80 cc,

   4. Poor candidate for other surgical interventions for BPH due to underlying disease (e.g., cardiac disease, pulmonary disease, etc.), or at high risk of bleeding

2. No contraindications including ALL of the following:

   1. Known or suspected prostate cancer (based on NCCN Prostate Cancer Early Detection guidelines) or a prostate specific antigen (PSA) >10 ng/mL

   2. Active urinary tract infection

   3. History of bacterial prostatitis in the past three months

   4. Prior prostate surgery

   5. Neurogenic bladder

   6. Active urethral stricture (i.e., the source of the current LUTS)

Approximately 50 percent of men at age 50, and up to 80 percent at age 80, have LUTS/BPH (1). In 2015, it was estimated that 12.2 million men were actively managed for LUTS/BPH; accounting for almost 25% of a urology practice (2). An aging population means the impact of LUTS/BPH will only increase. BPH develops primarily in the periurethral or transitional zone of the prostate (normally only 5% of prostate volume), and its pathogenesis remains incompletely understood. The natural history is variable; about one-third will ultimately require treatment, one-third remain stable, and one-third have some spontaneous regression of symptoms.  

The array of therapeutic options includes conservative approaches (watchful waiting), pharmacotherapy, and a burgeoning variety of surgical options (transurethral prostate resection or ablation). The need for surgical intervention is generally based upon the adequacy of medical therapy, the development of complications, and patient preference, rather than any specific urological parameter (3). The American Urologic Association/International Prostate Symptom Score (AUA/IPSS) (assessing for both storage (frequency, nocturia, urgency), and voiding (weak urinary stream, hesitancy, intermittence, incomplete emptying) symptoms, is useful for quantifying and monitoring BPH symptoms. Symptoms (individually ranked 0-5) are classified as mild (total score 0-7), moderate (total score 8-19), or severe (total score 20-35). Surgery is usually reserved for those with moderate to severe symptoms despite medical management (insufficient efficacy and tolerability, including drug side effects involving sexual dysfunction) (4). 

Transurethral resection of the prostate (TURP) has been the standard-of-care for decades. However, despite technical refinements that have improved safety, the procedure is still associated with a perioperative morbidity rate of 20% and long-term complications like ejaculatory dysfunction (EjD) (65%), erectile dysfunction (ED) (10%), urethral strictures (7%), urinary tract infection (4%), bleeding requiring transfusion (2%), urinary incontinence (2%) and a retreatment rate of 6% (5). EjD has a significant negative impact on quality-of-life (QoL), including on fertility, considering the relatively early onset of BPH.  

In recent years, an alphabet soup of minimally invasive treatment options have emerged with the main goal to be equally effective to TURP but with a more favorable safety and convenience profile. Ideally, this includes the rapid and durable relief of LUTS without compromise of sexual function, under local anesthesia in an ambulatory setting, with a short convalescence (6). Increasingly, a balance between symptomatic improvement in LUTS and preservation of sexual function is expected (7). The most apt comparators to water vapor thermal therapy include transurethral needle ablation (TUNA), and transurethral microwave thermotherapy (TUMT), both minimally invasive thermal ablative techniques.  

Transurethral needle ablation (TUNA)  

TUNA delivers radiofrequency energy to the prostate via needles inserted transurethrally into the prostatic parenchyma. The energy induces coagulation necrosis in the prostatic transition zone resulting in prostate volume reduction and LUTS reduction. There may also be a poorly understood neuromodulatory effect (8).  

Detailed comparisons between TUNA and other treatments can be found in two comprehensive, systematic reviews and meta-analyses (9,10). Improvements in urodynamic and symptom score parameters are generally inferior to TURP but TUNA is considered an alternative for men who are poor candidates for surgery, particularly men who require anticoagulation, but also for those who wish to undergo a procedure with fewer lower urinary and sexual side effects than TURP.      

Transurethral microwave therapy (TUMT)  

TUMT of the prostate works by emitting microwave radiation through an intra-urethral antenna in order to deliver heat into the prostate. Tissue is destroyed by being heated at temperatures above cytotoxic thresholds (> 45°C) (coagulation necrosis). It is thought that the heat generated by TUMT also causes apoptosis and denervation of alpha-receptors, thereby decreasing the smooth muscle tone of the prostatic urethra (8).  

A Cochrane systematic review of all available randomized controlled trials (RCTs) on TUMT shows roughly similar therapeutic efficacy to TUNA (11).  

Water vapor thermal therapy

Water vapor thermal therapy uses convective water vapor energy to ablate prostatic tissue. The Rezum system for delivering water vapor thermal therapy received FDA 510(k) clearance in 2015 to treat LUTS/BPH in men ≥ 50 years old with a prostate volume 30-80cc, and includes treatment of hyperplasia of the central prostate zone and median lobe (12).  

This technology uses radiofrequency current to generate “wet” thermal energy in the form of water vapor (steam). Using a TUNA approach, the steam is injected into the hyperplastic prostate, passing through the tissue interstices and disrupting cell membranes to effect rapid cell death and necrosis. Unlike conductive thermal ablation (TUNA, TUMT), steam convection at a physical phase change boundary best realizes a “prescribed temperature boundary condition”, effectively precluding a temperature gradient beyond the targeted prostate (usually the transition zone) (13). This was confirmed by histologic and imaging studies using gadolinium enhanced MRI (14,15). According to the manufacturer, water vapor thermal therapy requires “fewer joules per gram of tissue, ~1/6–1/23, to produce cell necrosis in prostate tissue compared to TUNA and TUMT, respectively (16).”  

A prospective, open-label, multicenter, pilot study reported the 1- and 2-year outcomes of 65 men with IPSS defined moderate (32.3%) to severe (67.7%) LUTS (overall mean IPSS: 21.6; Qmax: 7.9 mL/s; prostate volume (PV) 48.6 cc) (17,18). Clinically and statistically significant improvements in urinary symptoms were evident as early as one month after treatment and optimal at 3–12 months. The maximum IPSS improvement (-13.4) occurred at 3 months (N=62) and gradually decreased (-12.1) at 24 months (N=43); both were significantly different from baseline (p<.001). The maximum Qmax improvement (4.7 mL/s) occurred at 3 months (N=61) and decreased to (3.7 mL/s) at 24 months (N=39); both were significantly different from baseline (p<.001). Prostate volume was reported significantly decreased at all time points (p≤0.001). Adverse events were reported to be transient and mild to moderate, primarily related to endoscopic instrumentation. No clinically significant changes in sexual function were reported.  

A retrospective study analyzed 131 consecutive patients with moderate (53.1%) to severe (46.9%) LUTS treated with water vapor thermal therapy by seven urologists in a large group-community practice (19). While patient demographics were similar to the pilot study, some notable differences included older mean age (70.9 years), broader range of prostate volumes (mean 45.1 [12.9-183] cc), and higher post-void residual (PVR) volumes (mean 216.8 [0-2,000] mL, and three in retention. The maximum IPSS improvement (-10.1, -47.2%) occurred at 3-6 months (N=115) and decreased (-9.4, -45.2%) at 12 months (N=87); both were significantly different from baseline (p<.0001). The maximum Qmax improvement (3.0 mL/s, 75.3%) occurred at 3-6 months (N=38) but was markedly decreased (1.5 mL/s, 51.4%) at 12 months (N=7); only the 3-6 month value was significantly different from baseline (p=0.0388). PVR was significantly decreased at all time points. The safety profile was similar to the pilot study.  

The single level 1 study of water vapor thermal therapy is a multicenter RCT involving 197 men ≥50 years old with an IPPS ≥13, Qmax ≤15 mL/s, and PV 30-80 cc, randomized to thermal therapy with Rezum System or control (2:1) (20-22). Rigid cystoscopy with simulated active treatment sound effects served as the control procedure. The primary end point was the IPSS at 3 months. Both IPSS and Qmax (but not PVR) were significantly improved relative to sham at 3 months (p<0.0001). After the 3-month blinded comparison, 53 of 61 control subjects enrolled in a separate crossover active treatment study. The original active treatment group was followed annually for 3 years. The maximum IPSS improvement (-12.2, -54%) occurred at 6 months (N=129) and decreased (-11.0, -50%) at 36 months (N=97); both were significantly different from baseline (p<.0001). The greatest Qmax improvement (6.4 mL/s, 69%) occurred at 3 months (N=125) and decreased markedly (3.5 mL/s, 39%) by 36 months (N=80); both were significantly different from baseline (p<.0001). The surgical retreatment rate was 4.4 percent (6/135) over three years (open prostatectomy (1), plasma-button transurethral vaporization (3), water vapor thermal therapy re-treatment (2)). Subjects with a median lobe or central zone hyperplasia achieved similar significant relief of symptoms. Sexually active subjects had no negative changes in the International Index of Erectile Function (IIEF-15) and Male Sexual Health Questionnaire for Ejaculatory Dysfunction (MSHQ-EjD) function scores throughout 3 years of follow-up. Adverse events reported were infrequent and of short duration. The most common were dysuria (16.9%), hematuria (11.8%), frequency and urgency (5.9%), acute urinary retention (3.7%), and suspected urinary tract infection (3.7%); all were treated routinely or resolved without treatment within 3 weeks. There were no late occurring related adverse events.  Four year results were reassuring, with IPSS relatively stable (-10.1, -46.7%, N=90), and Qmax improved (4.2 mL/s, 49.5%, N=81) (33). The surgical retreatment rate was unchanged at 4.4%.

A retrospective analysis of 38 catheter-dependent men with complete urinary retention treated with water vapor thermal therapy found that 70.3% voided spontaneously and were catheter free a median of 26 days (range 4-65) post procedure (34). Adverse events were infrequent, mild, and resolved quickly. The authors conclude: “As a minimally invasive surgical procedure it represents an alternative for treatment of catheter-dependent urinary retention in elderly and frail patients who are at anesthesia risk for invasive surgical approaches to relieve retention.”

The table below compares the mid-term (3-4 -year) results of water vapor thermal therapy with traditional comparators (the subjective IPSS and objective Qmax are the almost universal primary outcome measures). 

Mid-term Thermal Ablation Results vs. Traditional Comparators  

A retrospective review of 182 patients undergoing water vapor thermal therapy at a single institution since 7/2017 were reviewed looking at 3 month postoperative outcomes including AUA symptom score, peak flow, and post-void residual. Complications such as hematuria and urinary tract infections were also assessed, of these 182 patients, 25.8% had prostate volumes over 80cc. Mean gland volume in this group was 119cc and 55.3% were catheter dependent. Following use of water vapor thermal therapy, statistically significant improvement was seen in AUASS from 22 to 13.4 (p+0.04) and post-void residual from 305cc to 149cc (0.05). Peak flow rates were statistically improved from 7.7mL/second to 12.7mL/second. In a subset of catheter dependent patients, the postoperative catheter free rate was 83% for men with glands >80cc which was comparable to 88% in the smaller gland group. The rate of postoperative complications was not significantly different between large or small glands (35).

A retrospective analysis of 206 patients who underwent water vapor thermal therapy between January 2017 and February 2020 at a single institution were queried from an internal database. The patients were subdivided based on preoperative prostate size, as determined by MRI, CT scan or transrectal ultrasound. Two of these patients were later excluded. For the remaining 204 patients, 36 had prostates greater than or equal to 80cc (mean 106.8cc). Data analysis showed these men with large prostates were significantly older and more likely to have a history of intermittent catheterization and prostate cancer. There were no differences in need for surgical retreatment after water vapor thermal therapy based on prostate size. Men with large prostates did not have an increased risk of urinary tract infections but did have an increased risk of urosepsis (36).

The European Association of Urology (EAU) guidelines state that TUNA and TUMT “achieve symptom improvement comparable with TURP, but both are associated with decreased morbidity and lower flow improvements. Durability is in favour of TURP with lower re-treatment rates compared to TUMT. (Level of evidence 1a, Grade A) (8).” The National Institute for Health and Care Excellence (NICE) guidelines do not recommend their use over TURP for men with LUTS/BPH (31). They are silent regarding water vapor thermal therapy as both predate water vapor thermal therapy study publication. UpToDate includes a summary of the 3-year water vapor thermal therapy data but makes no specific recommendation (3). Longstanding American Urological Association (AUA) guidelines considered both TUNA and TUMT “an appropriate and effective treatment alternative for bothersome moderate or severe LUTS secondary to BPH (30)." However, recently-issued, new guidelines no longer recommend TUNA based on “expert opinion,” and “conditionally recommend” both TUMT and water vapor thermal therapy (“evidence level: Grade C”) (32). The water vapor thermal therapy statement, based on the one RCT’s two-year data, is particularly cautious, noting “patients should be informed that evidence of efficacy, including longer-term retreatment rates, remains limited.”

Compared to TUNA and TUMT, water vapor thermal therapy data is limited in time (mid-term), scope (no studies comparing water vapor thermal therapy to other surgical options), and independence (no studies independent of manufacturer funding, and at least some author conflict of interest (“financial interest and/or other relationship with NxThera”)). The lack of long-term results is particularly important in view of the relatively low IPSS and Qmax percent improvement after water vapor thermal therapy at 3 years. Especially concerning is the sudden drop in Qmax improvement (53% to 39%) between years two and three, as this objective outcome metric is less subject to the placebo effect than IPSS (20,24,25). However, just published 4-year results show Qmax to have rebounded from the downward trajectory, allaying concerns somewhat.

The perception exists that utilization of TUNA and TUMT has not reached initial expectations due to insufficient long-term durability, despite advantages in more convenience and lower morbidity (30). Mid-term results suggest that durability after water vapor thermal therapy is no better, and may even be worse, than TUNA and TUMT. The new AUA water vapor thermal therapy recommendation based on one study’s two-year data seems premature, especially in light of the subsequent Qmax drop from year two to three. Conversely, unlike TUNA and TUMT, water vapor thermal therapy offers the potential for a low morbidity treatment of median lobe LUTS. NGS, therefore, will tentatively cover water vapor thermal therapy treatment for LUTS/BPH in poor surgical candidates, under criteria otherwise largely based on the RCT, pending long-term data.

NGS finds that though there is limited data currently in men with large prostates (prostate over 80cc), literature is not adequate to fully assess risks and benefits for increasing the prostate size to 120cc at this time. As more literature becomes available, this topic may be revisited.

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