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 30-120 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 (> 45C)
(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 (p0.001). 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   **

**Treatment** | **IPSS** | **Qmax**  
---|---|---  
**% Improvement**  
**Placebo*(20,24,25)** | 9-34 | 2-14  
**Pharmacologic** (25)** | 22-45 | 17-33  
**TUMT (26)** | 61 | 57  
**TUNA (9,28)***** | 45-58 | 41-66  
**Water vapor thermal therapy (33)** | 47 | 50  
**TURP (9,26,29)** | 67-76 | 71-141  
*3 month data; **F/U time varies, ***Zlotta 4-5 yr. data  
  
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), risks and benefits of water vapor thermal
therapy appear to be acceptable for increasing the prostate size eligible for
this treatment from an upper limit of 80cc to 120cc.