Polyethylene-glycol (PEG) hydrogel is covered **ONCE** in patients with
clinically localized prostate cancer with **BOTH** the following:

  1. Inclusion criteria including **ALL** of the following: 
    1. Low* or Favorable Intermediate Prostate Cancer Risk Group (1-5) (AUA or NCCN criteria (6,7))
    2. Dose escalated ( 76 Gy) conventional fractionation (1.8-2 Gy fractions) or moderate hypofractionation (HFX) (2.4-3.4 Gy fractions) IG-IMRT planned (7,8,9,25-27)
    3. Eastern Cooperative Oncology Group (ECOG) performance status  1 (4)
    4. Modern localization techniques insufficient to improve oncologic cure rates and/or reduce side effects due to **AT LEAST ONE** of the following (7): 
      1. Anatomic geometry precluding ideal rectal constraints 
        * Conventional fractionation (V70 <10%, V65 <20%, V40 <40%) (10)
        * Moderate HPX (dose constraints not yet standardized; employ those used in the supporting phase III trials) (25)
      2. Medication usage (e.g., anticoagulants) (8,11,12)
      3. Comorbid conditions (e.g., increased age, Hx MI or CHF) (11)
  2. No Exclusion criteria including **ALL** of the following: 
    1. Less than 5 year life-expectancy and asymptomatic (7)
    2. Prior prostate cancer treatment (surgery or RT) (1,3,4,8)
    3. Active bleeding disorder or clinically significant coagulopathy (8)
    4. Active inflammatory or infectious disease in the perineum or injection area (e.g., prostatitis, anorectal IBD) (1,3,8)
    5. Prostate volume > 80 cc (1,3,4)

*Life expectancy  20 y (very low risk);  10 y (low risk) (7)

Prostate rectal spacers are various materials or devices placed between the
prostate and anterior wall of the rectum for use in men receiving radiation
therapy for prostate cancer. The anterior wall of the rectum is considered a
major dose-limiting factor in radiation therapy of prostate cancer. Physical
separation is proposed to allow reduced toxicity and treatment
intensification.





Song et al. (2013) (1) conducted a prospective pilot clinical trial with 52
patients at four institutions. Spacer hydrogel was injected after CT and MRI
planning scans with repeat scans after the injection. IMRT plans were composed
using each set of CT and MRI scans. A prostate rectal separation of >7.5 mm
was achieved in 95.8% of the patients. A decreased rectal V70 >25% occurred in
95.7%. No significant differences were found in prostate, planning treatment
volume (PTV), rectal, and bladder volumes. Four of the 52 patients were not
successfully injected and a separate publication was planned detailing these
occurrences. Acute toxicity was not addressed in this report. The author
concluded statistically significant rectal dose reductions across the entire
dose range occurred in >90% of the patients.

Uhl et al. (2014) (3) reported on the 12 month toxicity of 52 patients who
received IMRT (78 Gy) for localized prostate cancer along with a prostate
rectal PEG spacer. Injection was not successful in four and in the rectal wall
in one patient, leaving 47 patients in the study. In addition to toxicity data
at 3, 6, and 12 months, proctoscopy was performed at 12 months. Grade 1 acute
rectal toxicity was noted in 19 (39.6%) and grade 2 in 6 (12.5%). No patients
had grade 3 or 4 acute toxicity. Late grade 1 toxicity was experienced by 2
(4.3%), but none had grades 2, 3, or 4 toxicity. Grades 1, 2, and 3
genitourinary (GU) toxicity occurred in 20 (41.7%), 17 (35.4%), and 1 (2.1%),
respectively. Forty-five of the 47 patients had proctoscopy at 12 months after
IMRT treatment. Using the Vienna Rectoscopy Scale (VRS), 32 (71%) had a score
of zero. Grade 2 congested mucosa was noted in 1 (3%) and telangiectasias were
found in 28%: grade 1 - 13%, grade 2 - 13%, and grade 3 - 2%. Ulceration,
stricture, or necrosis were not found.

Hamstra et al. (2017) (4) studied the extended three year follow-up data of
the above subjects. Patient participation was voluntary and included 63% of
both spacer (n=94) and control (n=46) patients. A comparison of the group
volunteer members was not presented, except that there was no difference
between groups regarding participation. A median follow-up of 37 months (range
26-46) occurred for the controls and 37.1 (range 32-47) months for the spacer
subjects.

Data showed the spacer group had a smaller volume of rectal radiation for all
volumes from V50 to V80 (p<.0001). Relative reductions were 54% for V50, 79%
for V70, and 96% for V80. Grade >1 rectal toxicity at three years was
decreased by 75% in the spacer patients (spacer 2%, 95% CI 1%- 6%) and
(control 9%, 95% CI 4% - 20%), p<.03. No grade >2 rectal toxicity was seen in
the spacer patients with 6% in the control group and one case of grade 3. It
was noted that the toxicity in the control group was less than usually
reported and no explanation was available. There were no differences in grades
1 or 2 urinary toxicities between the groups at three years with the exception
of urinary incontinence in 15% of the controls and 4% in the spacer group (p =
.046).

Susil et al. (2010) (13) injected 20 cadavers with hydrogel using a
transperineal approach achieving an average of 12.5 mm of separation.  Average
rectal volume receiving 70 Gy decreased from 19.9% to 4.5%.  The authors
discussed the potential advantages and possible risks as well as various
substances that could be used.

Mariados et al. (2015) (14) reported on a prospective, randomized, controlled,
multicenter trial with 222 patients with stage T1 or T2 prostate cancer.
Computed tomography (CT) and magnetic resonance imaging (MRI) scans were
performed for treatment planning, followed by placement of fiducial markers.
Patients were then randomized 2:1 to receive a polyethylene glycol (PEG)
prostate rectal absorbable spacer (SpaceOAR system) injection or no
injection. The planning CTs and MRIs were repeated prior to image-guided
intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). A primary
endpoint of a >25% reduction in the rectal volume (rV70) was achieved in 97.3%
of the spacer patients. The primary safety endpoint was the proportion of
patients experiencing grade 1 or greater rectal or procedural adverse events
(AEs) in the first six months. The treatment group had a reduction in pain
during RT (spacer 2.7% and control 11.8%, p = 0.022) but overall there were no
statistically significant differences in acute AEs between the treatment
(34.2%) and control (31.5%) groups. There were also no differences between
groups in urinary toxicity. Late rectal toxicity (3 - 15 months) was seen in
2.0% of the spacer patients and 7.0% of the controls which was statistically
significant (p = 0.044). No differences were found in bowel and urinary
quality-of-life (QOL) at three months and both groups had 5- and 10-point
bowel QOL declines at 6, 12, and 15 months. There was a statistically
significant difference (p = 0.003) in urinary QOL at six months between groups
favoring the treatment group, but there was no difference at 15 months.

Pieczonka et al. (2016) (15) also reported on the same group immediately
above. Insertion of the spacer was described as "very easy" in 98.7% and
successful in 99.3%. It was noted that the mean perirectal space was 12.6 mm
after implant and 10.9 mm at 12.4 weeks, with absorption at 12 months.

The Expanded Prostate Cancer Index Bowel Composite (EPIC) (16) quality of life
(QOL) and minimally important difference (MID) (17) tools were used to assess
patient opinions of treatment. Bowel QOL declined in both groups in the first
three months with return to baseline at six months. At three years the spacer
group was near or greater than baseline, but the control group had decreased
(p=.002). Differences were at the 5 point level of MID but not at the 10 point
level. A correlation between an increasing rectal V50 to V80 and a decline in
bowel QOL was found. Urinary QOL also declined in both groups in the first
three months with return to baseline at six months. At three years, there was
a statistical difference between the two groups favoring the spacer group, but
it did not meet the MID level. However, it was also stated that there was a
statistically significant difference between the groups regarding urinary
frequency favoring the spacer arm (5%) versus the controls (18%) p = .05. No
differences were found in the sexual QOL or vitality/hormonal QOL.

Hatiboglu et al. (2012) (18) reported on 29 of the patients in the study
immediately above. The method of selecting the 29 out of 52 patients is not
described, and the study is described as prospective, single-arm, open-label
performed at four institutions. Safety evaluation and performance of the
spacer were the main objectives. Scans (CT and MRI) were performed prior to
and after spacer injection and after IMRT at 3 and 6 months. An independent
reviewer measured the distance between the prostate and rectum. "Functional"
(7.5 mm space after spacer injection) and "clinical success" (> 25% reduction
in rectal V70) occurred in 28/29 (96.6%) and 26/27 (96.3%) of patients. Two
patients were excluded due to technical difficulties loading their data for
review.

Whalley et al. (2016) (19) studied 30 patients with T1-T3 prostate cancer for
whom dose-escalated radiation therapy was considered appropriate and who were
enrolled in a Phase I/II trial. A contemporary control group of 110 patients
receiving the same dose was identified for comparison. Primary endpoints were
comparison of the rectal volume receiving 30 - 82 Gy and post-operative
toxicity. Secondary endpoints were acute and late toxicity. Hydrogel (spacer)
was successfully injected into 29 patients with injection into the rectal
lumen in one. Mean difference of rectal- prostate separation was 10.5 mm.
Toxicity related to the injection occurred in five but resolved within a week.
Acute radiation gastrointestinal (GI) toxicity occurred in 13 (43%), which was
primarily increased stool frequency.  It was noted that stool softeners had
been prescribed. Two patients had grade 1 rectal bleeding. There was no >2
stage acute gastrointestinal toxicity. Late grade 1 GI toxicity of increased
stool frequency occurred in five (16.6%) spacer patients. One patient received
laser coagulation at 13 months and at 18 months the bleeding had not recurred.
In the control group, acute grade 1 toxicity occurred in 56 (50.6%) and grade
2 in five (4.5%).  Late grade 1 GI toxicity in the control patients was noted
in 46 (41.8%) occurring at a median of 11.5 months after radiation with a
range of 6 - 43 months.

Symptoms were increased stool frequency and rectal bleeding not requiring
intervention. Late grade 2 toxicity was seen in four (3.6%) patients and
occurred at a median of 20 months. There was no grade 3 toxicity in either
group. Late grade 1 toxicity was reduced in the spacer group compared to the
control (p = 0.04) but there was no difference in late grade 2 toxicity.
Median follow-up in this study was greater than two years. The authors noted
that GI toxicity occurs at a median of 17 months with peaks at 1.5 and 4.5
years [Zelefsky et al. (2008) (20) and Odrazka et al. (2010) (21)].

Habl et al. (2016) (22) stopped using the spacer gel due to the development of
rectal fistulae in two patients and the fistulae were presumed to be due to
the gradual accumulation of gel within the anterior rectal wall.
Correspondence from Fagundes et al. (2016) (23) has questioned the fistulae
being due to the use of the spacer.

The ECRI Institute which performs technology assessments recently evaluated
the SpaceOAR System. (24) A literature search of articles published between
January 1, 2000 and May 17, 2017 was performed.  The full text of seven
articles and seven abstracts were reviewed.  It was concluded from one RCT and
three non-RCTs that the hydrogel was well tolerated; worked as intended to
reduce rectal irradiation and long term but not acute toxicity, and improved
bowel quality of life.  Acute rectal toxicity reduction was not found. The
report stated studies with longer term follow-up of greater than five years
comparing different spacers are needed.

Hypofractionation (HFX) EBRT

Moderate HPX has become an accepted alternative to conventionally-fractioned
EBRT, despite lack of standardized dose constraints and follow-up beyond 5
years (7, 25-27). However, guideline support for ultra-HFX (sometimes referred
to as stereotactic body radiation therapy or SBRT) as a treatment option, even
in very low- to favorable intermediate-risk prostate cancer, is mixed. NCCN
guidelines include ultra-HPX treatment options (7), ASTRO/ASCO/AUA guidelines
(25) grade their ultra-HFX recommendation "conditional" ("remaining
uncertainty in the balance between benefit and risk"), and the European
Association of Urology (EAU) recommends restricting ultra-HFX to prospective
clinical trials (26).

Studies of HFX using the PEG spacer are lacking. A small, single institution,
retrospective chart review of 50 men with low- or intermediate-risk prostate
cancer treated with ultra-HFX after PEG placement claimed to show that "lower
rates of acute rectal toxicity were observed compared with previous,
similarly-fractionated SBRT reports that were performed without spacer
placement" (28).

NCCN Guidelines recommend selective use of the PEG spacer (standard EBRT or
HFX) when modern EBRT localization techniques are "insufficient to improve
oncologic cure rates and/or reduce side effects due to anatomic geometry or
other patient related factors, such as medication usage and/or comorbid
conditions" (7). ASTRO/ASCO/AUA HPX specific guidelines mention prostate-
rectal spacers as one of several techniques "to facilitate the meeting of
rectal and bladder dose-volume constraints" (25).



In summary, some of the literature endorses that the injection of the PEG
spacer is usually safe and without untoward events once the physician becomes
familiar with the procedure. Other references not cited here have described
materials used to increase the distance between the prostate and rectum during
radiation therapy for prostate cancer. Hyaluronic acid, human collagen,
interstitial balloons, as well as synthetic polyethylene glycols have been
used.

National PEG spacer commercial coverage varies from none as investigational
(29,30), to selective (31), to relatively unrestricted (32-35). Other MACs
have not weighed in with either specific positive or negative coverage.

Reducing rectal radiation exposure during prostate cancer radiotherapy is
desirable. The PEG spacer can be considered selectively when state-of-the-art
localization techniques do not suffice to either improve oncologic cure rates
or reduce side effects. Coverage criteria are meant to reflect a balanced
nexus between EBRT candidacy, PEG spacer RCT inclusion/exclusion criteria, and
national society guideline support.