Medical Policy

 

Subject: Perirectal Spacers for Use During Prostate Radiotherapy
Document #: SURG.00143 Publish Date:    08/29/2018
Status: Reviewed Last Review Date:    07/26/2018

Description/Scope

This document addresses the use of perirectal spacers for use during prostate radiotherapy. Such products include SpaceOAR®, an injectable liquid hydrogel product intended to create distance and serve as a spacer between the prostate and the anterior rectal wall in individuals undergoing radiotherapy for prostate cancer.

Position Statement

Investigational and Not Medically Necessary:

Use of perirectal spacers during prostate radiotherapy is considered investigational and not medically necessary for all indications.

Rationale

A concern during prostate radiotherapy is rectal toxicity due to the exposure of healthy rectal tissue to therapeutic doses of radiation intended for the prostate.  One proposed method of reducing rectal toxicity is to create a buffer area in the perirectal space between the prostate and the rectum.  Such a buffer is intended to create distance between the prostate and rectum to move the rectum away from the treatment field.  At this time, only one product has been approved by the U.S. Food and Drug Administration (FDA) for such use.

The SpaceOAR (Augmenix, Inc.) system received FDA de novo clearance in April, 2015.  At this time, there is insufficient evidence to adequately address the use of the SpaceOAR System.  Only a limited number of studies are currently published in the peer-reviewed literature on the safety and efficacy of this technology in decreasing rectal toxicity during prostate radiotherapy, and the short- and long-term benefits and hazards are not fully understood.

The largest published peer-reviewed study involving the use of the SpaceOAR device was reported by Mariados and colleagues (2015).  This pivotal prospective multicenter single-blind randomized controlled trial (RCT) involved 222 subjects with clinical stage T1 or T2 prostate cancer who were randomized in a 2:1 fashion to receive image-guided intensity modulated radiation therapy (IMRT) (79.2 Gy in 1.8-Gy fractions) either with (n=149) or without (n=73) placement of the SpaceOAR system and were followed for 15 months.  The authors reported that perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively.  No device-related adverse events, rectal perforations, serious bleeding, or infections were reported in either group.  The use of SpaceOAR was reported to have resulted in significant reduction in mean rectal V70 when comparing treatment plans with and without the device in place (12.4% to 3.3%, p<0.0001).  Acute rectal adverse event rates were similar between groups, with the exception that fewer spacer group subjects reported experiencing rectal pain (p=0.02).  Significant benefits were reported in the spacer group with regard to late (3-15 months) rectal toxicity severity, with a 2.0% and 7.0% late grade 1 rectal toxicity incidence in the spacer and control groups, respectively (p=0.04) and no late rectal toxicity greater than grade 1 in the spacer group.  At 15 months, 11.6% and 21.4% of spacer and control subjects, respectively, experienced 10-point declines in bowel quality of life.  MRI scans at 12 months verified spacer absorption.  The authors concluded that use of SpaceOAR increased the perirectal space and resulted in reduced rectal irradiation, rectal toxicity severity, and decreased rates of subjects experiencing declines in bowel quality of life.

In 2017, this same group reported the results of an extension study involving 46 control group subjects and 94 SpaceOAR subjects (63% of the original cohort reported at 15 months for both groups) (Hamstra, 2017).  No significant differences were reported for the mean follow-up times between groups (p>0.05).  With regard to the volume of the rectum treated to all volumes of V50 to V80, the SpaceOAR group received a significantly smaller volume (p<0.001).  For V50 a 54% relative reduction was found, 21% for controls vs. 10% for SpaceOAR subjects.  The relative reduction at V70 was 79% (10% vs. 2%, respectively) and at V80 96% (4% vs. 0.1%, respectively).  No dosimetry differences were reported for the bladder, bladder wall or bladder/bladder wall within 1 or 2 cm of the prostate.  The 3-year incidence of grade ≥ 1 rectal toxicity (9.2% vs. 2.0%; p=0.028) and grade ≥ 2 rectal toxicity (5.7% vs. 0%; p=0.012) were significantly lower in the SpaceOAR group vs. controls.  The rate of grade ≥ 1 urinary incontinence was also significantly lower in the SpaceOAR group (15% vs. 4%; p=0.046), but no difference in grade ≥ 2 urinary toxicity was found (7% vs. 7%; p=0.7).

Pinkawa and colleagues published the results of a prospective cohort study of 167 subjects with prostate cancer treated with SpaceOAR and either IMRT or volumetric-modulated arc therapy (VMAT).  The subjects were asked to complete the Expanded Prostate Cancer Index Composite (EPIC) quality of life (QOL) questionnaire at 2 months post-treatment and then at a median of 17 months.  The authors noted that the SpaceOAR group received a significantly higher dose of radiation to the planning target volume compared to the control group (p<0.01).  At the last data collection point (> 12 months) the control group reported that treatment for bowel symptoms (0% vs. 11%; p<0.01) and endoscopic examinations (3% vs. 19%; p<0.01) were performed significantly less frequently in the SpaceOAR group. No differences in acute toxicity were reported.  In the SpaceOAR group, mean bowel function scores did not change significantly, whereas control subjects reported a mean decrease of 5 points >1 year after radiation therapy (RT) compared to baseline (p<0.01).  The authors concluded that “Spacer injection is associated with a significant benefit for patients after prostate cancer RT.” 

Fischer-Valuck (2017) published the results of a prospective cohort study of 149 subjects undergoing radiotherapy with SpaceOAR.  The authors’ investigation was focused on the correlation of spacer symmetry with rectal dose reduction, as well as rectal wall infiltration (RWI) to acute and late toxicity.  They reported that SpaceOAR was symmetrically placed at midline for 71 (47.7%) subjects at the prostate mid-gland as well as 1 cm superior and inferior to mid-gland.  The remaining 78 (50.9%) subjects had some level of asymmetry.  However, only 2 (1.3%) had far lateral distribution > 2 cm.  It was noted that as SpaceOAR placement became more asymmetric, the level of rectal dose reduction relative to their control plans decreased.  However, all but the most asymmetrical 1.3% of subjects had significant rectal dose reduction (p<0.05).  Rectal wall infiltration with SpaceOAR was reported in 9 (6.0%) subjects.  No correlation between rectal wall infiltration and procedure-related adverse events or acute/late rectal toxicity was reported.

In 2017, Jones and others reported the results of two parallel cohort studies involving subjects being treated with prostate cancer with stereotactic body radiotherapy.  In one study subjects were treated using a rectal balloon (n=36) and in the other, with SpaceOAR (n=36).  The SpaceOAR group achieved dosimetric superiority over the rectal balloon with respect to the maximum dose to the rectum (42.3 vs. 46.2 Gy, p<0.001), dose delivered to 33% of the rectal circumference (28 vs. 35.1 Gy, p<0.001), and absolute volume of rectum receiving 45 Gy (V45Gy), V40Gy, and V30Gy (0.3 vs. 1.7 cc, 1 vs. 5.4 cc, and 4.1 vs. 9.6 cc, respectively; p<0.001 in all cases).  No differences between the 2 groups with respect to the V50Gy of the rectum or the dose to 50% of the rectal circumference was reported (p=0.29 and p=0.06, respectively).  The V18.3 Gy of the bladder was significantly larger with the rectal balloon (19.9 vs. 14.5 cc, p=0.003).  The authors concluded that SpaceOAR outperformed the rectal balloon in the majority of the examined and relevant dosimetric rectal-sparing parameters.

Song and colleagues (2013) reported the results of a prospective pilot clinical trial involving 54 subjects receiving intensity modulated radiation therapy for prostate cancer.  All subjects underwent baseline scans and then were injected with SpaceOAR and rescanned.  Intensity modulated radiation therapy plans were created on both scans for comparison.  The authors reported that use of SpaceOAR resulted in ≥ 7.5 mm prostate-rectal separation in 95.8% of subjects and 95.7% had decreased rectal V70 of ≥ 25%, with a mean reduction of 8.0 Gy.  No significant differences were reported in pre-injection and post-injection prostate planning target volume (PTV), or rectal and bladder volumes.  Plan conformities were significantly different before versus after injection (p=0.02).  Plans with worse conformity indexes after injection compared with before injection (n=13) still had improvements in rectal V70.  The authors reported that in multiple regression analysis, greater post-injection reduction in V70 was associated with decreased relative post-injection plan conformity (p=0.01).  No significant relationships between reduction in V70 and the other characteristics analyzed were reported.  The authors concluded that injection of SpaceOAR resulted in dose reductions to the rectum for > 90% of subjects treated.  Furthermore, they stated that rectal sparing was statistically significant across a range of 10 to 75 Gy.

Gastrointestinal and genitourinary toxicity were recorded during treatment for up to 12 months in 52 subjects in whom the SpaceOAR system was injected prior to IMRT radiotherapy to a dose of 78 Gy (Uhl, 2014).  Of the subjects treated, 39.6% and 12.5% experienced acute Grade 1 and Grade 2 gastrointestinal (GI) toxicity using the RTOG/EORTC (Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer) criteria, respectively.  No Grade 3 or Grade 4 acute GI toxicity was reported.  Only 4.3% of subjects showed late Grade 1 GI toxicity, and there was no late Grade 2 or greater GI toxicity experienced in the study.  A total of 41.7%, 35.4% and 2.1% of subjects experienced acute Grade 1, Grade 2 and Grade 3 genitourinary (GU) toxicity, respectively.  There was no Grade 4 acute GU toxicity experienced in the study.  Late Grade 1 and Grade 2 GU toxicity was experienced in 17.0% and 2.1% of subjects, respectively and no late Grade 3 or greater GU toxicity was reported.  Vienna Rectoscopy Scale (VRS) score of 0 was reported for 71% of subjects, and 1 subject (2%) had Grade 3 telangiectasia.  No evidence of ulceration, stricture or necrosis was noted at 12 months.  The authors concluded that the use of the SpaceOAR System is a safe and effective method to spare the rectum from higher dose and toxicity.

Many other smaller and less rigorous studies have been published addressing the use of SpaceOAR (Hedrick, 2017a and 2017b; Juneja, 2015; Pinkawa, 2011; Ruggieri, 2015; van Gysen, 2014; Whalley, 2016; Wilton, 2017; Wu, 2018).  Unfortunately the data from these studies is significantly hampered by their methodological flaws, which may include small sample size, lack of control group, absence of blinding, etc.  Additional data from prospective, randomized controlled studies with medium- to long-term follow-up would be helpful to fully understand the benefits and hazards related to use of the SpaceOAR system.

Other products have been investigated for the same indication as SpaceOAR. One such product is DuraSeal, a polyethylene glycol hydrogel which received FDA approval in 2005 as an adjunct to sutured dural repair during spinal surgery.  A few studies have been published addressing the use of DuraSeal during prostate radiotherapy.

Strom (2014) reported on a nonrandomized controlled trial involving 200 subjects with clinically localized prostate cancer who received high-dose rate brachytherapy with or without intensity modulated radiation therapy.  Subjects received treatment either with (n=100) or without (n=100) insertion of DuraSeal into the anterior perirectal fat between the prostate and rectum.  The authors reported a DuraSeal implantation success rate of 100%.  They also reported that implantation of DuraSeal significantly increased the prostate-rectal separation (12 ± 4 mm with vs. 4 ± 2 mm without DuraSeal, p<0.001) and significantly decreased the mean rectal D2 mL (47 ± 9% with vs. 60 ± 8% without DuraSeal, p<0.001).  It was noted that implantation of DuraSeal decreased rectal doses regardless of body mass index (BMI).  Subjects were followed for a median of 8.7 months.  No data were presented regarding adverse events, including rectal toxicity.

In 2016, another study was published addressing the use of DuraSeal (Yeh, 2016).  This non-controlled case series study involved 326 subjects with prostate carcinoma who underwent combination high-dose rate brachytherapy and external beam radiotherapy.  All subjects had DuraSeal implanted into the anterior perirectal fat space prior to radiotherapy.  The median follow-up was 16 months. The authors stated that the mean anterior-posterior separation achieved was 1.6 cm (standard deviation [SD]=0.4 cm).  Rates of acute Grade 1 and 2 rectal toxicity were 37.4% and 2.8%, respectively.  No acute Grade 3/4 toxicities were reported.  Rates of late Grade 1, 2, and 3 rectal toxicity were 12.7%, 1.4%, and 0.7%, respectively.  There were no late Grade 4 toxicities.  The authors concluded that DuraSeal is safe and well tolerated, and acute and chronic rectal toxicities were low despite aggressive dose escalation.

A small nonrandomized controlled trial involving 20 subjects undergoing proton beam therapy with (n=12) or without (n=8) DuraSeal was published by Chung in 2016.  However, this small study provides little generalizable information regarding the efficacy of this product.

Another product, Rectafix™, has been studied for the same indications as SpaceOAR.  Wilton (2017) described a retrospective study of 45 subjects from the PROMETHEUS trial who received a total dose (TD) of 19 or 20 Gy in two fractions followed by 46 Gy in 23 fractions.  This study compared the use of Rectafix (n=35) vs. SpaceOAR (n=10).  Based on the results of several subanalyses, the authors reported that Rectafix vs. SpaceOAR demonstrated lower mean doses at 9 out of 11 measured intervals (p=0.0012).  However, they noted that although dose levels were in favor of Rectafix, in absolute terms the differences were small (2.6-9.0%).  The findings of this study are weak due to the small subject pool, and retrospective methodology.  Further large, well-designed studies are warranted to investigate the safety and efficacy of this product.  Finally, at this time Rectafix is not currently approved by the FDA.

In 2018 the Cochrane Library published a new report titled Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers (Lawrie, 2018).  This report looked at the use of perirectal spacers and concluded that. “Low-certainty evidence on balloon and hydrogel spacers suggests that these interventions for prostate cancer RT may make little or no difference to GI outcomes.”

In March 2018 the National Comprehensive Cancer Network (NCCN) published their Clinical Practice Guidelines in Oncology for prostate cancer version 2.2018.  In that document they stated:
Ideally, the accuracy of treatment should be verified by daily prostate localization with any of the following: techniques of IGRT using CT, ultrasound, implanted feducials, or electromagnetic targeting/tracking. Endorectal balloons may be used to improve prostate immobilization. Perirectal spacer materials may be employed when the previously mentioned 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. Patients with obvious rectal invasion or visible T3 and posterior extension should not undergo perirectal spacer implantation.”

However, the NCCN did not provide any evidentiary support for this statement.

Background/Overview

Prostate cancer is the most common cancer among U.S. males, with approximately 3 million men living with the disease as of the end of 2014, and an incidence rate of approximately 230,000 new cases annually. 

Radiotherapy for the treatment of prostate cancer is very common, being one of the most used treatment methods available, supported by national guidelines from an array of authoritative organizations.  Unfortunately one potential adverse effect of radiotherapy is exposure of the tissue adjacent to the prostate to high doses of radiation, resulting in toxicity.  One method proposed to prevent that from occurring is to create space between those tissues and the prostate, and one method of doing this involves the injection of a polyethylene glycol hydrogel into the space between the rectum and prostate.  As stated above, SpaceOAR is the only product currently approved by the FDA for such purposes.

SpaceOAR is a biodegradable polyethylene glycol hydrogel that is injected as a liquid between the prostate and rectum under ultrasound guidance.  Once injected, the liquid solidifies within seconds into a hydrogel that pushes the anterior rectal wall away from the prostate.  SpaceOAR is completely resorbed by the body over time.  This device received FDA de novo clearance in April 2015.

Other polyethylene glycol hydrogel products have been proposed for use in decreasing rectal toxicity during prostate radiotherapy.  One such product is DuraSeal, which received FDA approval in 2005 as an adjunct to sutured dural repair during spinal surgery.

Definitions

De Novo Clearance: An FDA alternate pathway to classify novel devices of low to moderate risk that had automatically been placed in Class III after receiving a “not substantially equivalent” (NSE) determination in response to a premarket notification [510(k)] submission. This process allows a sponsor to submit a de novo classification request to the FDA for novel low to moderate risk devices without first being required to submit a 510(k) application.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the following procedure codes; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

55874

Transperineal placement of biodegradable material, peri-prostatic, single or multiple injection(s), including image guidance, when performed

 

 

ICD-10 Diagnosis

 

 

All diagnoses

References

Peer Reviewed Publications:

  1. Chung H, Polf J, Badiyan S, et al. Rectal dose to prostate cancer patients treated with proton therapy with or without rectal spacer. J Appl Clin Med Phys. 2017;18(1):32-39.
  2. Fischer-Valuck BW, Chundury A, Gay H, et al. Hydrogel spacer distribution within the perirectal space in patients undergoing radiotherapy for prostate cancer: impact of spacer symmetry on rectal dose reduction and the clinical consequences of hydrogel infiltration into the rectal wall. Pract Radiat Oncol. 2017; 7(3):195-202.
  3. Hamstra DA, Mariados N, Sylvester J, et al. Continued benefit to rectal separation for prostate radiation therapy: final results of a phase III trial. Int J Radiat Oncol Biol Phys. 2017; 97(5):976-985.
  4. Hedrick SG, Fagundes M, Case S, et al. Validation of rectal sparing throughout the course of proton therapy treatment in prostate cancer patients treated with SpaceOAR®. J Appl Clin Med Phys. 2017; 18(1):82-89.
  5. Hedrick SG, Fagundes M, Robison B, et al. A comparison between hydrogel spacer and endorectal balloon: an analysis of intrafraction prostate motion during proton therapy. J Appl Clin Med Phys. 2017; 18(2):106-112.
  6. Jones RT, Hassan Rezaeian N, Desai NB, et al. Dosimetric comparison of rectal-sparing capabilities of rectal balloon vs injectable spacer gel in stereotactic body radiation therapy for prostate cancer: lessons learned from prospective trials. Med Dosim. 2017. pii: S0958-3947(17)30067-5.
  7. Juneja P, Kneebone A, Booth JT, et al. Prostate motion during radiotherapy of prostate cancer patients with and without application of a hydrogel spacer: a comparative study. Radiat Oncol. 2015; 10:215.
  8. Mariados N, Sylvester J, Shah D, et al. Hydrogel spacer prospective multicenter randomized controlled pivotal trial: dosimetric and clinical effects of perirectal spacer application in men undergoing prostate image guided intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2015; 92(5):971-977.
  9. Pinkawa M, Berneking V, König L, et al. Hydrogel injection reduces rectal toxicity after radiotherapy for localized prostate cancer. Strahlenther Onkol. 2017; 193(1):22-28.
  10. Pinkawa M, Corral NE, Caffaro M, et al. Application of a spacer gel to optimize three-dimensional conformal and intensity modulated radiotherapy for prostate cancer. Radiother Oncol. 2011; 100(3):436-441.
  11. Ruggieri R, Naccarato S, Stavrev P, et al. Volumetric-modulated arc stereotactic body radiotherapy for prostate cancer: dosimetric impact of an increased near-maximum target dose and of a rectal spacer. Br J Radiol. 2015; 88(1054):20140736.
  12. Song DY, Herfarth KK, Uhl M, et al. A multi-institutional clinical trial of rectal dose reduction via injected polyethylene-glycol hydrogel during intensity modulated radiation therapy for prostate cancer: analysis of dosimetric outcomes. Int J Radiat Oncol Biol Phys. 2013; 87(1):81-87.
  13. Strom TJ, Wilder RB, Fernandez DC, et al. A dosimetric study of polyethylene glycol hydrogel in 200 prostate cancer patients treated with high-dose rate brachytherapy±intensity modulated radiation therapy. Radiother Oncol. 2014; 111(1):126-131.
  14. Uhl M, Herfarth K, Eble MJ, et al. Absorbable hydrogel spacer use in men undergoing prostate cancer radiotherapy: 12 month toxicity and proctoscopy results of a prospective multicenter phase II trial. Radiat Oncol. 2014; 9:96.
  15. van Gysen K, Kneebone A, Alfieri F, et al. Feasibility of and rectal dosimetry improvement with the use of SpaceOAR® hydrogel for dose-escalated prostate cancer radiotherapy. J Med Imaging Radiat Oncol. 2014; 58(4):511-516.
  16. Whalley D, Hruby G, Alfieri F, et al. SpaceOAR hydrogel in dose-escalated prostate cancer radiotherapy: rectal dosimetry and late toxicity. Clin Oncol (R Coll Radiol). 2016; 28(10):e148-154.
  17. Wilton L, Richardson M, Keats S, et al.  Rectal protection in prostate stereotactic radiotherapy: a retrospective exploratory analysis of two rectal displacement devices. J Med Radiat Sci. 2017; 64(4):266-273.
  18. Wu SY, Boreta L, Wu A, et al. Improved rectal dosimetry with the use of SpaceOAR during high-dose-rate brachytherapy. Brachytherapy. 2018; 17(2):259-264.
  19. Yeh J, Lehrich B, Tran C, et al. Polyethylene glycol hydrogel rectal spacer implantation in patients with prostate cancer undergoing combination high-dose-rate brachytherapy and external beam radiotherapy. Brachytherapy. 2016; 15(3):283-287.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Lawrie TA, Green JT, Beresford M, et al. Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers. Cochrane Database Syst Rev. 2018; 1:CD012529.\
  2. NCCN Clinical Practice Guidelines in Oncology™ (NCCN). © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on June 4, 2018.
    • Prostate Cancer (V2.2018). Revised March 8, 2018
Index

DuraSeal
SpaceOAR

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed

07/26/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

07/18/2018

Hematology/Oncology Subcommittee review. Updated Rationale and References sections.

Reviewed

11/02/2017

MPTAC review.

Reviewed

11/01/2017

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Rationale and References sections. Updated Coding section with 01/01/2018 CPT changes; removed 0438T deleted 12/31/2017.

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Revised title. Clarified MN statement. Updated Rationale and Reference sections.

New

05/05/2016

MPTAC review.

New

05/04/2016

Hematology/Oncology Subcommittee review. Initial document development.