Medical Policy

Policy Num:       07.001.123
Policy Name:     Hydrogel Spacer use During Radiotherapy for Prostate Cancer
Policy ID:           [7.001.123]  [Ac / L / M+ / P+]  [7.01.164]

Last Review:    October 24, 2024
Next Review:    October 24, 2025

Related Policies:

06.001.057 - Intensity-Modulated Radiotherapy (IMRT)

Hydrogel Spacer use During Radiotherapy for Prostate Cancer

Summary

Description

For low- or intermediate-risk prostate cancer, radiation therapy is an option. Because the rectum lies in close proximity to the prostate, the risk of rectal toxicity is high. One approach is to push the rectum away from the prostate, increasing the space between the 2 and reducing the radiation dose to the rectum. A variety of biomaterials, including polyethylene glycol hydrogels (eg, SpaceOAR™System), hyaluronic acid hydrogels (Barrigel Injectable Gel), or absorbable balloon implants (BioProtect Balloon Implant™ System), have been evaluated as perirectal spacers.

Summary of Evidence

For individuals who have prostate cancer and are undergoing radiation therapy who receive a hydrogel spacer, the evidence includes a pivotal randomized controlled trial (RCT) with a 3-year follow-up for the SpaceOAR system, a pivotal RCT with up to 6-month follow-up for the Barrigel, observational studies, and systematic reviews of these studies. Relevant outcomes include symptoms, quality of life, and treatment-related morbidity. The combined evidence indicates that the hydrogel spacer can reduce the radiation dose to the rectum with a statistically significant decrease in Grade 1 or greater late toxicity and an number needed to treat (NNT) of 14.3. There were few events of greater than Grade 1 toxicity in either group across all trials, and the NNT for a reduction in clinically significant Grade 2 toxicity has been reported as 68 for SpaceOar. Patient-reported declines in rectal and urinary quality of life at 3 years in the SpaceOAR studies were statistically lower in the spacer group and met the threshold for a clinically significant difference, although patients were not blinded to treatment at the longer-term follow-up. The NNT for late improvement in rectal and urinary quality of life was 6.3 to 6.7, respectively, for SpaceOAR analysis. Limitations to all RCTs include the lack of blinding and the exclusion of patients who might be at greater risk of rectal toxicity. Evidence from observational studies is inconclusive but generally shows a decrease in radiation dose to the rectum with the insertion of a hydrogel spacer. However, the potential benefits of the hydrogel spacer must be balanced against the risks of an additional procedure. Additional studies are needed to corroborate the findings of the pivotal RCTs, to identify the factors that increase the risk of rectal toxicity, and to determine who is likely to benefit from the use of a spacer. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Clinical input: Evidence Summary For individuals who have prostate cancer and are undergoing radiation therapy who receive a perirectal spacer, the evidence includes a pivotal randomized controlled trial with three year follow-up, observational studies, and systematic reviews of these studies. Relevant outcomes include symptoms, quality of life, and treatment-related morbidity. The combined evidence indicates that the hydrogel spacer can reduce the radiation dose to the rectum with a statistically significant decrease in Grade 1 or greater late toxicity and a number needed to treat of 14.3. There were few events of greater than Grade 1 toxicity in either group, and the number needed to treat for a reduction in clinically significant Grade 2 toxicity has been reported as 68. Patient-reported declines in rectal and urinary quality of life at 3 years were statistically lower in the spacer group and met the threshold for a clinically significant difference, although patients were not blinded to treatment at the longer-term follow-up. The number needed to treat for late improvement in rectal and urinary quality of life were 6.3 to 6.7, respectively

Objective

The objective of this evidence review is to determine whether the use of a perirectal hydrogel spacer in patients with prostate cancer who are undergoing external beam radiation therapy improves the net health outcome.

Policy Statements

Hydrogel spacer use radiotherapy for prostate cancer may be considered medically necessary in individuals receiving external beam radiotherapy for prostate cancer (ie SpaceOAR) when it is determined to be medically necessary because the medical criteria and guidelines shown below have been met. 

Use of a hydrogel spacer for any other indication is experimental / investigational.

Policy Guidelines

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:

. Low* or favorable intermediate prostate cancer risk group.

• Dose escalated (≥ 76 Gy) conventional fractionation (1.8 – 2 Gy fractions) or moderate hypofractionation (2.4 – 3.4 Gy fractions) image-guided, intensity-modulated radiation therapy planned.

• Eastern Cooperative Oncology Group performance status ≤ 1.

• Modern localization techniques would be insufficient to improve oncologic cure rates and/or reduce side effects due to AT LEAST ONE of the following:

• Anatomic geometry precluding ideal rectal constraints (V70 < 10%, V65 < 20%, V40 < 40%):

1.  • Conventional fractionation (V70 < 10%, V65 < 20%, V40 < 40%).

2. • Moderate HPX (dose constraints not yet standardized; employ those used in the supporting phase III trials). 

• Medication usage (e.g., anticoagulants). 

• Comorbid conditions (e.g., increased age, history of myocardial infarction or congestive heart failure).

2. No Exclusion criteria including ALL of the following:

• Less than five-year life expectancy and asymptomatic.

• Prior prostate cancer treatment (surgery or radiation therapy).   

• Active bleeding disorder or clinically significant coagulopathy.

• Active inflammatory or infectious disease in the perineum or injection area (e.g., prostatitis, anorectal inflammatory bowel disease).

• Prostate volume > 80 cc.

* Life expectancy ≥ 20 years (very low risk); ≥ 10 years (low risk)

Limitations: All other uses of hydrogel spacer are investigational/not clinically proven.

Please see the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain FDA approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.

Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Prostate cancer is a complex, heterogeneous disease, ranging from microscopic tumors unlikely to be life-threatening to aggressive tumors that can metastasize, leading to morbidity or death. It is the second most common cancer in men, with approximately 1 in 8 men diagnosed with prostate cancer over their lifetime.^1, Cancer is typically suspected due to increased levels of prostate-specific antigen upon screening. A digital rectal exam may detect nodules, induration, or asymmetry, which is then followed by an ultrasound-guided biopsy with an evaluation of the number and grade of positive biopsy cores.

Clinical staging is based on the digital rectal exam and biopsy results. T1 lesions are not palpable while T2 lesions are palpable but appear to be confined to the prostate. T3 lesions extend through the prostatic capsule, and T4 lesions are fixed to or invade adjacent structures. The most widely used grading scheme for a prostate biopsy is the Gleason system.^2, It is an architectural grading system ranging from 1 (well-differentiated) to 5 (poorly differentiated); the score is the sum of the primary and secondary patterns. A Gleason score of 6 or less is low-grade prostate cancer that usually grows slowly; 7 is an intermediate grade; 8 to 10 is high-grade cancer that grows more quickly. A revised prostate cancer grading system has been adopted by the National Cancer Institute and the World Health Organization.^3, A cross-walk of these grading systems are shown in Table 1.

Table 1. Prostate Cancer Grading Systems

Regulatory Status

In October 2014, SpaceOAR™ (Augmenix, a subsidiary of Boston Scientific) was cleared by the U.S. Food and Drug Administration (FDA) through the De Novo process (DEN140030). Barrigel Injectable Gel (Palette Life Sciences) was approved by the FDA via the premarket approval process in March 2022 (K220641; FDA product code: OVB), followed by BioProtect Balloon Implant™ System (BioProtect, Ltd) in 2023 (K222972; FDA product code: OVB).The intended and approved use of SpaceOAR System, Barrigel, and BioProtect Balloon Implant is to temporarily position the anterior rectal wall away from the prostate during radiotherapy for prostate cancer and in creating this space it is the intent of these hydrogel spacers to reduce the radiation dose delivered to the anterior rectum.

DuraSeal® Exact (Integra) was approved by the FDA through the premarket approval process as a spine and cranial sealant (dura mater) and has been used off-label as a perirectal spacer.

Rationale

This policy was created in January 2019 with searches of the PubMed database. The most recent literature update was performed through May 22, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Hydrogel Perirectal Spacer

Clinical Context and Therapy Purpose

Early localized prostate cancer can usually be treated with surgery and radiotherapy, although active surveillance may be adopted in men whose cancer is unlikely to cause major health problems during their lifespan or for whom the treatment might be dangerous. In patients with inoperable or metastatic disease, treatment consists of hormonal therapy and possibly chemotherapy. Treatment decisions are based on the anatomic extent of the lesion, the histologic grade from biopsy, and serum prostate-specific antigen level. Other factors in treatment decisions are expected outcomes, potential complications, other medical conditions, age, and comorbidities, and personal preferences. For patients with clinically localized low-risk cancer (no palpable tumor and prostate-specific antigen of 10 or less), active surveillance is an option. Definitive therapy with radical prostatectomy or radiation therapy (RT) with external beam and/or brachytherapy is also an option for low- or intermediate-risk disease. Dose escalation of RT improves cancer outcomes but also increases the risk of urinary or rectal toxicity. Image-guided RT and intensity-modulated RT may be used to limit margins and reduce toxicity, but because the rectum lies in close proximity to the prostate, the risk of rectal toxicity remains high. Hypofractionation that reduces the number of treatments, dose-escalation, and salvage RT protocols can be particularly prone to rectal toxicity.

One approach to the problem of rectal toxicity is to push the rectum away from the prostate, increasing the space between the 2 organs and reducing the radiation dose to the anterior rectal wall. A variety of biomaterials, including collagen, polyethylene glycol (PEG) hydrogels, hyaluronic acid (HA) hydrogels, and absorbable balloons have been evaluated as a means to reduce rectal radiation exposure. The SpaceOAR System is the first PEG hydrogel that was cleared by the U.S. Food and Drug Administration (FDA) specifically for use during RT of the prostate. Subsequently, Barrigel Injectable Gel, an HA hydrogel, and BioProtect Balloon Implant, an absorbable balloon hydrogel spacer, were FDA-approved in 2022 and 2023, respectively.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is men with prostate cancer who are being treated with EBRT or brachytherapy.

Interventions

The therapy being considered is a PEG hydrogel (SpaceOAR System), an HA hydrogel (Barrigel), and an absorbable balloon hydrogel (BioProtect Balloon Implant) that is injected or implanted between the prostate and rectum.

The chemical composition of the SpaceOAR is similar to a PEG-based hydrogel that is FDA-approved as a dural sealant. Hydrodissection is achieved with saline between the retroprostatic (Denonvilliers') fascia and the anterior rectal wall using a transperineal approach. Once the needle placement is confirmed, 2 solutions in a 2-channel syringe are injected into the perirectal space. The hydrogel then polymerizes to form a soft mass. The hydrogel maintains the space for approximately 3 months, the duration of radiotherapy, and is completely absorbed by 12 months. The PEG hydrogel may be injected at the same time as the placement of fiducial markers in the prostate. The gel increases the space between the rectum and the prostate to about 12 mm. It maintains space for approximately 3 months and then is gradually absorbed and cleared.

Barrigel is composed of non-animal HA in phosphate buffered saline and is implanted transperineally between the rectum and prostate. It does not require hydrodissection prior to injection and maintains space (about 10 mm) for approximately 3 months before gradually being absorbed and cleared.

The BioProtect Balloon Implant System is composed of an inflatable, bioresorbable copolymer balloon implant, meant to be implanted transperineally between the rectum and prostate. The balloon implant is inflated with saline and can be deflated and repositioned, if needed, providing 10 to 18 mm space height. It maintains space for approximately 3 months and then is gradually absorbed and cleared.

Comparators

The following therapies are currently being used to make decisions about the treatment of prostate cancer: EBRT or brachytherapy without a spacer. Rectal toxicity of Grade 2 or greater was reported to be 1.5% at 3 to 15 months following moderate hypofractionated EBRT, indicating a number needed to treat (NNT) of 68 to avoid 1 case of clinically significant rectal toxicity.^4,

Outcomes

The outcomes of interest are symptoms of rectal toxicity, adverse events, and QOL.

Rectal toxicity according to the Common Terminology Criteria for Adverse Events is classified as Grade 0: no symptoms or complications; Grade 1: mild symptoms are present but no intervention is required; Grade 2: a moderate event affecting daily activities, intervention is required; Grade 3: a severe event that requires hospitalization; Grade 4: a life-threatening event; and Grade 5: death. Clinically significant rectal toxicity requiring intervention is considered to be Grade 2 or higher.

Prostate cancer-specific QOL can be measured by the Expanded Prostate Cancer Index Composite (EPIC) health-related QOL questionnaire, with 5- and 10-point thresholds for minimum clinically important differences (MCID). Skolarus et al (2015)^5,reported the bowel and vitality/hormonal domains had an MCID 4 to 6 point range, while the sexual domain had an MCID range of 10 to 12. Urinary incontinence had a greater MCID range (6 to 9) compared with the urinary irritation/obstruction domain (5 to 7).

Although considered a surrogate outcome, studies may also report estimated radiation doses to the rectum from radiation planning, with the rectal volume predicted to receive a radiation dose over the threshold (eg, rectal volume receiving 70 Gray [Gy]). Guidelines recommend that the volume of rectum receiving 70 Gy should be less than 10 ml.^6,

Beneficial outcomes would be reduced rectal toxicity and reduced impairment in QOL following radiotherapy.

Harmful outcomes would be the adverse effects of the spacer, spacer insertion, or spacer absorption.

Follow-up should be for at least 2 years since the median time for the occurrence of radiation toxicity is 18 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

External Beam Radiotherapy

Pivotal Randomized Controlled Trial

Results from the pivotal RCT for the SpaceOAR System were published by Mariados et al (2015), with a 3-year follow-up published by Hamstra et al (2017) (see Table 2)^7,8, A total of 222 men were randomized 2:1 to the spacer or control group. All individuals were implanted with fiducial markers for image-guided intensity-modulated radiation therapy and received 79.2 Gy in 1.8-Gy fractions to the prostate. The primary outcome was the percent of the rectal volume receiving 70 Gy in dose planning studies, which was 3.3% with the peri-rectal spacer and 11.7% in the control group (p<.001, see Table 3). Blinded adjudication identified no spacer-related adverse events. Grade 1 or greater adverse events were similar between the groups at 6 and 15 months but were reduced at 3 years in the group with the SpaceOAR System (2% vs. 9%, p<.03) with an NNT of 14.3. Fewer patients reported a clinically significant decline in bowel or urinary-related QOL with an NNT of 6.3 and 6.7, respectively (see Table 3). Individuals were not blinded to treatment at the 3-year follow-up.

Results from the pivotal RCT for Barrigel were published by Mariados et al (2023) to evaluate whether an HA spacer could improve rectal dosimetry and affect acute grade 2 or higher gastrointestinal toxic effects for hypofractionated radiation therapy.^9, A total of 201 men were randomized 2:1 to the spacer or control group. All individuals were implanted with fiducial markers for image-guided intensity-modulated radiation therapy and received 60 Gy in 20 fractions to the prostate. The primary outcome was the percent of patients who achieved at least a 25% reduction in rectal volume receiving 54 Gy (V54) after placement of the HA spacer compared with the baseline rectal V54 before spacer placement, which was based on primary effectiveness end points for the PEG hydrogel pivotal trial. The primary hypothesis tested if the percentage of patients achieving the primary effectiveness outcome was greater than a minimally acceptable success rate of 70%, with 1-sided significance defined as p<.03. Of the 133 evaluable patients in the HA spacer group, 131 (98.5%) patients experienced at least a 25% reduction in rectum V54, which was significantly higher than the minimally acceptable rate of 70% (p<.001) (Table 3). In terms of adverse effects, 4 of 136 patients (2.9%) in the spacer group and 9 of 65 (13.8%) in the control group experienced acute grade 2 or higher toxic effects (p=.01). Patients were blinded to treatment assignment throughout the trial.

Table 2. Summary of Key Randomized Controlled Trial Characteristics

  HA: hyaluronic acid; HFRT: hypofractionated radiation therapy; Gy: gray; IG-IMRT: image-guided intensity-modulated radiation therapy; PSA: prostate-specific antigen.

Table 3. Summary of Key Randomized Controlled Trial Results

  CI: confidence interval; GI: gastrointestinal; GU: genitourinary; Gy: gray; NA: not applicable; NNT: number needed to treat; NS: not significant; OR: odds ratio; QOL: quality of life. a Expanded Prostate Cancer Index Composite health-related QOL questionnaire b Difference between groups due primarily to grade 1 toxicity. There was one case of grade 3 toxicity in the control group and no cases of grade 4 toxicity. c There was no grade ≥ 2 rectal toxicity in the spacer arm compared with 6% (95% CI, 2% to 17%, p<.015) in the control arm.

Limitations in relevance and design and conduct are shown in Tables 4 and 5. The primary limitation of all trials in relevance was the population, which was restricted for this pivotal controlled trial. The primary limitations in design and conduct were the lack of investigator blinding and the loss to follow-up at 3 years for the SpaceOAR trial and 6 months for the HA spacer trial.

Table 4. Study Relevance Limitations

  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 5. Study Design and Conduct Limitations

  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials). e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p-values not reported; 4.Comparative treatment effects not calculated.

Fischer-Valuck et al (2017) reported secondary analysis of magnetic resonance imaging for the 149 patients enrolled in the pivotal trial who received the hydrogel spacer.^10, The spacer was symmetrically placed at midline for 71 (47.7%) patients, with 78 (50.9%) having some asymmetry and 3 (2.0%) with greater than 2 cm lateral distribution. The greater the asymmetry the lower the decrease in rectal radiation, although all but 4 patients achieved a 25% or greater reduction in rectal volume receiving 70 Gy. Infiltration of the rectal wall occurred in 9 (6%) patients but was not associated with procedure-related adverse events or acute or late rectal toxicity.

Systematic Reviews

Forero et al (2018) conducted a systematic review for the Technology Assessment Unit of the McGill University Health Centre.^4, They included the RCT reported by Mariados et al (2015) and Hamstra et al (2017) and 5 non-randomized comparative studies (3 from the same institution) that evaluated the effect of SpaceOAR on rectal radiation exposure, rectal toxicity, or QOL (See Table 6). Four studies found that placement of SpaceOAR resulted in lower rectal radiation exposure, but 3 studies that assessed rectal toxicity did not show important differences between the SpaceOAR and control groups. The RCT and 3 observational studies that evaluated QOL found no major differences between the SpaceOAR and control groups in the first year of follow-up. Longer-term results were inconsistent across studies. All of the studies had major limitations. The review concluded that while SpaceOAR does reduce rectal radiation exposure, it is unclear whether this impacts rectal toxicity and QOL.^4,

Miller et al (2020) reported a manufacturer-sponsored meta-analysis that included the studies described in Table 6 plus 2 additional prospective cohort studies, and 2 retrospective comparative studies on SpaceOAR for brachytherapy.^11, The percentage of rectal radiation over 70 Gy was 3.5% with SpaceOAR compared to 10.4% in controls (mean difference, −6.5%; 95% confidence interval [CI], -10.5% to -2.5%; p=.001). The spacer did not reduce the risk of early grade 2 or greater rectal toxicity, but was associated in this analysis with a reduced risk of late grade 2 or higher rectal toxicity (1.5% vs 5.7%; risk ratio, 0.23; 95% CI, 0.06 to 0.99; p=.05). These results were driven by the studies by Mariados et al (2015) and Pinkawa et al (2017) described in Table 6. There was imprecision in the other 2 studies included for this outcome (te Velde et al 2019 and Whalley et al, 2016) and did not show a significant reduction of rectal toxicity. Bowel-related QOL was reported in only 2 studies (Mariados et et 2015 and Pinkawa et al 2017), with higher QOL reported in patients treated with SpaceOAR. Interpretation of these results is limited by the small number of included studies, most of which were non-randomized, and limited follow-up duration for the detection of long-term outcomes of rectal irradiation.

Babar et al (2021) conducted a systematic review describing clinical outcomes of SpaceOAR in men undergoing EBRT for localized prostate cancer.^12, Eight studies were included, including all those analyzed in the systematic review by Miller et al (2020), plus an additional retrospective review by Navaratnam et al (2019) and a pooled analysis on long-term outcomes by Seymour et al (2020) (summarized in the Longer-term Follow-up section below). Unlike the publication by Miller et al (2020), a meta-analysis of the data was not performed. However, following a review of the available evidence, the authors concluded that SpaceOAR may be beneficial for those patients who 1) do not meet the standard rectal dose-volume criteria 2) have higher risk factors for the development of rectal toxicities post-radiation, and 3) wish to decrease the length and costs of radiotherapy by increasing the dose of radiation per fraction.

Table 6. Characteristics of Included Studies

  Gy: gray; IMRT: intensity-modulated radiation therapy; RCT: randomized controlled trial. 

Longer-term Follow-up

Te Velde et al (2019) published a 3-year follow-up of patients from their 2017 report (See Table 6).^18, Patients were excluded from analysis if their follow-up evaluations were not completed. The cumulative incidence of Grade 1 diarrhea (6.2% vs. 21.4%, p=.016) and Grade 2 proctitis (0% vs. 7.1%, p=.043) were statistically lower in the SpaceOAR group, but these outcome measures were not significantly different when assessed at 3 years after radiotherapy. The clinical significance of a difference between groups of Grade 1 diarrhea at any time during follow-up, but not at final follow-up, suggests that mild rectal toxicity resolves by 3 years. Fecal incontinence and hemorrhoids were not significantly different at any time point. In addition to questions of clinical significance, this study is limited by the potential for selection bias and detection bias due to unblinded and non-randomized methodology. All patients had been offered the SpaceOAR, but only patients with private insurance underwent the procedure, raising the possibility of differences in health or other personal factors between patients who had received the SpaceOAR and those who had not.

Seymour et al (2020) published 5-yr QOL outcomes from a combined data set that included patients in the studies by Mariados et al (2015) and Pinkawa et al (2017) described in Table 6.^19, Out of 125 patients from the RCT by Mariados and 165 non-randomized patients from Pinkawa (64% with the spacer and 36% without) there were 199 men who had prospective QOL data (EPIC) with at least 24-month follow-up (median 39.5 months, range 31 to 71.4). With a prespecified clinically important decline in EPIC of at least 5 points, controls had a decline of 5.1 points compared to an increase of 0.3 points in the spacer group (difference = 5.4, p <.001). A lower percentage of patients had a decline in bowel-related QOL of at least 5 points (14% vs 36%, p=.01) and 10 points (6% vs 19%, p=.008). Out of 13 questions, 4 were significantly impaired for bowel function (urgency, loose stools) and bother (urgency, frequency) at 36 months. Limitations of the long-term follow-up remain the same as in the original RCT (Tables 4 and 5), since the patients were no longer blinded to treatment and there was a high loss to follow-up (47%).

Brachytherapy with External Beam Radiotherapy

Non-Randomized Comparative Studies

Studies on the use of a hydrogel spacer with brachytherapy and EBRT for the treatment of prostate cancer are described in Tables 7 and 8.

Several retrospective comparative studies have been published that evaluated the effect of a hydrogel spacer on rectal toxicity and quality of life in men who are treated with brachytherapy and EBRT for prostate cancer.^20,21,22, The studies are consistent in showing a decrease in rectal dose with insertion of a hydrogel spacer, with no adverse effect on the dose to the prostate. No study has demonstrated a benefit of a hydrogel spacer on late rectal toxicity or quality of life in these patients. Investigators have noted that there may be some instances where the brachytherapy beads have migrated close to the rectum that might benefit from a spacer, but this will require further study.

Table 7. Characteristics of Non-Randomized Comparative Studies

  EBRT: external beam radiotherapy; Gy: gray; HDR: high dose rate; LDR: low dose rate; NR: not reported; SBRT: stereotactic body radiotherapy.

Table 8. Summary of Non-Randomized Comparative Study Results

  NS: not significant. V75 = volume of structure (X%) receiving 100% of the dose V100 = volume of structure (X%) receiving 100% of the dose

For individuals who have prostate cancer and are undergoing radiation therapy who receive a hydrogel spacer, the evidence includes a pivotal RCT with a 3-year follow-up, observational studies, and systematic reviews of these studies. Relevant outcomes include symptoms, quality of life, and treatment-related morbidity. The combined evidence indicates that the hydrogel spacer can reduce the radiation dose to the rectum with a statistically significant decrease in Grade 1 or greater late toxicity and an NNT of 14.3. There were few events of greater than Grade 1 toxicity in either group, and the NNT for a reduction in clinically significant Grade 2 toxicity has been reported as 68. Patient-reported declines in rectal and urinary quality of life at 3 years were statistically lower in the spacer group and met the threshold for a clinically significant difference, although patients were not blinded to treatment at the longer-term follow-up. The NNT for late improvement in rectal and urinary quality of life was 6.3 to 6.7, respectively. Limitations to the study include the lack of blinding and the exclusion of patients who might be at greater risk of rectal toxicity. Evidence from observational studies is inconclusive but generally shows a decrease in radiation dose to the rectum with the insertion of a hydrogel spacer. However, the potential benefits of the hydrogel spacer must be balanced against the risks of an additional procedure. Additional study is needed to corroborate the findings of the pivotal RCT, to identify the factors that increase the risk of rectal toxicity, and to determine who is likely to benefit from the use of a spacer. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

As per clinical input: : Evidence Summary For individuals who have prostate cancer and are undergoing radiation therapy who receive a perirectal spacer, the evidence includes a pivotal randomized controlled trial with three year follow-up, observational studies, and systematic reviews of these studies. Relevant outcomes include symptoms, quality of life, and treatment-related morbidity. The combined evidence indicates that the hydrogel spacer can reduce the radiation dose to the rectum with a statistically significant decrease in Grade 1 or greater late toxicity and a number needed to treat of 14.3. There were few events of greater than Grade 1 toxicity in either group, and the number needed to treat for a reduction in clinically significant Grade 2 toxicity has been reported as 68. Patient-reported declines in rectal and urinary quality of life at 3 years were statistically lower in the spacer group and met the threshold for a clinically significant difference, although patients were not blinded to treatment at the longer-term follow-up. The number needed to treat for late improvement in rectal and urinary quality of life were 6.3 to 6.7, respectively

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

PRACTICE GUIDELINES

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Radiology

American College of Radiology appropriateness criteria, last reviewed in 2016,^24, for dose-volume constraints for the rectum with external beam radiotherapy are described in Table 9.

Table 9. Dose Constraints for the Rectum With External Beam Radiotherapy

  EBRT: External beam radiotherapy; Gy: gray. V100 = volume of structure (X%) receiving 100% of the dose

American Society of Clinical Oncology, the American Urological Association, and the American Society for Radiation Oncology

In 2018, the American Society of Clinical Oncology, the American Urological Association, and the American Society for Radiation Oncology published a joint guideline on hypofractionated radiation therapy for localized prostate cancer.^25, The guideline recommends that men be counseled about the small increased risk of acute gastrointestinal (GI) toxicity with hypofractionation. "Moderately fractionated EBRT [external beam radiotherapy] has a similar risk of acute and late genitourinary and late GI toxicity compared with conventionally fractionated EBRT. However, physicians should discuss the limited follow-up beyond 5 years for most existing RCTs [randomized controlled trials] evaluating moderate hypofractionation." This was a strong recommendation based on high-quality evidence and 100% consensus. Additionally, the guideline mentions that prostate-rectal spacers can be used to allow rectal dose sparing.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network guideline for prostate cancer (v4.2024) provides the following recommendation in principles of radiation therapy (PROS-F), "Overall, the panel believes that biocompatible and biodegradable perirectal spacer materials may be implanted between the prostate and rectum in patients undergoing external radiotherapy with organ-confined prostate cancer in order to displace the rectum from high radiation dose regions."^26,

National Institute for Health and Care Excellence

In 2023, NICE updated their guidance on the biodegradable spacer.^27, The NICE recommendations state that: "Evidence on the safety and efficacy of biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research."

U.S. Preventive Services Task Force Recommendations

Not applicable.

MEDICARE NATIONAL COVERAGE

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 10.

Table 10. Summary of Key Trials

  NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.

References

1. American Cancer Society. Key Statistics for Prostate Cancer. https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.html. Updated January 19, 2024. Accessed May 22, 2024.
2. Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep. Mar 1966; 50(3): 125-8. PMID 5948714
3. SEER Database. https://seer.cancer.gov/seerinquiry/index.php?page=view&id=20170036&type=q. Accessed May 22, 2024.
4. Forero DF, Almeida N, Dendukuri N. Hydrogel Spacer to reduce rectal toxicity in prostate cancer radiotherapy: a health technology assessment. Report No. 82. April 16, 2018. https://muhc.ca/sites/default/files/micro/m-TAU/SpaceOAR.pdf. Accessed May 22, 2024.
5. Skolarus TA, Dunn RL, Sanda MG, et al. Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form. Urology. Jan 2015; 85(1): 101-5. PMID 25530370
6. McDonald AM, Baker CB, Popple RA, et al. Different rectal toxicity tolerance with and without simultaneous conventionally-fractionated pelvic lymph node treatment in patients receiving hypofractionated prostate radiotherapy. Radiat Oncol. Jun 03 2014; 9: 129. PMID 24893842
7. 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. Aug 01 2015; 92(5): 971-977. PMID 26054865
8. 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. Apr 01 2017; 97(5): 976-985. PMID 28209443
9. Mariados NF, Orio PF, Schiffman Z, et al. Hyaluronic Acid Spacer for Hypofractionated Prostate Radiation Therapy: A Randomized Clinical Trial. JAMA Oncol. Apr 01 2023; 9(4): 511-518. PMID 36757690
10. 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. PMID 28089528
11. Miller LE, Efstathiou JA, Bhattacharyya SK, et al. Association of the Placement of a Perirectal Hydrogel Spacer With the Clinical Outcomes of Men Receiving Radiotherapy for Prostate Cancer: A Systematic Review and Meta-analysis. JAMA Netw Open. Jun 01 2020; 3(6): e208221. PMID 32585020
12. Babar M, Katz A, Ciatto M. Dosimetric and clinical outcomes of SpaceOAR in men undergoing external beam radiation therapy for localized prostate cancer: A systematic review. J Med Imaging Radiat Oncol. Jun 2021; 65(3): 384-397. PMID 33855816
13. 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). Oct 2016; 28(10): e148-54. PMID 27298241
14. Te Velde BL, Westhuyzen J, Awad N, et al. Can a peri-rectal hydrogel spaceOAR programme for prostate cancer intensity-modulated radiotherapy be successfully implemented in a regional setting?. J Med Imaging Radiat Oncol. Aug 2017; 61(4): 528-533. PMID 28151584
15. Pinkawa M, Piroth MD, Holy R, et al. Quality of life after intensity-modulated radiotherapy for prostate cancer with a hydrogel spacer. Matched-pair analysis. Strahlenther Onkol. Oct 2012; 188(10): 917-25. PMID 22933033
16. Pinkawa M, Berneking V, König L, et al. Hydrogel injection reduces rectal toxicity after radiotherapy for localized prostate cancer. Strahlenther Onkol. Jan 2017; 193(1): 22-28. PMID 27632342
17. Pinkawa M, Berneking V, Schlenter M, Krenkel B, Eble MJ. Quality of Life After Radiation Therapy for Prostate Cancer With a Hydrogel Spacer: 5-Year Results. International journal of radiation oncology, biology, physics. 2017;99(2):374-377.
18. Te Velde BL, Westhuyzen J, Awad N, et al. Late toxicities of prostate cancer radiotherapy with and without hydrogel SpaceAOR insertion. J Med Imaging Radiat Oncol. Dec 2019; 63(6): 836-841. PMID 31520465
19. Seymour ZA, Hamstra DA, Daignault-Newton S, et al. Long-term follow-up after radiotherapy for prostate cancer with and without rectal hydrogel spacer: a pooled prospective evaluation of bowel-associated quality of life. BJU Int. Sep 2020; 126(3): 367-372. PMID 32333714
20. Chao M, Ow D, Ho H, et al. Improving rectal dosimetry for patients with intermediate and high-risk prostate cancer undergoing combined high-dose-rate brachytherapy and external beam radiotherapy with hydrogel space. J Contemp Brachytherapy. Feb 2019; 11(1): 8-13. PMID 30911304
21. Kahn J, Dahman B, McLaughlin C, et al. Rectal spacing, prostate coverage, and periprocedural outcomes after hydrogel spacer injection during low-dose-rate brachytherapy implantation. Brachytherapy. 2020; 19(2): 228-233. PMID 32085930
22. Nehlsen AD, Sindhu KK, Moshier E, et al. The impact of a rectal hydrogel spacer on dosimetric and toxicity outcomes among patients undergoing combination therapy with external beam radiotherapy and low-dose-rate brachytherapy. Brachytherapy. 2021; 20(2): 296-301. PMID 33199175
23. Butler WM, Kurko BS, Scholl WJ, et al. Effect of the timing of hydrogel spacer placement on prostate and rectal dosimetry of low-dose-rate brachytherapy implants. J Contemp Brachytherapy. Apr 2021; 13(2): 145-151. PMID 33897787
24. American College of Radiology. ACR appropriateness criteria for external beam radiation therapy treatment planning for clinically localized prostate cancer. 2016. https://acsearch.acr.org/docs/69396/Narrative/. Accessed May 22, 2024.
25. Morgan SC, Hoffman K, Loblaw DA, et al. Hypofractionated Radiation Therapy for Localized Prostate Cancer: An ASTRO, ASCO, and AUA Evidence-Based Guideline. J Urol. Oct 09 2018. PMID 30316897
26. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer v4.2024. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed May 22, 2024.
27. National Institute for Health and Care Excellence. Biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer. IPG752 2023 https://www.nice.org.uk/guidance/ipg752. Last Accessed May 22, 2024.

Codes

 Modifiers

As per Correct Coding Guidelines

Policy History