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# Biodegradable Rectal Spacers for Prostate Cancer Radiotherapy Section 1: Recommendations and Key Evidence

# OBJECTIVES
The objective of this guideline is to provide clinical practice recommendations for the use of biodegradable spacers for prostate cancer treatment.

# TARGET POPULATION
Patients undergoing radiation treatment for localized prostate cancer.

# INTENDED USERS
Radiation oncologists and genitourinary oncologists involved in the management of prostate cancer.

# RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE Recommendation 1
Biodegradable spacer insertion is a technology that may be used to decrease toxicity and maintain quality of life (QOL) in appropriately selected prostate cancer patients receiving radiotherapy (RT).

# Qualifying Statements for Recommendation 1 
Spacer insertion should be performed by individuals trained in the use of transperineal interventional procedures and where there is institutional support.
Selection of appropriate patients remains to be fully defined but may include: those in whom standard rectal dose-volume criteria are not met; those treated with ultrahypofractionated RT; and those at higher baseline risk of rectal toxicity.

# Key Evidence for Recommendation 1 
In a multicentre randomized controlled trial (RCT), 222 patients receiving the rectal spacer experienced significantly lower incidence and lower severity of long-term (greater than 3 months) rectal complications compared with patients not receiving spacers. There were significantly fewer patients experiencing grade 2 or greater longterm rectal toxicity (3 to 15 months) in the spacer (2%) group, compared with the nonspacer group (7%) (p=0.044). However, there were no significant differences observed in the rates of early rectal toxicity. Overall safety of the spacer was excellent, with no device-related adverse events, and no rectal infections or rectal complications . - A follow-up report for this RCT involved 63% of the original sample at a median followup of 37 months. . Grade 1 rectal toxicity at three years of follow-up was decreased by 75% in relative terms in the spacer group (hazard ratio , 0.24; 95% confidence interval , 0.06 to 0.97; p0.5) or grade 2 urinary toxicity . - There were no statistically significant differences in QOL measures for the one RCT examined in this report .
- In a cohort study of 167 patients, mean bowel function scores did not change for patients with a spacer in contrast to patients without a spacer more than one year after RT in comparison to baseline, with 0% versus 12% reporting a new moderate/big problem with passing stools (p<0.01) .
The RCT discussed in this recommendation report received an overall judgment of "unclear' as to risk of bias, mainly due to uncertainty regarding missing data, the potential for selective reporting, and the study being funded by Augmenix Incorporated, makers of the biodegradable rectal spacer (SpaceOAR) and two of the authors were stakeholders in the company.
Evidence in the three non-randomized studies presented in Section 3  showed small magnitude of benefit for relatively mild symptoms and were considered to be at "high risk of bias" mainly due to inadequate study design.

# Interpretation of Evidence for Recommendation 1
The evidence is adequate to support the use of biodegradable rectal spacers for RT in patients with localized prostate cancer. However, given the low rates of toxicity observed overall in both arms of the RCT, there may be limited benefit to routine application of this technology. Further evidence to direct the appropriate selection of patients and to evaluate the efficacy of this technology beyond conventionally fractionated RT is warranted.

# IMPLEMENTATION CONSIDERATIONS
Biodegradable rectal spacers are approved for use by Health Canada and thus implementation is left to the discretion of individual cancer centres. It is envisaged that each individual cancer centre may consider their local operational environment in facilitating the adoption of this technology. For example, centres with brachytherapy services may choose to adapt their system to allow for the transperineal insertion of the rectal spacer within the RT department, whereas those without brachytherapy services may choose to engage their local (interventional) radiology or urology departments. The associated costs, such as disposables, related to the transperineal procedure and the costs of the technology itself may need to be taken into account depending on the model of implementation.

# FUTURE RESEARCH
More phase II/III randomized trials to further evaluate the efficacy of this technology are warranted. Additional research is also needed to identify the clinical and dosimetric risk factors that can determine those at greatest risk of rectal toxicity and who might benefit most from the use of this technology. As conventional fractionation was used exclusively in the completed RCT, evaluation of rectal spacer technology in the setting of hypofractionated RT is also warranted.

# Biodegradable Rectal Spacers for Prostate Cancer Radiotherapy Section 2: Recommendation Report Methods Overview
This section summarizes the methods used to create the guideline. For the systematic review, see Section 3.

# THE PROGRAM IN EVIDENCE-BASED CARE
The Program in Evidence-Based Care (PEBC) is an initiative of the Ontario provincial cancer system, Cancer Care Ontario (CCO). The PEBC mandate is to improve the lives of Ontarians affected by cancer through the development, dissemination, and evaluation of evidence-based products designed to facilitate clinical, planning, and policy decisions about cancer control.
The PEBC is a provincial initiative of CCO supported by the Ontario Ministry of Health and Long-Term Care (OMHLTC). All work produced by the PEBC is editorially independent from the OMHLTC.

# BACKGROUND FOR RECOMMENDATION REPORT
The PEBC was asked to develop recommendations for the use of biodegradable rectal spacer insertion for prostate cancer treatment. The PEBC identified an 'interventional procedural guidance (IPG)' document developed by the National Institute for health and Care Excellence (NICE) in the United Kingdom  and a Cochrane systematic review  assessing hydrogel spacers as a subsection of a document on interventions to reduce acute and late adverse gastrointestinal effects of pelvic RT as relevant to this report. A recent report on the use of hydrogel spacer insertion prepared for the Health Technology Assessment Unit of the McGill University Health Centre (MUHC) was also deemed relevant . Since the abovementioned documents differed in their conclusions as to the efficacy of biodegradable spacers, the relevant primary literature was assessed directly by the PEBC methodologist.

# RECOMMENDATION REPORT DEVELOPERS
This recommendation report was developed by a Working Group consisting of four radiation oncologists (see Appendix 1) at the request of the biodegradable spacer insertion during radiotherapy for prostate cancer recommendation report group (hereby known as the SPACER RRG).
The Working Group was responsible for reviewing the evidence base, drafting the recommendations, and responding to comments received during the document review process. Conflict of interest declarations for all authors are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy.

# RECOMMENDATION REPORT DEVELOPMENT METHODS
The PEBC produces evidence-based and evidence-informed guidance documents using the methods of the Practice Guidelines Development Cycle . For Recommendation Reports this process includes a systematic review, interpretation of the evidence by the Working Group and draft recommendations, internal review by a methodology experts, and final approval by the Sponsoring Committee.
The PEBC uses the AGREE II framework  as a methodological strategy for guideline development. AGREE II is a 23-item validated tool that is designed to assess the methodological rigour and transparency of guideline development.
The currency of each document is ensured through periodic review and evaluation of the scientific literature and, where appropriate, the addition of newer literature to the original evidence-base. This is described in the PEBC Document Assessment and Review Protocol. PEBC guideline recommendations were based on clinical evidence, along with consideration of implementation issues with magnetic resonance imaging. A list of implementation considerations such as costs, human resources, and unique requirements for special or disadvantaged populations is provided along with the recommendations for information purposes. PEBC guideline development methods are described in more detail in the PEBC Handbook and the PEBC Methods Handbook.

# Search for Existing Guidelines
A search for existing guidelines is generally undertaken prior to searching for existing systematic reviews or primary literature. This is done with the goal of identifying existing guidelines for adaptation, using the ADAPTE framework , or endorsement in order to avoid the duplication of guideline development efforts across jurisdictions. For this project, the following sources were searched for existing guidelines that addressed the research questions:

# RECOMMENDATION REPORT REVIEW AND APPROVAL

# Internal Review
The recommendation report was reviewed by the PEBC Report Approval Panel (RAP). The Working Group was responsible for ensuring the necessary changes were made. If those changes could be made without substantially altering the recommendations, the altered draft would not need to be resubmitted for approval again. Table 2-1 shows the Working Group's responses to the RAP review. While the majority of the evidentiary base concerned hydrogel spacers, we considered spacers of all types in our literature search and therefore have decided to leave the title unchanged. Of note, one trial that employed hyaluronic acid spacers (Prada et al.) was included and discussed in the report. Well written -Magnitude of absolute benefit is small (2% vs. 7%) -Could highlight this This has been pointed out in the recommendation section and in the discussion.

# Report Approval by SPACER RRG
After internal review, the SPACER RRG reviewed the document on November 29 th , 2018 and formally approved the document. Of the eight SPACER RRG members approached, one abstained and one did not submit a conflict of interest statement. All of the remaining six eligible members approved (100%) the document. Table 2-2 shows comments addressed by the Working Group.

# Table 2-2. Working Group Responses to Recommendation Report Group SPACER RRG member
Working Group Response I do have some concern that the main piece of evidence is a small phase 2 RCT that was sponsored by the company, conducted by some investigators with COIs and with short follow-up (< 60 mo). Margins used in the trial were hugely variable considering all patients got gold-seed IGRT (5 -10mm CTV-PTV margin). There's no documentation of what the median (IQR) margins were in each group.
I would have liked to see 4-5mm margins in both groups but alas that was the way the study was designed.
Having said that, I think the conclusion is reasonably cautious given the above. It would be interesting to see a cost effectiveness analysis in the Canadian setting -SpaceOAR at $2700 (not including MD fees, disposibles or other personnel costs) doubles the cost of 60 Gy in 20fx and triples the cost of SBRT (40 Gy / 5fx).
Yes, we agree and the wording of the recommendation reflects that the evidence is only adequate to support the use of biodegradable rectal spacers for RT in patients with localized prostate cancer. We also state that since both arms of the RCT experienced low toxicity, there may be limited benefit to routine application of this technology.
Is there any data about when all hydrogel is either absorbed or congealed after instillation in humans/animals? Is it worthwhile to either allude to that data if available or to add a one liner indicating the absence of such data. One presumes this is going to be not at all like silicone implants.
We do not have evidence of rate of absorption but in addition to the estimates, in the RCT of 149 patients only 3 (2%) had any visible remnant of the get which consisted of water density cyst on MRI, as patients had MRI performed at 12 months after hydrogel insertion. This will be added to the findings sections of this report.