Interventional procedure overview of biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer

Article

Number of patients/follow-up

Direction of conclusions

Reasons for non-inclusion in summary of key evidence section

Inert liquid-to-solid gels for prostate-rectum separation during prostate radiation therapy November (2010, 2013). Horizon scanning technology prioritising summary and Technology brief update: Prepared by Australian Safety and Efficacy Register of New Interventional Procedures – Surgical (ASERNIP-S). Accessed 2021 September 29.

Horizon scanning summary report for Australia and New Zealand

A Horizon Scanning prioritising summary report concluded that 'some form of injected liquid-to-solid inert substance (mostly recently cross-linked hyaluronan gel) for prostate-rectum separation appears to be safe. It also appears to have the potential to lower rates of rectal toxicity and improve QOL for men having radiotherapy for prostate cancer. However, the technology is very early in its lifecycle and is not yet in clinical use'. A 2013 technology update 'provides continued support for the safety and effectiveness of this modality. Although the evidence base remains small, injection of hyaluronic acid or the SpaceOAR^TM System gel appears to successfully increase the distance between the posterior prostatic capsule and the anterior rectal wall which resulted in reduced gastrointestinal toxicity. Based on this, and the claim that inert liquid‐to‐solid gels have the potential to reduce the incidence of severe proctitis, necrosis, fistula or rectal bleeding by 50%, this technology will be monitored for a further 24 months'

More recent assessments included.

Afkhami Ardekani M, Ghaffari H. Optimization of prostate brachytherapy techniques with

polyethylene glycol-based hydrogel spacers: a systematic review. Brachytherapy. 2019:S1538-

4721(19)30574-4.

Systematic review

12 studies, involving 615 patients with PEG hydrogel injection, were included.

overall, patients well tolerated the implantation of PEG hydrogel spacers with an excellent safety profile. However, although there were some procedure-related complications, rates of

these complications were very rare. Toxicities related to the spacer were limited to Grade 1 rectal

discomfort and pain (9/615 patients), Grade 2 rectal ulceration (1 in 615 patients), perineal abscess

(1 in 615 patients), and bacterial prostatitis (2/615 patients) according to Common Terminology

Criteria for Adverse Events v4.0 grading scheme. The application of PEG hydrogel spacers significantly reduced radiation doses to the rectum during prostate brachytherapy in the different setting.

Although there was no prospective randomized clinical trial, retrospective studies showed that

reducing rectal doses by the implantation of PEG hydrogel may result in an improvement in rectal

toxicity

More comprehensive and recent reviews added.

Aditama, E (2015).

Evaluation of Hydrogel Spacer (SpaceOAR) to reduce rectal toxicity in dose-escalated intensity modulated radiotherapy (IMRT) 82Gy for prostate cancer. Journal of Medical Radiation Sciences (62) 89.

Case report

A 54-year-old man was diagnosed with T1c prostate adenocarcinoma and treated with dose-escalated IMRT 82 Gy with injection of hydrogel spacer.

Follow-up: 6 months

The injection of spacer results in reduction of rectal dose with V70 = 0% for post injection of spacer plan compared with V70Gy = 15% for pre injection of spacer plan. The distance created due to spacer is 7-10 mm.

Larger studies are included.

Alongi F, Cozzi L, Arcangeli S, Iftode C, Comito T, Villa E, et al. Linac based SBRT for prostate cancer in 5 fractions with VMAT and flattening filter free beams: Preliminary report of a phase II study. Radiation Oncology. 2013;8 (1) (no pagination)(171)

Case series

N=40 patients prostate adenocarcinoma (T1-T2).

hypo-fractionated SBRT programme with Volumetric Modulated Arc Therapy (VMAT) and Flattening Filter Free (FFF) beams. SpaceOAR™ gel was optionally implanted (in 8 patients).

Median follow-up was 11 months (range: 5-16)

No acute G3 or greater toxicity was found. Median treatment time was 126 sec (120-136). Early findings suggest that SBRT with RapidArc and FFF beams for prostate cancer in 5 fractions is feasible and tolerated in acute setting.

Larger studies are included.

Alongi F, Riog M, Figlia V et al. (2020) Rectal spacer hydrogel in 1.5T MR-guided and daily adapted SBRT for prostate cancer: dosimetric analysis and preliminary patient-reported outcomes. Br J Radiol; 94: 20200848.

Case series

N=20 patients with prostate cancer (cT1-T2 stage) treated using 1.5T MR-guided adaptive stereotactic body radiotherapy [SBRT -35 Gy schedule delivered in 5 fractions] (10 patients in spacer group and 10 patients in no-spacer group).

Statistically significant dosimetric advantages were observed in favour of the spacer insertion, improving the planning target volume coverage in terms of V33.2Gy >95% and planning target volume 37.5 Gy <2% mainly during daily-adapted SBRT.

Also, rectum V32, V28 and V18Gy and bladder V35Gy

<1 ccs were significantly reduced in the spacer cohort. PROMS, showed no difference between the pre- and post-SBRT evaluation in both arms, excepting the physical functioning item of EORTC QLQ-C30 questionnaire that was declined in the no-spacer group.

Larger studies are included.

Ahmad Khalil D, Jazmati D, Geismar,D et al. (2022) Dosimetric feasibility of moderately hypofractionated/dose escalated radiation therapy for localised prostate cancer with intensity-modulated proton beam therapy using simultaneous integrated boost (SIB-IMPT) and impact of hydrogel prostate-rectum spacer. Radiation oncology. 17 (1); 64

N=23 patients with intermediate- and high-risk prostate cancer treated using IMPT -SIB technique prescribing 60 GyRBE and 72GyRBE in 30 fractions to PTV1 (prostate and seminal vesicle) and PTV2 boost (prostate and proximal seminal vesicle), respectively

(15 had spacer, 8 were non spacer).

Hypofractionated/dose escalated radiotherapy with SIB-IMPT is dosimetrically feasible. Further reduction of the rectal volumes receiving high and medium dose levels (73-50 Gy) and rectal NTCP could be achieved through injection of spacers between rectum and prostate.

Dosimetry study. Larger studies with longer follow-up included.

Alshak MN, Eidelberg A, Diaz SM et al. (2022) Natural history of lower urinary tract symptoms among men undergoing stereotactic body radiation therapy for prostate cancer with and without a Rectal Hydrogel Spacer. World journal of urology. 40,1143–1150 

Retrospective analysis n= 87 men (50 had SBRT+ SpaceOAR and 37 had SBRT with no SpaceOAR).

Follow-up 6 months

Post-SBRT urinary frequency was more common in the non-SpaceOAR group versus the SpaceOAR group (68% versus 38%, p = 0.006), as was nocturia (35% vs. 8%, p = 0.002). Acute gastrointestinal symptoms did not differ. 58.8% of men were on α-inhibitors at 6-months of follow-up post-SBRT, an increase from 27.6% baseline usage (p < 0.001). Importantly, there was a difference of α-inhibitor use between non-SpaceOAR and SpaceOAR groups at the end of SBRT and at 1.5-, 3-, and 6-months follow up (86% vs. 53% [p = 0.002], 83% vs. 53% [p = 0.005], 72% vs. 49% [p = 0.038], respectively).

Larger studies with longer follow-up included.

Babar M, Katz A, Ciatto M et al. (2021) Dosimetric and clinical outcomes of SpaceOAR in men undergoing external beam radiation therapy for localized prostate cancer: A systematic review. Journal of Medical Imaging and Radiation Oncology 65 (2021) 384–397

systematic review on controlled studies on the dosimetric and clinical outcomes of SpaceOAR in men undergoing external beam radiation therapy for localized prostate cancer. 8 studies were included.

All of the studies showed SpaceOAR to reduce the radiation dose volume to the rectum over numerous dosimetry levels. Of the four studies that assessed toxicity, one reported SpaceOAR to significantly decrease acute Grade 1 diarrhoea and two reported SpaceOAR to significantly decrease late Grade 1 and Grade ≥2 rectal toxicities. Two studies assessed cumulative incidence of toxicity at 3 years in which one reported SpaceOAR to significantly decrease urinary incontinence and Grade ≥1 and Grade ≥2 rectal toxicities, and the other reported SpaceOAR to significantly decrease Grade 1 diarrhoea and Grade 2 proctitis. Moreover, one study reported that fewer SpaceOAR patients experienced 10-point declines in bowel quality of life at 3 years, but another study reported no significant difference in 10-point declines in bowel quality of life between the SpaceOAR and control groups at 5 years. With the current research available, SpaceOAR may be beneficial to those who did not meet the standard rectal dose-volume criteria, have higher risk factors of developing rectal toxicities post-radiation, or wish to decrease the length and costs of radiotherapy by increasing the dose of radiation per fraction.

Similar comprehensive review on hydrogel spacers included.

Bahl A, Challapalli A, Jain S et al. (2021) Rectal spacers in patients with prostate cancer undergoing radiotherapy: A survey of UK uro-oncologists. Int J Clin Pract. 2021;75:e14338

Survey

online questionnaire was completed by members of the British Uro-oncology Group (BUG).

63 specialists completed the survey (50% of BUG members at that point in time). Only 37% had used rectal spacers, mostly for private patients or those with pre-existing bowel conditions. However, many (68%) would like to use these devices in future. More than 70% of the uro-oncologists felt that bowel toxicity was under-reported, but 60% believed that the use of radiotherapy without bowel toxicity was achievable with the use of rectal spacers. The current use of rectal spacers by UK uro-oncologists for patients with localised or locally advanced prostate cancer receiving radiotherapy is low and largely restricted by resourcing issues.

Survey

Beydoun N, Bucci JA et al (2013). First report of transperineal polyethylene glycol hydrogel spacer use to curtail rectal radiation dose after permanent iodine-125 prostate brachytherapy.

Brachytherapy 12 (4) 368-374.

Case series

n=5 prostate cancer patients with suboptimal rectal dosimetry after iodine 125 seed brachytherapy implant (low dose rate) and had hydrogel PEG spacer

Follow-up: 6 weeks

All patients had a clinically significant reduction in the volume of rectum having greater than or equal to the prescription dose (RV100) on the post spacer postimplant dosimetry, compared with the pre-spacer postimplant dosimetry. Mean prostate-rectum separation that was achieved with the insertion of the spacer was 15.1 mm (+/-3.4). The mean difference in separation from before to after spacer insertion was 12.5 mm (+/-4.5). This was associated with a reduction in mean RV100 from 3.04 (+/-1.2) to 0.06 (+/-0.1) cc. Toxicities were limited to grade 1 perineal pain and rectal discomfort (3/5 patients). There were no grade 2 or greater toxicities reported after insertion of the spacer.

Larger and longer follow-up studies included.

Berlin A, Tomasso AD, Ballantyne H et al. (2017) Use of hydrogel spacer for improved rectal dose-sparing in patients undergoing radical radiotherapy for localized prostate cancer: First Canadian experience. : Can Urol Assoc J;11(12):373-5. http://dx.doi.org/10.5489/cuaj.4681

Case series

N=5 patients with localised prostate cancer planned to undergo radical hypofractionated, image-guided, intensity-modulated radiotherapy (IG-IMRT using a hydrogel spacer SpaceOAR)

Authors discuss the impact of SpaceOAR in the context of hypofractionated IG-IMRT, and the particular considerations for its applications in the Canadian setting.

Larger studies included.

Boissier R, Udrescu C, Rebillard X et al (2017). Technique of Injection of Hyaluronic Acid as a Prostatic Spacer and Fiducials Before Hypofractionated External Beam Radiotherapy for Prostate Cancer.

Urology (99) 265-269.

Case series

n=30 patients with prostate cancer at low or intermediate risk.

Implantation of fiducials and a prostatic spacer (hyaluronic acid [HA]) during image-guided external beam radiotherapy (EBRT) of 62 GY in 20 fractions of 3.1 GY with intensity-modulated radiotherapy.

The quality score increased from patients 1-10, 11-20, to 21-30 with respective median scores: 7 [2-10], 5 [4-7], and 8 [3-10]. The average thicknesses of HA between the base, middle part, and apex of the prostate and the rectum were the following: 15.1mm [6.4-29], 9.8mm [5-21.2], and 9.9mm [3.2-21.5]. The injection of the HA induced a median pain score of 4 [1-8] and no residual pain at mid-long term.

Larger studies included.

Brooks E, Hu J, Yu J, et al. Cost effectiveness of the insertion of hydrogel spacer in men treated with radiation therapy for prostate cancer. Managed Care 2020;

Cost effectiveness

Costs not in remit.

Butler WM, Kurko BS, Scholl WJ et al. (2021) Effect of the timing of hydrogel spacer placement on prostate and rectal dosimetry of low-dose-rate brachytherapy implants. J Contemp Brachytherapy; 13, 2: 145–151

Retrospective study

N=174 intermediate- and high-risk patients with hydrogel compared with 174 patients without hydrogel for prostate brachytherapy. Of the SpaceOAR™ patients, 91 had hydrogel upon completion of after brachytherapy implant, while 83 had hydrogel prior to EBRT, followed 2-10 weeks later by brachytherapy.

There was a significant rectal dose sparing in the cohort with hydrogel spacer compared to a reference group without spacer injection. The rectal dose sparing effect was similar in the sub-group of patients injected with hydrogel prior to EBRT and the sub-group injected with hydrogel at the conclusion of brachytherapy.

Larger studies included in table 2.

Chao M, Ho H, Chan Y et al. (2018) Prospective analysis of hydrogel spacer for patients with prostate cancer undergoing radiotherapy. BJU international, 122, 427-433.

Case series

N=76 patients with prostate cancer

Clinical stage T1-T3a

Fiducial marker insertion plus injection of the hydrogel spacer into the perirectal space before intensity-modulated RT (IMRT) or volumetric-modulated arc RT (VMAT)

78 Gy in 2 Gy

Follow-up Median 14 (IQR 12-29) months

16 patients (21%) developed acute Grade 1 GI toxicity, with all symptoms resolved within 3 months after completion of treatment.

1 patient (1%) developed a late Grade 1 rectal haemorrhage at 9 months after treatment; however, this was due to rectal haemorrhoids.

1 patient (1%) developed late Grade 1 proctitis at 8 months after treatment.

No patients developed late GI toxicity of Grade ≥2.

Larger studies with controls included.

Chao, M. 2018. The use of hydrogel spacers in prostate radiation therapy. BJU International, 122, 10.

Case series

N=31 patients with

stage T1-T3a prostate cancer

IMRT

78 Gy in 2 Gy fractions

Follow-up median 12 (range 6-18) months

Larger studies included.

Chao M, Lim Joon D, Khoo V et al. (2019) The use of hydrogel spacer in men undergoing high-dose prostate cancer radiotherapy: results of a prospective phase 2 clinical trial. World J Urol. 2019;37(6):1111-6.

Case series

N=31 patients with cT1-3aN0M0 prostate adenocarcinoma receiving radical radiotherapy to 78 G and hydrogel spacer (SpaceOAR) implantation.

Follow-up 12 months.

All patients had successful insertion of spacer with no peri-operative toxicity. The mean prostate-rectal separation achieved was 10.5 mm. 29 (93.5%) patients achieved a reduction in rV70 of at least 25%. Acute grade 1 GI toxicity was reported in 3 patients. All symptoms had resolved by 3 months post RT. Late grade 1 GI toxicity was reported in one patient (3.2%) with bowel frequency occurring at 6 months and resolving by 12 months post RT.

Larger studies with controls included.

Chao M, Ow D, Ho H, et al. (2019) 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. Journal of Contemporary Brachytherapy. 11(1):8-13

Comparative study (retrospective)

N=97 patients with prostate cancer

32 patients (33%) who had hydrogel spacer insertion compared with 65 patients (67%) without hydrogel spacer receiving combined HDR and EBRT.

Median follow-up 60 months (12-125 months).

The median prostate-rectal separation achieved with hydrogel spacer (HS) was 10 mm (range, 5-14 mm). There were no post-operative complications following HS insertion. Patients with HS had significantly lower radiation dose to the rectum across all rectal dose volumes from rV30 to rV80, (p < 0.001). There was also significantly less acute > grade 1 GI toxicity (12.5% vs. 30.8%, p = 0.05) and a trend towards less late grade 1 GI toxicity (0% vs. 7.7%; p = 0.11) in the HS group compared to the non-HS group.

Larger studies included. Included in systematic review added.

Chao M, Bolton D, Joon DL et al. (2019) High dose rate brachytherapy boost for prostate cancer: Biochemical control and the impact of transurethral resection of the prostate and hydrogel spacer insertion on toxicity outcomes. Journal of Medical Imaging and Radiation Oncology 63, 415–421.

Retrospective case series

N=95 patients with intermediate and high risk prostate cancer treated with high dose rate brachytherapy boost (HDR-BT, 50.4 Gy) combined with external beam radiotherapy (EBRT)

Hydrogel spacers (HS) were used in 30 patients.

Median follow-up was 58 months.

The 5-year biochemical progression free survival, local recurrence free survival (LRFS), metastatic free survival (MFS) and overall survival were 92%, 100%, 92% and 88%. Late > grade 2 genitourinary (GU) toxicity was 6.3%. The use of HS or prior TURP had no impact on late GU toxicity. Late Grade 1 gastrointestinal (GI) toxicity was 5.3%.

Larger studies included.

Chapet O, Udrescu C, Devonec M, et al (2013). Prostate hypofractionated radiation therapy: Injection of hyaluronic acid to better preserve the rectal wall. Int J Radiat Oncol Biol Phys; 86:72-76.

Case series

n=16 patients with prostate cancer.

Hyaluronic acid injection combined with hypofractionated radiotherapy (62Gy in 20 fractions) delivered via IMRT.

The mean rectal V90% 955.8Gy) for pre-implantation plans was 7.65cc compared with 2,1cc on plans generated in scans of patients who have implants. The mean rectal V90%, V705 AND v50% were reduced by 73.8% (p<0.001), 43% (p=0.007) and 25% (p=0.036) respectively.

Larger and longer follow-up studies.

Chapet O, Udrescu C, Tanguy R, et al (2014). Dosimetric implications of an injection of hyaluronic acid for preserving the rectal wall in prostate stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys; 88:425-432.

Case series

n=10 patients with prostate cancer

Hyaluronic acid injection combined with hypofractionated radiotherapy (62Gy in 20 fractions) delivered via IMRT.

The mean rectal V90% and V80% were reduced by at least 90% (p=0.002) and 77% (p=0.002) respectively, regardless of the prescription dose.

Larger and longer follow-up studies.

Chapet O, Decullier E et al (2015). Prostate hypofractionated radiation therapy with injection of hyaluronic acid: Acute toxicities in a phase 2 study. International Journal of Radiation Oncology Biology Physics.91 (4) 730-736

Case series

N=36 patients with low-risk to intermediate-risk localised prostate cancer.

Injection of 10 ml hyaluronic acid (HA) during hypofractionated intensity modulated radiation therapy (IMRT)(with 20 fractions of 3.1 Gy, up to 62 Gy total dose over 4 weeks)

Follow-up 3 months

The HA injection induced a mean pain score of 4.6/10 ± 2.3. 33 patients had at least 1 acute genitourinary toxicity and 20 patients at least 1 acute gastrointestinal toxicity. Grade 2 toxicities were reported for 19 patients with urinary obstruction, frequency, or both and for 1 patient with proctitis. No grade 3 or 4 toxicities were reported. At the 3-month visit, 4 patients described grade 2 obstruction or frequency, and no patients had any grade 2 gastrointestinal toxicities.

Larger studies included.

Chung H, Polf J, Badiyan S, Biagioli M, Fernandez D, Latifi K, 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):32-9.

Comparative study

N=20 patients with prostate cancer treated with in silico with pencil beam scanning (PBS) photon therapy (12 with rectal spacer (DuraSealTM gel and 8 without).

Rectal spacers can significantly decrease rectal dose and predicted ≥grade 2 rectal toxicity in prostate cancer patients treated in silico with PBS. A minimum of 9 mm separation between the prostate and anterior rectal wall yields the largest benefit.

Larger studies included.

Cousins MM, Heckman P, Short E et al. (2022) Rectal sparing in prostate radiotherapy with combination-brachytherapy and hydrogel spacer. Brachytherapy.

Retrospective review

N=60 patients

(30 who had brachytherapy followed by EBRT with hydrogel spacer compared with 30 patients without spacer).

Through effective use of CBT and HS, extreme rectal dose restriction is possible. The goal for HS placement should be thickness >=1 cm from base to apex.

Dosimetry outcomes.

Larger studies with longer follow-up included.

Cuccia F, Mazzola R, Nicosia L et al. (2020) Impact of hydrogel peri-rectal spacer insertion on prostate gland intra-fraction motion during 1.5 T MR-guided stereotactic body radiotherapy. Radiation Oncology 15:178.

Case series

N= 20 patients who underwent MRI-guided prostate SBRT for low-to-intermediate risk prostate cancer with or without spacer.

A significant difference between spacer and no-spacer patients in terms of rotational shifts in the antero-posterior direction (p = 0.033) was observed; also for translational shifts a positive trend was detected in antero-posterior direction (p = 0.07), although with no statistical significance. We observed statistically significant differences in the pre-treatment planning phase in favor of the spacer cohort for several rectum dose constraints: rectum V32Gy < 5% (p = 0.001), V28 Gy < 10% (p = 0.001) and V18Gy < 35% (p = 0.039). Also for bladder V35 Gy < 1 cc, the use of spacer provided a dosimetric advantage compared to the no-spacer subpopulation (p = 0.04). Furthermore, PTV V33.2Gy > 95% was higher in the spacer cohort compared to the no-spacer one (p = 0.036).

Rectal spacer impact on intrafraction prostate motion was assessed.

Dihn TK T, Lee HJ, Macomber MW et al. (2020) Rectal hydrogel spacer improves late gastrointestinal toxicity compared to rectal balloon immobilization after proton beam radiation therapy for localized prostate cancer: A retrospective observational study. Int J Radiation Oncol Biol Phys,108 (3), 635-643.

Retrospective review

N=267 patients with localized, clinical stage T1-4 prostate adenocarcinoma treated with PBT (with rectal balloon, n=192 versus a hydrogel rectal spacer, n=75).

Median follow-up 19-22 months

The 2- year actuarial rate of grade 2+ late rectal bleeding was 19% and 3% in the rectal balloon and hydrogel spacer groups, respectively (P =0.003). In univariable analysis, the probability of grade 2+ rectal bleeding was significantly correlated with increasing rectal dose. In multivariable analysis, only receipt of spacer hydrogel and anticoagulation use were significantly associated with grade 2+ bleeding. At 2-year follow-up, patient-reported EPIC bowel quality of life composite scores were less diminished in the hydrogel spacer group.

Larger studies included.

Drabble J, Drury-Smith H. What is the quality of hydrogel spacer insertions and which patients will benefit. A literature review. J Radiother Pract. 2019;Epub ahead of print doi: http://dx.doi.org/10.1017/S1460396919000979

Systematic review

N=26 studies

HS showed a clinically significant relative reduction in rectal planning dose volumes for both high- and low-risk prostate cancer patients in a range of radiotherapy treatment modalities including volumetric modulated arc therapy, intensity-modulated radiotherapy, intensity-modulated proton therapy, stereotactic ablative body radiotherapy and brachytherapy. Spacer placements were successfully inserted in 99% of patients. However, rectal wall infiltration occurrence was 6% and ≥2 cm unsymmetrical placements in 2%. A spacer scoring system based on the HS symmetry has provided evidence of the quality of the position inserted, which was visually aided by T2-wieghted MRIs. Despite optimal HS placements ranging from 62 to 72%, HS had a clinically significant reduction of ≥25% in planned rectal V70 dose in 97% of patients

More comprehensive reviews on hydrogel spacers included.

Eckert F, Alloussi S et al (2013). Prospective evaluation of a hydrogel spacer for rectal separation in dose-escalated intensity-modulated radiotherapy for clinically localized prostate cancer. BMC Cancer.13 (no pagination).

Case series

n=11 patients with T1-2 N0 M0 localised prostate cancer having dose-escalated IMRT after injection of a hydrogel spacer. 78 Gy in 2 Gy fractions.

Follow-up; 12 weeks

In 1 patient hydrodissection of the Denonvillier space was not possible. Radiation treatment planning showed low rectal doses despite dose-escalation to the target. Acute rectal toxicity was mild without grade 2 events and there was complete resolution within 4 to 12 weeks.

Larger and longer follow-up studies included.

Forero D, Dendukuri N, Almeida N. Hydrogel spacer to reduce rectal toxicity in prostate cancer radiotherapy: a health technology assessment. (Report No. 82). Montreal (QC): Technology Assessment Unit (TAU) of the McGill University Health Centre (MUHC); 2018: https://muhc.ca/sites/default/files/users/user192/SpaceOAR%20Final%20May%2010%202018%20updated%20Dec13.pdf . Accessed 2021 September 21.

Systematic review informing an HTA

N=10 studies (852 patients treated with EBRT)

Included 1 RCT and 5 non-randomised studies, 1 HTA and 3 economic evaluations.

Space OAR versus no spacer

prostate cancer treatment: EBRT

Follow-up: 3 to 72 months

Spacer OAR, a type of hydrogel spacer, was reported to be significantly associated with lower rectal radiation exposure; nonetheless, authors concluded that it may not contribute to an important reduction in rectal toxicity based on the review of one RCT and three observational studies. Quality of life within the first year of follow-up was not found to be significantly different between Spacer OAR and no spacer and the results of the four primary studies reporting on long-term quality of life were not consistent. Due to the high costs and limited benefits in long-term quality of life, routine use of Spacer OAR at the MUHC for patients with prostate cancer receiving radiotherapy was not recommended by the authors of the systematic review.

More comprehensive and recent reviews added.

Fagundes M, Rodrigues MA, Olszewski S et al. (2021) Expanding the Utilization of Rectal Spacer Hydrogel for Larger Prostate Glands (>80 cc): Feasibility and Dosimetric Outcomes. Advances in Radiation Oncology, 6, 100651

N=33 patients with localised prostate cancer with larger glands (>80 cm3) treated with intensity modulated radiation therapy (in 15) and proton therapy (PT in 18 patients). Conventional fractionation (CF) to 78 Gy in 39 fractions was used in 16 and moderate hypofractionation EBRT (HF) to 70 Gy in 28 fractions in 17 patients.

Rectal hydrogel spacers inserted in all.

Median follow-up was 10 months (range, 3-26)

In the CF group, mean rectum (r) V75, 70, 60, 50 was 0.87%, 2.25%, 5.61%, and 10.5%, respectively. For glands >80 to 100 cm3 and >100 cm3 , rV70 was 2.55% and 2%, respectively. In HF patients, mean rV65, 63, 60, and 50 was 1.67%, 2.3%, 3.4%, and 8.6%. For glands >80 to 100 cm3 and >100 cm3 , rV63 was 2% and 2.56%, respectively. Overall, the mean mid gland rectoprostatic hydrogel separation was 9.3 mm (range, 4.7-19.4 mm). All patients tolerated treatment well; no acute grade 2 or higher adverse gastrointestinal events were observed

Larger and more relevant studies included.

Farjam R Mahase, SS, Chen SL et al. (2021) Quantifying the impact of SpaceOAR hydrogel on inter-fractional rectal and bladder dose during 0.35 T MR-guided prostate adaptive radiotherapy.

Journal of applied clinical medical physics. 22 (9); 49-58

Comparative case series

N=20 prostate cancer patients (10 with and 10 without rectal spacer) who had SBRT. Compared SBRT plans.

Inter-fractional changes in rectal and bladder dose were quantified in patients who underwent SBRT with/without rectal SpaceOAR hydrogel. Rectal spacer does not eliminate the need for adaptive planning but reduces its necessity.

Dosimetry study. Larger and longer follow-up studies included in table 2.

Fischer-Valuck BW, Chundury A et al (2016). 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.

Practical Radiation Oncology no pagination.

Secondary analysis of a randomised controlled trial.

149 patients in a prospective randomised trial who had transperineal hydrogel spacer (SpaceOAR system) injection were assessed for hydrogel spacer symmetry with rectal dose reduction and rectal wall infiltration using a semi-qualitative scoring system. All patients had control treatment plans created before spacer injection.

Hydrogel spacer was symmetrically placed at midline for 71 (47.7%) patients at the prostate mid-gland as well as 1 cm superior and inferior to mid-gland. The remaining 78 (50.9%) patients had some level of asymmetry, with only 2 (1.3%) having far lateral distribution (i.e., >2 cm) of hydrogel spacer. All but the most asymmetrical 1.3% had significant rectal dose reduction (P < .05). Rectal wall hydrogel spacer infiltration was seen in 9 (6.0%) patients. RWI does not correlate with patient complications.

Spacer distribution and impact of spacer symmetry assessed. Included in HTA, systematic review added.

Folkert MR, Zelefsky MJ, Hannan R et al. (2021) A multi-institutional phase 2 trial of high-dose SAbR for prostate cancer using rectal spacer. Int J Radiation Oncol Biol Phys, Vol. 000, No. 00, pp. 1−9.

Prospective study

N=44 men with stage ≤T2c localized grade group 1 to 3 prostate cancer underwent perirectal hydrogel spacer placement, followed by SABR of 45 Gy in 5 fractions.

Median follow up 48 months.

Temporary hydrogel spacer placement before high-dose SABR treatment for localized prostate cancer and use of strict dose constraints are associated with a significant reduction in the incidence of rectal ulcer events compared with prior phase 1/2 trial results.

Larger studies included.

Fukumitsu N, Mima M, Demizu Y et al. (2022) Separation Effect and Development of Implantation Technique of Hydrogel Spacer for Prostate Cancers. Practical Radiation Oncology. 12 (3), 226-235.

N=160 patients with prostate cancer

No spacer (group 1; n = 30), spacer placed using conventional technique-at the middle of the prostate gland (group 2; n = 100), and spacer placed using new technique-cranial:caudal ratio of 6:4 and close to the prostate gland (group 3; n = 30)

The separation, spacer thickness, and rectal exclusion from the middle to the apex of the prostate and the laterality of the hydrogel spacer affected the reduction in the rectal dose. The rectal dose can be further reduced by implanting a spacer on the caudal and prostate side.

Implantation technique and separation effect.

Gez E, Cytron S et al (2013). Application of an interstitial and biodegradable balloon system for prostate-rectum separation during prostate cancer radiotherapy: a prospective multi-center study. Radiation Oncology 2013, 8:96.

Case series

N=27patients with localised prostate cancer treated with biodegradable balloon implantation during external beam radiotherapy (EBRT).

Follow-up 6 months.

The distance between the prostate and rectum increased 10-fold, from a mean 0.22 ± 0.2 cm to 2.47 ± 0.47 cm. Adverse events included mild pain at the perineal skin and in the anus and acute urinary retention. The implantation of the biodegradable balloon was safe and achieved a significant and constant gap between the prostate and rectum. This separation resulted in an important reduction in the rectal radiation dose. 

Larger studies included.

Gross A, Yuan J, Spratt D et al  (2021) Case Report: Role of an Iodinated Rectal Hydrogel Spacer, SpaceOAR VueTM, in the Context of Low-Dose-Rate Prostate Brachytherapy, for Enhanced Post-Operative Contouring to Aid in Accurate Implant Evaluation and Dosimetry

Frontiers in Oncology; 11; 810955.

Case series.

N=13 patients with prostate cancer (low/ intermediate/high risk) treated with LDR brachytherapy/boost and iodinated hydrogel spacer (SpaceOAR VueTM).

Follow-up 3 months.

The mean separation between the prostate and the rectum was 12.2 ± 2.1 mm. A favourable dose coverage was achieved in all. At 1-month follow-up, 54% of the patients experienced grade 2 urinary toxicity, and 46% had grade 0–1 urinary toxicity (urgency and frequency). There was a mean increase of 4.3 points on the International Prostate Symptom Score (IPSS) from baseline. At 3 months, 38.5% maintained grade 2 urinary toxicity, and reported a mean decrease of 4 points in IPSS compared to baseline. At 1-month follow-up, 92% reported no rectal toxicities, with only one patient experiencing grade 1 mild diarrhoea. No rectal toxicities were reported at 3 months.

Larger and longer follow-up studies included.

Giuliani J Fiorica, F (2021) Cost-effectiveness of SpaceOAR system during prostate cancer radiation therapy: Really helpful or excess of expectations?.

Brachytherapy. 20 (6); 1341-1342.

Costs not in remit.

Jones S White N, Holt, T et al. (2021) Cost-effectiveness analysis of hydrogel spacer for rectal toxicity reduction in prostate external beam radiotherapy.

Journal of medical imaging and radiation oncology. 65 (7); 931-939

The influence of parameter uncertainty currently limits the cost-effectiveness of this intervention in the Australian public health setting. However, a cost variation solution has been demonstrated to improve cost-effectiveness estimates for selected patients and should be examined further.

Costs not in remit.

Guimas V, Quivrin M, Bertaut A et al (2016).

Focal or whole-gland salvage prostate brachytherapy with iodine seeds with or without a rectal spacer for postradiotherapy local failure: How best to spare the rectum? Brachytherapy 15 (4) 406-411.

Retrospective non-randomised comparative study

n=18

Intervention: salvage prostate permanent implant (sPPI) with (125) I seed for local failure after external beam radiation therapy.

(10 patients had whole-prostate sPPI, and 8 patients had focal sPPI).

In 8 patients, hyaluronic acid (HA) gel was injected into the prostate-rectum space.

The median cumulative dose after EBRT + sPPI was higher in patients treated with whole-gland sPPI than in patients treated with focal sPPI (313.5 Gy2 vs. 174.4 Gy2; p = 0.06 and 258.1 Gy3 vs. 172.6 Gy3; p < 0.01, respectively). The median D0.1cc was significantly lower in patients who had HA gel: 63.3 Gy (29.0-78.3) vs. 83.9 Gy (34.9-180.0) (p = 0.04).Cumulative prostate and rectum biological effective doses were lower with focal sPPI.

Larger studies included.

Hamstra DA, Mariados N, Sylvester J, Shah D, Karsh L, Hudes R, 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):976-85.

Randomised controlled trial

N=222 men with low-risk or intermediate-risk prostate cancer

Randomised 2:1 to spacer hydrogel (n=149) or control (n=73).

Radiation treatment received: G-IMRT 79.2 Gy in 1.8-Gy fractions

Follow-up 3 years

The 3-year incidence of grade >1 (9.2% vs 2.0%; P=.028) and grade >2 (5.7% vs 0%; P=.012) rectal toxicity favoured the spacer arm. Grade >1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P=.046), with no difference in grade >2 urinary toxicity (7% vs 7%; P=0.7). From 6 months onward, bowel QOL consistently favoured the spacer group (P=.002), with the difference at 3 years (5.8 points; P<0.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P<0.05) but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; P=.002) and urinary QOL (30% vs 17%; P=.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P=.02) and urinary QOL (23% vs 8%; P=.02).

Included in HTAs, systematic reviews added.

Hamstra DA, Mariados N, Sylvester J, et al. Sexual quality of life following prostate intensity modulated radiation therapy (IMRT) with a rectal/prostate

spacer: secondary analysis of a phase 3 trial. Pract Radiat Oncol. 2018;8(1):e7-e15.

Randomised controlled trial

N=222 men with low-risk or intermediate-risk prostate cancer

Randomised 2:1 to spacer hydrogel (n=149) or control (n=73).

Radiation treatment received: G-IMRT 79.2 Gy in 1.8-Gy fractions

Sexual quality of life measured by the Expanded Prostate Cancer Index Composite (EPIC).

Median follow-up of 37 months.

Hydrogel reduced penile bulb mean dose, maximum dose, and percentage of penile bulb receiving 10 to 30 Gy (all P < .05) with mean dose indirectly correlated with erections sufficient for intercourse at 15 months (= 0.03). Statistically nonsignificant differences favouring spacer for the proportion of men with MID and 2× MID declines in sexual QoL with 53% vs 75% having an 11-point decline (p=0.064) and 41% vs 60% with a 22-point decline (p=0.11). At 3 years, more men potent at baseline and treated with spacer had "erections sufficient for intercourse" (control 37.5% vs spacer 66.7%, p=0.046) as well as statistically higher scores on 7 of 13 items in the sexual domain (all p<0.05). The use of a hydrogel spacer decreased dose to the penile bulb, which was associated with improved erectile function compared with the control group based on patient-reported sexual QoL.

Included in HTAs, systematic reviews added.

Hatiboglu G, Pinkawa M et al (2012). Application technique: Placement of a prostate-rectum spacer in men undergoing prostate radiation therapy. BJU International 110:E647-E652.

Case series

n=29 patients with prostate cancer

Hydrogel injected during radiotherapy

Hydrogel injection resulted in mean (SD) additional prostate – rectum space relative to baseline of 9.87 (5.92) mm. The mean (SD) procedure time was 6.3 (3.2) min. The relative reduction in rectal V70 Gy was 60.6%. There were no unanticipated adverse events.

Larger and longer follow-up studies included.

Hayes, Inc. Absorbable perirectal spacer (SpaceOAR System; Augmenix Inc.) during radiation therapy for prostate cancer. Heath Technology Assessment. HAYES, Inc. 2018.

Heath Technology Assessment

More recent HTAs added.

Fagundes MA, Robison B, Price SG et al. (2015) High-dose rectal sparing with transperineal injection of hydrogel spacer in intensity modulated proton therapy for localized prostate cancer. International Journal of Radiation Oncology Biology Physics.1: E230.

N=10 patients with localized prostate cancer treated with intensity modulated proton therapy and transperineal rectal hydrogel spacer.

pre- and post-spacer scans were assessed.

The use of a rectal spacer significantly reduced the amount of rectal volume exposed to high doses of radiation in patients planned with intensity modulated proton therapy. The rectal dose-sparing benefit was achieved without compromising target coverage or bladder dose sparing.

Larger and longer follow-up studies included.

Dosimetry study.

Hedrick SG, Fagundes M, Case S et al. (2017) Validation of rectal sparing throughout the course of proton therapy treatment in prostate cancer patients treated with SpaceOAR((R)). J Appl Clin Med Phys, 18, 82-89.

Case series

N=41 patients with low/intermediate prostate cancer

Image-guided proton therapy

Conventional fractionation (n=27)

Hypofractionation (n=14)

Follow-up 5 weeks

By extrapolating patient anatomy from 3-4 QACT scans, we have shown that the use of hydrogel in conjunction with our patient diet program and use of stool softeners is effective in achieving consistent rectal sparing in patients undergoing proton therapy.

Toxicity not reported.

Larger studies included.

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.

Prospective cohort study

N=26 patients with prostate cancer treated with proton therapy and an endorectal balloon (n=10) or a hydrogel spacer (n=16) using orthogonal x-rays acquired before and after each treatment field.

Patients from 2 different trials included.

Follow-up time not reported.

There was a statistically significant difference in the mean vector shift between ERB (0.06 cm) and GEL (0.09 cm), (p<0.001). There was no statistical difference between ERB and GEL for shifts greater than 0.3 cm (p=0.13) or greater than 0.5 cm (p=0.36). Prostate motion is clinically comparable between an ERB and a hydrogel spacer, and the time dependencies are similar.

Included in HTA report.

Hojjat F, Fritsche-Polanz S et al (2016). Goldmarker and spacer balloon implantation for prostate radiation therapy (RT). European Urology, Supplements (15) 11 e1353-e1355.

Case series

n=40 patients with localized prostate cancer.

Gold marker and bio-protect-balloon- implanted transperineally during image-guided volumetric arc therapy (VMAT).

Median distance of 1.6 cm between the prostate and the anterior wall of the rectum was obtained. Localisation of the balloon was achieved in 33/40 patients. Implantation well tolerated, no intestinal bleeding, no mucosal injury and no postoperative infection have been observed. Mild perineal foreign body sensation was present, only 2/40 patients reported on moderate symptoms. Acute GI and GU toxicity were very favourable and assessed using the RTOG scale system. In 66% of patients no GI-side effect was seen, while 28% and 6% had grade 1 and 2 toxicity, respectively. GU-symptoms grade 1 were about 66% and 3% grade 2, whereas 31% had no adverse effect. For both, GI and GU, grade 3-5 toxicity was not observed.

Larger studies included.

Hoe V, Yao HH, Huang JG et al. Abscess formation following hydrogel spacer for prostate cancer radiotherapy: a rare complication. BMJ Case Rep. 2019 Oct 5;12(10). pii: e229143. doi: 10.1136/bcr-2018-229143

Case report

Patient with hydrogel spacer during prostate cancer radiotherapy.

Periprostatic abscess is a rare complication of hydrogel spacers in radiotherapy for prostate cancer. We present the case of a 61-year-old man who developed this condition. Abdominopelvis CT scan revealed a 54×35×75 mm collection in the location of the SpaceOAR, for which ultrasound-guided transperineal percutaneous drainage of the periprostatic abscess was performed. The patient remains well with serial CT scans showing near resolution of the collection.

Adverse event already reported in included studies.

Hwang ME, Black PJ, Elliston CD, Wolthuis BA, Smith DR, Wu CC, et al. A novel model to correlate hydrogel spacer placement, perirectal space creation, and rectum dosimetry in prostate stereotactic body radiotherapy. Radiation Oncology. 2018;13 (1) (no pagination)(192).

Case series (retrospective)

N=20 men with low- and intermediate-risk prostate cancer treated with stereotactic

body radiotherapy to 36.25 Gy in 5 fractions underwent hydrogel (SpaceOAR) placement.

Median follow up of 14 months

no rectal toxicity >grade 2 was observed. Low grade rectal toxicity was observed in a third of men and resolved. Optimal hydrogel placement occurs at prostate midgland, midline. The novel parameter θ*hydrogel volume describes a large proportion of rectum dosimetric benefit derived from hydrogel placement and can be used to assess the learning curve phenomenon for hydrogel placement.

Larger studies included. analysed the symmetry of hydrogel placement, developed new metric to correlate the effect of hydrogel placement on rectum dosimetry.

Hwang ME, Mayeda M, Liz M, Goode-Marshall B, Gonzalez L, Elliston CD, et al. Stereotactic body radiotherapy with periprostatic hydrogel spacer for localized prostate cancer: Toxicity profile and early oncologic outcomes. Radiation Oncology. 2019;14 (1) (no pagination)(136).

Case series

N=50 men with low- or intermediate-risk prostate cancer treated with SBRT (3625 cGy in 5 fractions) with or without androgen deprivation therapy (ADT) also had periprostatic hydrogel spacer (SpaceOAR).

Median follow up 20 (range 4–44) months.

Mean prostate-rectum separation achieved with SpaceOAR was 9.6±4 mm at the prostate midgland. No grade ≥ 3 GU or GI toxicity was recorded. During treatment, 30% of men developed new grade 2 GU toxicity (urgency or dysuria). GI toxicity was limited to grade 1 symptoms (16%), 4% of men developed grade 2 symptoms during the first 4 weeks after SBRT. No acute or late rectal toxicity was reported > 1 month after treatment. Periprostatic hydrogel placement followed by prostate SBRT resulted in minimal GI toxicity, and favourable early oncologic outcomes.

Larger studies included.

Hwang ME, Mayeda M, Shaish H, et al. (2021) Dosimetric feasibility of neurovascular bundle-sparing stereotactic body radiotherapy with periprostatic hydrogel spacer for localized prostate cancer to preserve erectile function. Br J Radiol; 94: 20200433.

Case series

N= 35 men with low- and intermediate risk prostate cancer underwent rectal hydrogel spacer placement and treated with prostate SBRT (36.25 Gy in 5 fractions).

Neurovascular bundle (NVB) sparing SBRT with rectal hydrogel spacer significantly reduces the volume of NVB treated with high-dose radiation. Rectal spacer contributes to this effect through a dosimetrically meaningful displacement of the NVB.

Nerve sparing treatment planning.

Hutchinson RC, Sundaram V, Folkert M, and Lotan Y (2016).

Decision analysis model evaluating the cost of a temporary hydrogel rectal spacer before prostate radiation therapy to reduce the incidence of rectal complications.

Urologic Oncology 34 (7) 291-26.

Decision analysis to evaluate the cost effectiveness of a rectal spacer gel (SpaceOAR) for the reduction of rectal toxicity of prostate radiation therapy (RT).

The overall standard management cost for RT was $3,428 vs. $3,946 with rectal spacer for an incremental cost of $518 over 10 years. A 1-way sensitivity analyses showed the breakeven cost of spacer at $2,332 or a breakeven overall risk reduction of 86% at a cost of $2,850. For high-dose SBRT, spacer was immediately cost effective with a savings of $2,640 and breakeven risk reduction at 36%. The use of a rectal spacer for conformal RT results in a marginal cost increase with a significant reduction in rectal toxicity assuming recently published 15 month rectal toxicity reduction is maintained over 10 years. For high-dose SBRT it was cost effective.

Costs not in remit of interventional procedures programme.

Jones RT, Hassan Rezaeian N, Desai NB, et al. (2017) 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. 42(4):341-347.

Prospective cohort study

N=72 patients with low- to intermediate risk prostate cancer treated with stereotactic body radiation therapy in combination with rectal balloons (n=36) or absorbable injectable spacer gel (n=36).

Patients from 2 different trials included.

Follow-up time not reported.

injectable spacer gel was superior based on 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). There was no difference between the 2 groups with respect to the V50Gy of the rectum or the dose to 50% of the rectal circumference (p=0.29 and 0.06, respectively). The V18.3Gy of the bladder was significantly larger with the rectal balloon (19.9 vs 14.5 cc, p=0.003). Injectable spacer gel outperformed the rectal balloon in the majority of the examined and relevant dosimetric rectal-sparing parameters.

Included in HTA report added.

Dosimetric and volumetric outcomes, comparative costs of balloons and gel out of remit.

Karsh LI, Gross ET, Pieczonka CM, et al. Absorbable hydrogel spacer use in prostate radiotherapy: a comprehensive review of phase 3 clinical trial published data. Urology. 2018;115:39-44.

Randomised controlled trial

N=222 men with low-risk or intermediate-risk prostate cancer

Randomised 2:1 to spacer hydrogel (n=149) or control (n=73).

Radiation treatment received: G-IMRT 79.2 Gy in 1.8-Gy fractions

Rectal and urinary adverse events and quality of life measured with the EPIC questionnaire.

Median follow-up of 37 months

Spacer application was well tolerated with a 99% technical success rate. The mean additional space created between the prostate and the rectum was just over 1 cm, which allowed significant rectum and penile bulb radiation dose reduction, resulting in less acute pain, lower rates of late rectal toxicity, and improved bowel and urinary QoL scores from 6 months onward. Improvements in sexual QoL were also observed at 37 months in baseline-potent men, with 37.5% of control and 66.7% of spacer men capable of "erections sufficient for intercourse."

Study included in HTAs added.

Kamran SC; McClatchy DM, Pursley J et al. (2022) Characterization of an Iodinated Rectal Spacer for Prostate Photon and Proton Radiation Therapy. Practical radiation oncology; 12 (2); 135-144

Retrospective study N=100 patients with intact prostate cancer treated with photon and proton radiation therapy (n = 50 with iodine spacers and 50 with conventional spacers)

Iodine spacers provide a manifest CT contrast, allowing for delineation on planning CT alone with no MRI necessary. Iodine spacers radiopacity, size, and relative position remained stable over courses of treatment from 28 to 44 fractions. No changes in plan quality or robustness were seen comparing iodine spacers and conventional spacers.

Description of spacers, no clinical outcomes reported.

Khan J, Dahman B, McLaughlin C et al. (2020) Rectal spacing, prostate coverage, and periprocedural outcomes after hydrogel spacer injection during low-dose-rate brachytherapy implantation. Brachytherapy 19 228e233

Case series

N= 80 patients with prostate cancer treated with low-dose-rate (LDR) prostate brachytherapy. 40 had bioabsorbable hydrogel rectal spacer injected.

Follow-up 1 month.

There were no acute genitourinary or rectal toxicities attributed to the hydrogel spacer. Comparing patients with and without hydrogel, the mean separation between the prostate and rectum was 13.9±5.2 mm vs. 6.5±5.0 mm (p<0.0001), respectively. The adjusted mean dose to 1 cc, 2 cc, and 5 cc of the rectum relative to prescription dose was decreased by 32% (p<0.01), 26% (p<0.01), and 17% (p< 0.01), respectively. There were no statistically significant differences in prostate coverage: mean V100 (92% vs. 91%), V150 (45% vs. 48%), and D90 (106% vs. 106%), respectively. At 1 month follow-up, grade 1 rectal toxicity was 12.5% vs. 17.5% (p 5 0.35). No patients developed Grade 2 rectal toxicity with hydrogel, although one did without.

Larger studies included.

King RB, Osman SO, Fairmichael C, Irvine DM, Lyons CA, Ravi A, et al. Efficacy of a rectal spacer with prostate SABR-first UK experience. Br J Radiol. 2018;91(1083):20170672

Case series

N=6 patients with prostate cancer treated with SABR -VMAT and rectal hydrogel spacer (SpaceOAR)

Substantial improvements in rectal dose metrics were observed in post-spacer plans, e.g. rectal volume receiving 36 Gy reduced by ≥42% for all patients. Median NTCP for Grade 2 + rectal bleeding significantly decreased from 4.9 to 0.8% with the use of a rectal spacer (p=0.031). The spacer resulted in clinically and statistically significant reduction in rectal doses for all patients.

Larger studies included.

Kouloulias V, Kalogeropoulos T et al (2013). Feasibility and radiation induced toxicity regarding the first application of transperineal implementation of biocompatible balloon for high dose radiotherapy in patients with prostate carcinoma.

Radiation Oncology.8 (1) (no pagination).

Case series

n=15 patients with prostate carcinoma

treated with high dose external 3DCRT (76-78 Gy in 38-39 daily fractions) combined with injection of biodegradable balloon (ProSpace)

Follow-up: 3 months

The acute toxicities were as follows: grade 1 GI toxicity in 2 patients and GU toxicity -3 patients with grade 1 nocturia, 4 patients with grade 1 frequency, 2 patients with grade 1 and 2 patients with grade 2 dysuria. The mean score of rectal toxicity according to S-RS score was 1.8 ±0.6. The mean VAS score related to ProSpace was 1.4±0.5. Erectile dysfunction was unchanged. The ProSpace was found stable in sequential CT scans during irradiation.

Larger and longer follow-up studies included.

Kobayashi H, Eriguchi T, Tanaka T et al. (2021) Distribution analysis of hydrogel spacer and evaluation of rectal dose reduction in Japanese prostate cancer patients undergoing stereotactic body radiation therapy. International Journal of Clinical Oncology. 26:736–743.

Retrospective analysis

70 patients with low and intermediate-risk prostate cancer treated with SBRT. Hydrogel spacers were inserted in 53 patients.

Follow-up 6 months.

Hydrogel spacers could contribute to rectal dose reduction, especially in high dose regions, by creating a prostate–rectum distance. There was no grade≥3 toxicity observed, but grade 2 toxicity of GU and GI occurred in 17.1% and 1.4% of the patients, respectively.

Larger studies included.

Kundu P, Lin EY, Yoon SM (2022) Rectal Radiation Dose and Clinical Outcomes in Prostate Cancer Patients Treated With Stereotactic Body Radiation Therapy With and Without Hydrogel. Frontiers in Oncology. 12; 853246

Retrospective case series

92 patients with prostate cancer treated with SBRT (51 hydrogel and 41 without hydrogel)

Median follow-up of 14.8 months.

Hydrogel reduces rectal radiation dose in patients receiving prostate SBRT and is associated with a decreased rate of acute GI toxicity. hydrogel group experienced significantly less acute overall GI toxicity (16% hydrogel vs. 28% non-hydrogel, p=0.006), while the difference in late GI toxicity trended lower with hydrogel but was not statistically significant (4% hydrogel vs. 10% non-hydrogel, p=0.219).

Larger studies with longer follow-up included.

Juneja P, Kneebone A (2015). Prostate motion during radiotherapy of prostate cancer patients with and without application of a hydrogel spacer: a comparative study. Radiation Oncology 10: 215.

Prospective cohort study (data from 2 clinical trials)

n=26 patients with prostate cancer treated with radiotherapy (12 with hydrogel and 14 without hydrogel).

Type of radiotherapy not specified.

Follow-up time not reported.

The average of the mean motion during the treatment for patients with and without hydrogel was 1.5 (+/-0.8 mm) and 1.1 (+/-0.9 mm) respectively (p<0.05). The average time of motion >3 mm for patients with and without hydrogel was 7.7 % (+/-1.1 %) and 4.5 % (+/-0.9 %) respectively (p>0.05). The hydrogel age, fraction number and treatment time were found to have no effect (R (2) <0.05) on the prostate motion. This result confirms that the addition of a spacer does not negate the need for intrafraction motion management if clinically indicated.

Study evaluating prostate position. Included in HTA added.

Lawrie TA, Green JT, Beresford M, Wedlake L, Burden S, Davidson SE, Lal S, Henson CC, Andreyev HJN. Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers. Cochrane Database of Systematic Reviews 2018, Issue 1. Art. No.: CD012529. DOI: 10.1002/14651858.CD012529.pub2.

Cochrane review

N=92 studies (RCTs) included. (0nly 2 studies were related to this overview).

n= 229 and 69 men undergoing RT for prostate cancer.

transperitoneal hydrogel spacer/injection versus no spacer Prostate cancer treatment: all types of pelvic radiation therapy eligible; IG-IMRT (79.2 Gy in 1.8-Gy fractions) in Mariados 2015 and brachytherapy in Prada 2009.

Follow-up: up to 15 months in Mariados 2015 and a median of 26 months in Prada 2009.

"IMRT may be better than 3DCRT in terms of GI toxicity, but the evidence to support this is uncertain".

"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".

Only 2 of these studies were eligible for analysis within this review.

More comprehensive reviews added.

Haute Autorite de Sante. SpaceOAR, espaceur synthétique résorbable en hydrogel.: HAS; 2020.

French article

Lehrich BM, Moyses HM, Ravera J et al. (2019) Five-year results of post-prostatectomy patients administered a hydrogel rectal spacer implant in conjunction with dose escalated external beam radiation therapy. Journal of Radiation Oncology (2019) 8:31–38.

Case series

N= 21 patients who underwent radical prostatectomy and received high dose (> 72 Gy) radiation therapy with an absorbable polyethylene glycol (PEG) rectal spacer implant.

Mean follow-up time was 59 months (SD 12, range 40–97).

Gastrointestinal [GI] toxicities for acute, 3 months, and after 6 months are as follows: grade 0 (57%, 86%, 86%), grade 1 (43%, 14%, 14%), and grade 2 (0%, 0%, 5%). Our genitourinary [GU] toxicities for acute, 3 months, and after 6 months are as follows: grade 0 (43%, 48%, 62%), grade 1 (48%, 43%, 24%), and grade 2 (10%, 5%, 14%). There were no late grade 3 GI/GU toxicities. The 5-year overall biochemical-relapse free survival rate was 62.2% (95% CI 42.6–90.9%, SE 12.0%).

Large studies included.

Lin YH, Loon W, Tacey M et al. (2021) Impact of hydrogel and hyaluronic acid rectal spacer on rectal dosimetry and toxicity in low-dose-rate prostate brachytherapy: a multi-institutional analysis of patients' outcomes. Journal of Contemporary Brachytherapy. 13 (6); 605-614

Retrospective comparative case series

N=70 men with prostate cancer treated with iodine-125 LDR brachytherapy (28 with or 42 without hydrogel spacer or hyaluronic acid spacer).

Median follow-up was 23.5 months.

The median prostate-rectal separation with spacer at mid prostate was 10 mm (IQR, 8-11.5 mm). There were no post-operative complications. There was significantly reduced rectal dosimetry in spacer-group versus non-spacer group; the median RV100 was 0.0 cc (IQR, 0.0-0.0 cc) vs. 0.4 cc (IQR, 0.1-1.1 cc) (p < 0.001), respectively. There were significantly less grade 1 acute and late GI toxicities in spacer-group when compared to non-spacer group (0% vs. 24%, p=0.004 for acute GI toxicity; 4% vs. 33%, p=0.003 for late GI toxicity). There were no reported acute or late grade 2 or above GI toxicities.

Similar studies included.

Latorzeff I, Bruguiere E, Bogart E et al. (2021) Use of a Biodegradable, Contrast-Filled Rectal Spacer Balloon in Intensity-Modulated Radiotherapy for Intermediate-Risk Prostate Cancer Patients: Dosimetric Gains in the BioPro-RCMI-1505 Study

 Frontiers in Oncology; 11; 701998

Prospective case series

n=24 patients with intermediate-risk prostate cancer had mage-guided, IMRT(in 20) or VMAT (in 3) with a biodegradable rectal spacer balloon.

Follow-up 24 months.

86% of the implantation procedures were easy. Dosimetric gains associated with spacer implantation were highly significant (p<0.001). For the rectum, the median relative gain was 15.4% for D20cc to 91.4% for V70 Gy (%). 15 patients (62%) experienced an acute grade 1 adverse event (AE), 8 (33%) experienced a late grade 1 AE, 1 (4.2%) experienced an acute grade 2 AE, and 3 experienced a late grade 2 AE. No grade 3 AEs were reported. Quality of life was good at baseline) and did not worsen during RT and up to 24 months.

Similar studies on balloon spacers included.

Levy Y, Paz A et al (2009).Biodegradable inflatable balloon for reducing radiation adverse effects in prostate cancer.J Biomed Mater Res B Appl Biomater 91: 855-867.

The proper functionality of the insertion-mounting device as well as the balloon capability to retain its inflated form during patients' radiation session was demonstrated both in vitro and in vivo.

Preclinical study with in-vitro and in-vivo data.

Levy JF, Khairnar R, Louie AV et al. (2019) Evaluating the Cost-Effectiveness of Hydrogel Rectal Spacer in Prostate Cancer Radiation Therapy. Practical Radiation Oncology (2019) 9, e172-e179

Cost effectiveness analysis

patients with prostate cancer undergoing external beam RT (EBRT alone versus EBRT + hydrogel rectal spacer [HRS]).

The per-patient 5-year incremental cost for spacers administered in a hospital outpatient setting was $3578, and the incremental effectiveness was 0.0371 QALYs. The incremental cost-effectiveness ratio was $96,440/QALY for patients undergoing HRS insertion in a hospital and $39,286/QALY for patients undergoing HRS insertion in an ambulatory facility. Based on the current Medicare Physician Fee Schedule, HRS is cost-effective at a willingness to pay threshold of $100,000. These results contain uncertainty, suggesting more evidence is needed.

Costs not in remit of interventional procedures programme.

Liu H, Borden L, Wiant D, Sintay B, Hayes L, Manning M. Proposed hydrogel-implant quality score and a matched-pair study for prostate radiation therapy. Pract Radiat Oncol. 2020;10(3):202-208. doi: http://dx.doi.org/10.1016/j.prro.2020.02.006

Matched paired study (retrospective)

LDR BT +/- EBRT

N= 81 patients with prostate cancer had SpaceOAR implantation

21 had EBRT only, 7 had combined EBRT and Iodine-125 LDR, and 53 had Iodine-125 LDR only.

The average HIQS was 77 ± 10.8 (range, 49-97). Rectal anatomic distortions were seen in 17 cases. Significant rectal dose reductions between intraoperative and postoperative plans were found for SpaceOAR patients compared with non-SpaceOAR patients (25.1 Gy vs -5.0 Gy for D2cc and 65.7 Gy vs 13.0 for D0.1cc). Additional rectal dose reductions (8.4 Gy for D2cc and 12.7 Gy for D0.1cc) were found for patients without rectal distortion when SpaceOAR was used.

Included in systematic review.

Mahal BA, Ziehr DR, Hyatt AS et al. (2014) Use of a rectal spacer with low-dose-rate brachytherapy for treatment of prostate cancer in previously irradiated patients: Initial experience and short-term results. Brachytherapy, 13, 442-9.

Case series

N=11 patients with prostate cancer and prior radiotherapy received (125)I brachytherapy after placement of 10cc of a diluted hydrogel spacer between the prostate and rectum.

Follow-up median 15.7 months

Spacing was achieved in 8 of the 11 (73%) patients but was not possible in 3 owing to fibrosis and adhesions. The median space between the prostate and rectum was 10.9mm (prior EBRT) vs. 7.7mm (prior brachytherapy), p=0.048. One patient developed a prostato-rectal fistula requiring a diverting colostomy. The 16-month estimate of late Grade 3 or 4 gastrointestinal or genitourinary toxicity was 26%. One patient developed lymph node-positive recurrence. The 16-month prostate-specific antigen failure-free survival rate was 89%.

Included in systematic review added.

Mazzola R, Sicignano G, Cuccia F et al. (2021) Impact of hydrogel peri-rectal spacer insertion on seminal vesicles intrafraction motion during 1.5 T-MRI-guided adaptive stereotactic body radiotherapy for localized prostate cancer.

The British journal of radiology; 94 (1126); 20210521

Comparative case series

n=10 patients with prostate cancer had MRI guided SBRT (5 had hydrogel spacer and 5 did not).

A favourable impact of the hydrogel-spacer on seminal vesicles motion was observed only in cranio-caudal translational shifts, although not clinically significant. Further studies are required to fully investigate the potential contribution of this device on vesicles motion.

Intrafraction motion assessed.

Mark EH, Paul JB, Carl DE et al. (2018) A novel model to correlate hydrogel spacer placement, perirectal space creation, and rectum dosimetry in prostate stereotactic body radiotherapy. Radiation oncology (London, England), 13, 192.

Case series

N= 20 men with low- and intermediate-risk prostate cancer underwent hydrogel placement.

Median follow up of 14 months

no rectal toxicity >grade 2 was observed. Low grade rectal toxicity was observed in a third of men and resolved within 1 month of SBRT. Men who had these symptoms had higher rD_max 1 cc and smaller θ*hydrogel volume measurements

Larger studies included.

Mariados N, Sylvester J, Shah D, Karsh L, Hudes R, Beyer 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):971-7.

Randomised controlled trial

N=222 men with low-risk or intermediate-risk prostate cancer

Randomised 2:1 to spacer hydrogel (n=149) or control (n=73).

Radiation treatment received: G-IMRT 79.2 Gy in 1.8-Gy fractions

Follow-up 15 months.

Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, p<0.001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (PZ.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (PZ.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption.

Included in HTAs and systematic reviews added.

Manabe Y, Hashimoto S, Mukouyama H et al. (2021) Stereotactic body radiotherapy using a hydrogel spacer for localized prostate cancer: A dosimetric comparison between tomotherapy with the newly-developed tumor-tracking system and cyberknife. Journal of applied clinical medical physics. 22 (10); 66-72

Comparative case series

N=20 patients with localised prostate cancer using a hydrogel spacer and had SBRT.

10 tomotherapy and 10 cyberknife SBRT plans were compared.

The tomotherapy plans were superior to the cyberknife plans for the rectum (V80% = 0.4 vs. 1.0 ml, p<0.001; D1ml = 26.4 vs. 29.0 Gy, p=0.013). Results suggested that tomotherapy with the tumour-tracking system has reasonable potential for SBRT for localized prostate cancer using a hydrogel spacer.

Dosimetry study. Larger and longer follow-up studies included in table 2.

Morita M, Fukagai T, Hirayama K, Yamatoya J, Noguchi T, Igarashi A, et al. (2019) Placement of SpaceOAR hydrogel spacer for prostate cancer patients treated with iodine-125 low-dose-rate brachytherapy. International Journal of Urology. 27, 1, 60-66.

Case series

N=100 patients with prostate cancer undergoing iodine-125 low-dose-rate brachytherapy and, SpaceOAR hydrogel spacer was placed.

Post-plan dosimetric data were compared with 200 patients treated without a spacer.

Follow-up not reported.

No complications were found during either the intraoperative or perioperative periods. The mean displacement distance of 11.64 mm was created, the mean value before spacer placement was 0.28 mm (P < 0.0001). The change of the prostate diameters showed a positive increase in all directions, with no significant negative change in any one direction. Regarding the change in distance between pubic symphysis and the prostate, no significant shortening trend was observed between the two groups (p=0.14). Whereas the dosimetric parameters showed means of 0.001 and 0.026 cc for RV150 and RV100 in the spacer group, they were 0.025 and 0.318 cc, respectively, in the non-spacer group, showing a significant decrease in both parameters (p<0.001).

Included in systematic review added.

Melchert C, Gez E et al (2013).Interstitial biodegradable balloon for reduced rectal dose during prostate radiotherapy: results of a virtual planning investigation based on the pre and post-implant imaging data of an international multicenter study. Radiother Oncolo 106:210-214.

Case series

n=26 patients with localized prostate cancer

Interstitial inflatable and biodegradable balloon with radiotherapy (3D conformal external beam radiation treatment or IMRT).

Follow-up; post implant CT imaging.

The dorsal prostate–ventral rectal wall separation resulted in an average reduction of the rectal V70% by 55.3% (±16.8%), V80% by 64.0% (±17.7%), V90% by 72.0% (±17.1%), and V100% by 82.3% (±24.1%). In parallel, rectal D2 ml and D0.1 ml were reduced by 15.8% (±11.4%) and 3.9% (±6.4%) respectively.

Study by same group reporting clinical and dosimetric outcomes included I systematic review added.

Muller AC, Mischinger J et al (2016).

Interdisciplinary consensus statement on indication and application of a hydrogel spacer for prostate radiotherapy based on experience in more than 250 patients.

Radiology and Oncology (50) 3 329-336.

Interdisciplinary meeting to develop consensus statement on hydrogel injections (SpaceOAR) in prostate cancer patients before dose-escalated radiotherapy.

A consensus was reached on the application of a hydrogel spacer. Current experience demonstrated feasibility, which could promote initiation of this method in more centres to reduce radiation-related gastrointestinal toxicity of dose-escalated IGRT. However, a very low rate of a potential serious adverse event could not be excluded. Therefore, the application should carefully be discussed with the patient and be balanced against potential benefits.

Interdisciplinary meeting to develop consensus statement.

Navaratnam A, Cumsky J, Abdul-Muhsin H et al. Assessment of polyethylene glycol hydrogel spacer and its effect on rectal radiation dose in prostate cancer patients receiving proton beam radiation therapy. Adv Radiat Oncol 2019; 5: 92–100.

Retrospective cohort study

N= 72 patients with prostate cancer (T1, T2, T3)

EBRT-PBT-total dose 79.2

1.8 Gy per fraction

51 with hydrogel spacers versus 21 without spacer

Dose volume V70, , V75

Follow-up 9.5 months.

There was a 42.2% reduction in rectal dosing (mL3 rectum) in hydrogel patients (p<0.001). Increasing midline sagittal lift resulted in a greater mitigation of total rectal dose (p=0.031). The degree of prostate surface area coverage on coronal plane did not correlate with further reductions in rectal radiation dose (p=0.673). Patients who had PEG hydrogels placed reported more rectal side effects during treatment compared with those patients who did not (35.3% vs 9.5%, p =0.061). At median 9.5-month follow-up, there was no difference in reporting of grade >2 rectal toxicity between the 2 groups (7.7% vs 7.1%, p=0.145).

Included in systematic review added.

Nehlsen AD, Sindhu KK, Moshier E et al. (2021). 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 20, 296-301.

Retrospective analysis

N=168 patients with intermediate or high risk prostate cancer with a hydrogel spacer (n=22) or without a hydrogel spacer (n=146) prior external beam radiotherapy and low-dose-rate brachytherapy.

Spacer group follow-up 9 months.

LDR brachytherapy appears feasible after the placement of a rectal hydrogel spacer. While there was a significantly reduced V100 _rectum among patients who had received a hydrogel spacer, there was no statistically significant difference in patients achieving a D90_prostate of >100 Gy. Although there was no difference appreciated in QOL scores, the length of follow-up was limited in the rectal-spacer group.

Larger studies included.

Newman NB, Rajkumar, A, Cleary RK et al. (2021) Patient Reported Quality of Life Outcomes After Definitive Radiation Therapy With Absorbable Spacer Hydrogel for Prostate Cancer. Advances in Radiation Oncology; 6 (6); 100755

Prospective case series

N=59 patients with low risk or favourable-intermediate risk localized prostate cancer had SBRT/ LDR brachytherapy, conventionally fractionated RT, or moderately hypofractionated RT with hydrogel spacer. Median follow-up 366 days.

There were no grade 3 toxicities. There were no significant changes in the American urology association symptom index (AUA-SI) score (p=0.69) compared with baseline, nor was there any change in Expanded Prostate Cancer Index Composite (EPIC-26) domain scores (p=0.19). There were no significant associations between AUA scores and EPIC-26 scores and the dose to the rectum, bladder, or urethra with the exception being dose to the 2 mL rectum correlated with decline in EPIC-26 rectal score (beta, -0.002; p=0.006). Patient-reported declines in bowel domains were less than previously reported data.

Larger and longer follow-up studies included.

SpaceOAR®

perirectal spacing system

for prostate cancer radiation. (December 2014) Technology Alert. National Institute for Health Research (NIHR) Horizon Scanning Centre.

Technology alert

This technology is predicted to have an impact on the following domains of the NHS Outcomes Framework: enhancing quality of life for people with long-term conditions; ensuring that people have a positive experience of care, treating and caring for people in a safe environment; and protecting them from avoidable harm. If clinical and cost-effectiveness can be demonstrated, the SpaceOAR® system may offer an additional option for patients requiring prostate cancer radiation therapy.

More comprehensive and recent assessments added.

Nguyen PL, Devlin PM et al (2013). High-dose-rate brachytherapy for prostate cancer in a previously radiated patient with polyethylene glycol hydrogel spacing to reduce rectal dose: Case report and review of the literature.

Brachytherapy.12 (1) 77-83.

Case report

n=1 high risk prostate cancer patient previously irradiated.

Hydrogel spacer during high dose rate brachytherapy.

The spacer allowed the rectal dose constraint goals to be easily met. Injecting an absorbable polyethylene glycol hydrogel to separate the prostate and rectum appears to be associated with decreased maximum and mean rectal doses and may have particular utility in previously irradiated patients.

Larger and longer follow-up studies included.

Noyes WR, Hosford CC et al (2012). Human collagen injections to reduce rectal dose during radiotherapy. International Journal of Radiation Oncology Biology Physics. 82: 1918-1922.

Case series

N=11 patients with localised prostate cancer

Injection of human collagen during IMRT (dose of 75.6 Gy in 42 fractions)

Follow-up 12 months

The injection of human collagen in the outpatient setting was well tolerated. The mean separation between the prostate and anterior rectum was 12.7 mm. The mean reduction in dose to the anterior rectal wall was 50%. All men denied any rectal symptoms during the study.

Included in systematic review added.

Ogita M, Yamashita H, Nozawa Y et al. (2021) Phase II study of stereotactic body radiotherapy with hydrogel spacer for prostate cancer: acute toxicity and propensity score-matched comparison. Radiat Oncol.16:107, pp 1-11

Trial registration: UMIN-CTR, UMIN000026213

Case series

N=40 patients with prostate cancer treated with SBRT (36.25 Gy in 5 fractions with volumetric modulated arc therapy) in combination with a hydrogel spacer.

Grade 2 acute GI and GU toxicity occurred in 7 (18%) and 17 (44%) patients. The EPIC bowel and urinary summary score declined from the baseline to the first month (p<0.01, p=0.04). For propensity score-matched analyses, no significant differences in acute GI and GU toxicity were observed between the two groups. The EPIC bowel summary score was significantly better in the spacer group at 1 month (82.2 in the spacer group and 68.5 in the control group). SBRT with a hydrogel spacer had the dosimetric benefits of reducing the rectal doses, did not reduce physician-assessed acute toxicity, but it improved patient-reported acute bowel toxicity.

Larger studies included.

Ogita M, Yamashita H, Sawayanagi S et al. (2020) Efficacy of a hydrogel spacer in three-dimensional conformal radiation therapy for prostate cancer. Japanese Journal of Clinical Oncology, 50(3)303–309.

Case series

N=39 patients who received stereotactic body radiotherapy for prostate cancer inserted with a hydrogel spacer and underwent computed tomography scans before and after spacer insertion.

3D-CRT plans according to NCCN classification, low-, intermediate- and high-risk, were made.

Dose constraints for rectum and bladder were V70 Gy ≤ 15%, V65 Gy ≤ 30% and V40 Gy ≤ 60%.

Among 39 patients, 35 (90%), 19 (49%) and 13 (33%) and 38 (97%), 38 (97%) and 34 (87%) patients before and after the spacer insertion fulfilled rectum dose constraints for low-, intermediate- and high-risk plans, respectively. A hydrogel spacer significantly reduced rectum dose and improved the rectum dose constraints fulfilment rate in intermediate (p<0.01) and high (p<0.01), but no difference was found in low-risk 3D-CRT plan (P = 0.25). Although IMRT is the standard treatment, 3D-CRT using a hydrogel spacer may be a treatment option.

Larger studies included.

Osman SOS; Fairmichael C, Whitten G et al. (2022) Simultaneous integrated boost (SIB) to dominant intra-prostatic lesions during extreme hypofractionation for prostate cancer: the impact of rectal spacers.

Radiation oncology. 17 (1); 38

Case series

N=12 patients with unfavourable intermediate or high risk prostate cancer treated with 5-fraction stereotactic ablative radiotherapy (SABR) volumetric modulated arc therapy (VMAT) 40 Gy or boosting up to 50 Gy in dominant intraprostatic lesions.

Pre and post insertion plans assessed.

Compared to plans before spacer insertion, higher dose were achieved with spacer in situ for 25% of the patients. Moreover, significant reduction in rectal dose and better target coverage were also achieved for all patients with spacers in situ.

Dosimetry study. Larger studies with longer follow up included.

Padmanabhan R, Pinkawa M, Song DY. Hydrogel spacers in prostate radiotherapy: a promising approach to decrease rectal toxicity. Future Oncol. (2017) 13(29), 2697–2708

Review

Strategies for reducing dose to rectum include endorectal balloons as well as injection of rectal spacers like hydrogels. Early clinical studies with hydrogels have shown favourable outcomes. A low incidence of major procedural adverse effects with hydrogel use has been reported and it is well tolerated by patients. Hydrogel holds promise in establishing itself as an adjunct to standard of care in prostate radiation.

Review

Pepe P, Tamburo M, Pennisi M et al. (2021) Clinical Outcomes of Hydrogel Spacer Injection Space OAR in Men Submitted to Hypofractionated Radiotherapy for Prostate Cancer. In vivo (Athens, Greece); 35 (6); 3385-3389.

Case series

N=32 patients with localized prostate cancer underwent hydrogel spacer (SpaceOAR) before hypofractionated radiotherapy.

Median follow up 15 months

PSA levels was 0.52 nanograms/ml; 28.1% vs. 78.1% patients had GI vs. GU Grade 0 acute toxicity and 93.7% vs. 0% had GI vs. GU Grade 0 late toxicity. Furthermore, 88.1% of patients kept pretreatment sexual potency. The use of the hydrogel Spacer OAR before HRT is useful for reducing acute and late GU and GI toxicities.

Larger studies with longer follow-up included.

Patel AK, Houser C, Benoit R et al. (2020) Acute patient-reported bowel quality of life and rectal bleeding with the combination of prostate external beam radiation, low-dose-rate brachytherapy boost, and SpaceOAR. Brachytherapy 19, 477-483.

Retrospective review

N=69 patients with prostate cancer treated with EBRT (45 Gy), cesium-131 LDR-BT (85 Gy), and SpaceOAR

3 months follow-up

With combination EBRT, LDR-BT, and SpaceOAR, bowel QOL returned to the baseline 3 months after LDR-BT. Clinically significant rectal bleeding was !5%. Further follow-up will confirm if low acute rectal toxicity translates to reduced late toxicity

Larger studies included.

Paetkau O, Gagne IM, Pai HH et al. (2019) Maximizing rectal dose sparing with hydrogel: A retrospective planning study. J Appl Clin Med Phys; 20:4: 91–98.

Retrospective study

N= 13 prostate cancer patients implanted with 10 cc of SpaceOAR hydrogel.

Overall, treatment plans using the RW optimization structure offered the lowest rectal dose while VMAT treatment technique offered the lowest bladder and penile bulb dose.

Treatment planning study.

Pinkawa M, Bornemann C et al (2013). Treatment planning after hydrogel injection during radiotherapy of prostate cancer. Strahlentherapie und Onkologie.189 (9) 796-800.

Case study

n=3 injection of 10 ml hydrogel in prostate cancer patients during IMRT.

Treatment planning based on imaging shortly after hydrogel injection overestimates the actual hydrogel volume during the treatment as a result of not-yet-absorbed saline solution and air bubbles.

Imaging for treatment planning study.

Pinkawa M, Piroth MD et al (2013). Spacer stability and prostate position variability during radiotherapy for prostate cancer applying a hydrogel to protect the rectal wall. Radiotherapy and Oncology.106 (2) 220-224.

Comparative case series

n=15 prostate cancer patients with 10ml hydrogen spacer injection (SpaceOAR) (G1) versus 30 patients without a spacer (g2) during radiotherapy

Follow-up: 12 weeks

Mean volume of the hydrogel increased slightly (17%; p< 0.01), in 4 of 15 patients >2 cm. The average displacement of the hydrogel centre of mass was 0.6 mm (87% < 2.2 mm), -0.6 mm (100% < 2.2 mm) and 1.4 mm (87% < 4.3 mm) in the x-, y- and z-axes (not significant). The average distance between prostate and anterior rectal wall before/at the end of radiotherapy was 1.6 cm/1.5 cm, 1.2 cm/1.3 cm and 1.0 cm/1.1 cm at the level of the base, middle and apex (G1). Prostate position variations were similar with or without hydrogel but significant systematic posterior displacements were only found in those without hydrogel.

Study evaluating prostate position variability and spacer stability. Larger and longer follow-up studies.

Pinkawa, M (2015). Current role of spacers for prostate cancer radiotherapy. World Journal of Clinical Oncology 6 (6) 189-193.

General review.

Several studies have shown well tolerated injection procedures and treatments. Apart from considerable reduction of rectal irradiation, a prospective randomised trial demonstrated a reduction of rectal toxicity after hydrogel injection in men having prostate image-guided intensity-modulated radiation therapy.

General review.

Pinkawa M, Piroth MD et al (2012). Quality of life after intensity-modulated radiotherapy for prostate cancer with a hydrogel spacer Matched-pair analysis. Strahlentherapie und Onkologie.188 (10) 917-925.

Case –control study (matched pair analysis)

n= 28 prostate cancer patients in each sub-group.

Dose in spacer subgroup was 78 Gy in 2 Gy fractions compared with 2 matched-pair subgroups (treated without spacer): 3D conformal 70.2 Gy in 1.8 Gy fractions (3DCRT) and intensity-modulated radiotherapy (IMRT) 76 Gy in 2 Gy fractions.

Bowel bother scores were only significantly different in comparison to baseline levels in the spacer subgroup. The percentage of patients reporting moderate/big bother with specific symptoms did not increase for any item (urgency, frequency, diarrhoea, incontinence, bloody stools, pain). Moderate bowel quality-of-life changes can be expected during radiotherapy irrespective of spacer application or total dose.

Study evaluating quality of life. Larger and longer follow-up studies included.

Pinkawa M, Escobar Corral N et al (2011). Application of a spacer gel to optimize three-dimensional conformal and intensity modulated radiotherapy for prostate cancer. Radiotherapy and Oncology.100 (3) 436-441.

Case series

n=18 patients with prostate cancer. Injection of a spacer gel (10 ml SpaceOAR^TM) done and 3D CRT and IMRT treatment plans used (78 Gy in 39 fractions).

Follow-up: after injection

The injection of a spacer gel between the prostate and anterior rectal wall is associated with considerably lower doses to the rectum and consequentially lower NTCP values irrespective of the radiotherapy technique. Mean rectal V70 Gy of 14.4% on preimplantation scans compared with 6.1% on post implantation scans reported. A similar rectal V70Gy reduction was reported in IMRT plans (pre-implantation 17.2%, post implant 7.2%). The spacer had no impact on the doses delivered to the PTV, bladder and femoral heads. 94% of IMRT plans met planning constraints compared with only 67% of 3D-CRT plans despite presence of spacers.

Dosimetric study. Larger and longer follow-up studies included.

Pinkawa M, Schubert C et al (2015). Application of a hydrogel spacer for postoperative salvage radiotherapy of prostate cancer. Strahlentherapie und Onkologie 191 (4) 375-379.

Case report

n=1 prostate cancer patient presented 20 years after radical prostatectomy with a digitally palpable local recurrence at the urethrovesical anastomosis.

hydrogel spacer application during salvage radiotherapy (IMRT total dose 76Gy in 2 Gy fractions)

Local recurrence was displaced more than 1 cm from the rectal wall. Patient reported rectal urgency during radiotherapy, resolved after treatment. PSA levels dropped after treatment. A hydrogel spacer was successfully applied for dose-escalated radiotherapy in a patient with macroscopic local prostate cancer recurrence at the urethrovesical anastomosis to decrease the dose at the rectal wall.

Larger and longer follow-up studies included.

Pinkawa M, Klotz J, Djukic V et al (2013).

Learning curve in the application of a hydrogel spacer to protect the rectal wall during radiotherapy of localized prostate cancer. Urology; 82: 963-968

Case series

n=64 patients with prostate cancer.

PEG hydrogel with IMRT (78Gy in 38 fractions)

Follow-up – until last day of radiotherapy.

A smaller mean perirectal separation of 1.1cm in the first 32 patients compared with 1.5 in the second 32 patients reported. Rectal V70 Gy in the first group was 6% compared with 2% in the second cohort. A greater relative reduction of 80% was reported in the second cohort compared with 62.5% in the first cohort. An increasingly symmetrical hydrogel distribution and significantly larger prostate-rectum distances with the same hydrogel volume was seen. An improved dosimetric rectum protection and smaller acute bowel quality-of-life changes resulted.

Learning curve, RT dosimetric study.

Pinkawa, M, Berneking, VK et al (2017). Hydrogel injection reduces rectal toxicity after radiotherapy for localized prostate cancer. Hydrogelinjektion vermindert die rektale Toxizitat nach Radiotherapie bei lokalisiertem Prostatakarzinom. (193) 1 22-28.

Prospective comparative study

n=167 consecutive patients who received prostate RT with 2-Gy fractions up to 76 Gy (without hydrogel, n = 66) or 76-80 Gy (with hydrogel, n = 101)

Follow-up: 17 months after RT.

Baseline patient characteristics were well balanced. Treatment for bowel symptoms (0 vs 11%; p<0.01) and endoscopic examinations (3 vs 19%; p<0.01) were performed less frequently with a spacer. Mean bowel function scores did not change for patients with a spacer in contrast to patients without a spacer (mean decrease of 5 points) >1 year after RT in comparison to baseline, with 0 vs. 12% reporting a new moderate/big problem with passing stools (p<0.01). Statistically significant differences were found for the items "loose stools", "bloody stools", "painful bowel movements" and "frequency of bowel movements".

Multiple publication of Pinkawa 2016 included in systematic review added.

Pinkawa M, Berneking V, Schlenter M et al. (2017) Quality of Life After Radiation Therapy

for Prostate Cancer with a Hydrogel Spacer: 5-Year Results. International Journal of Radiation Oncology

Biology Physics. 99(2):374-7.

Case series

N=114 prostate cancer patients (low/intermediate/high-risk) received external beam radiation therapy 76 -78Gy fractions (54 had hydrogel spacer and 60 had no spacer).

QoL was measured by the EPIC-50 items scale.

Follow-up 5 years

Mean bowel function and bother score changes of >5 points in comparison to baseline levels before treatment were found only at the end of RT (10-15 points; p < .01) for patients treated with a hydrogel spacer. No spacer patient reported moderate or big problems with his bowel habits overall. Mean bother score changes of 21 points at the end of RT, 8 points at 2 months, 7 points at 17 months, and 6 points at 63 months after RT were found for patients treated without a spacer. A bowel bother score change >10 points was found in 6% versus 32% (P<0.01) at 17 months and in 5% versus 14% (P=0.2) at 63 months with versus without a spacer.

Included in systematic review added.

Pinkawa M (2016).

Rectal spacers to minimise morbidity in radiotherapy for prostate cancer.

Radiotherapy and Oncology (119) S8.

Review

Biodegradable spacers, including hydrogel, hyaluronic acid, collagen or an implantable balloon can be injected or inserted in a short procedure under transrectal ultrasound guidance via a transperineal approach. A distance of about 1.0-1.5cm is usually achieved between the prostate and rectum, excluding the rectal wall from the high isodoses. Several studies have shown well tolerated injection procedures and treatments. Apart from considerable reduction of rectal dose compared to radiotherapy without a spacer, clinical toxicity results are favourable.

Review

Pinkawa M, Schubert C, Escobar-Corral N et al. (2018) Optimization of prostate cancer radiotherapy using of a spacer gel, volumetric modulated arc therapy and a single biological organ at risk objective. International Journal of Radiation Research, 16, 169-176.

Case series

N=27 patients with localised prostate cancer: stage T1-T2c

IMRT, VMAT

78 Gy in 2 Gy fractions VMAT versus IMRT plans and plans before versus after spacer injection were compared.

In addition to decreased rectal dose following spacer injection, VMAT with single biological organ at risk optimization resulted in further dose reduction to the organs at risk and improved dose homogeneity and conformity in comparison to the step-and-shoot IMRT technique with conventional objectives.

Larger studies included. Toxicity not reported.

Pieczonka CM, veados N et al (2016). Hydrogel Spacer Application Technique, Patient Tolerance, and Impact on Prostate IMRT: Results from a Prospective Multicenter Pivotal Randomized Controlled Trial. Urology Practice 3 (2), 141–146.

RCT

n=222 (149 spacer group versus 73 control group) men with stage T1 or T2 prostate cancer treated to 79.2 Gy with image guided intensity modulated radiation therapy in 44 fractions.

Fiducial markers and perirectal spacer injection (spacer group) or fiducial markers alone (control group).

Follow-up: 15 months

Follow-up:15 months

Procedures were rated easy or very easy in 98.7% of cases with a 99.3% success rate. Mild transient rectal events were noted in 10% of patients in the spacer group (for example, pain, discomfort). Mean perirectal space was 12.6 mm after implant and 10.9 mm at 12.4 weeks with absorption at 12 months. A 25% or greater reduction in rectal V70 dose was produced in 97.3% of patients in the spacer group. The spacer group had a significant reduction in late rectal toxicity severity (p=0.044) as well as lower rates of decrease in bowel quality of life at 6, 12 and 15 months compared with the control group. There were no unanticipated adverse spacer effects or spacer related adverse events.

Multiple publication (of Mariados et al 2015) included in systematic review added.

Picardi C, Rouzaud M, Kountouri M et al. (2016) Impact of hydrogel spacer injections on interfraction prostate motion during prostate cancer radiotherapy. ACTA ONCOLOGICA, VOL. 55, NO. 7, 834–838

Prospective cohort study

N=20 patients with prostate cancer had radiotherapy-IGRT (10 with or 10 without hydrogel spacers).

Follow up time not reported.

In patients with or without HS, the overall mean interfraction prostate displacements were 0.4 versus -0.4 mm (p=0.0001), 0.6 versus 0.6 mm (p =0.85), and -0.6 mm versus -0.3 mm (p=0.48) for the left right, anterior-posterior (AP), superior-inferior (SI) axes, respectively. Prostate displacements 45 mm in the AP and SI directions were similar for both groups. No differences in setup errors were observed in the three axes between HS + or HS- patients. HS implantation does not significantly influence the interfraction prostate motion in patients treated with RT for prostate cancer. The major expected benefit of HS is a reduction of the high-dose levels to the rectal wall without influence in prostate immobilization.

Included in HTA added.

Polamraju P, Bagley AF, Williamson T et al. (2019) Hydrogel Spacer Reduces Rectal Dose during Proton Therapy for Prostate Cancer: A Dosimetric Analysis. Int J Particle Therapy, 23-31

N=9 patients

hydrogel spacer on rectal dose on plans for treating prostate cancer with intensity-modulated proton therapy (IMPT) or passive scattering proton therapy (PSPT)

Significant reductions in rectal dose occurred in both PSPT and IMPT plans, with the greatest reduction for IMPT-with-spacer relative to PSPT alone. Prospective studies are ongoing to assess the clinical impact of reducing rectal dose with hydrogel spacers.

Dosimetric analysis.

Porkhun K, Hagen G. "Hydrogel rectal spacer SpaceOAR™ in prostate cancer radiation therapy - Health economic evaluation" 2021. Oslo: Norwegian Institute of Public Health, 2021.

Health technology assessment.

Absolute shortfall for patients suffering from radiation-induced adverse events is 1.85 QALYs.

• The cost-utility analysis indicated that SpaceOAR™ in combination with radiation therapy was more costly (incremental costs: 15,330 NOK) and slightly more effective (incremental effects: 0.008 QALYs) than radiation therapy alone.

• The health benefit of the intervention is very uncertain. Our analysis indicates that the intervention only has a 59% likelihood of generating a net health benefit as measured in QALYs.

• The incremental cost-effectiveness ratio (ICER) is NOK 2,006,985 per QALY.

• The results of sensitivity analysis indicated that the price of the spacer, the quality of life weights and the efficacy of the treatment have the greatest impact on the results.

• The budget impact analysis indicated that costs of the intervention would be approximately 15 million NOK per year. This report has assessed to what degree the technology meets the Norwegian priority setting criteria (health benefits, resource use and disease severity). The absolute shortfall is 1.85 QALY, placing the disease in the lowest priority setting group following the approach suggested by the Magnussen group (https://www.regjeringen.no/no/dokumenter/pa-ramme-alvor/id2460080/ ). The health benefit of the intervention is small (0.008 QALYs) and very uncertain.

Economic evaluation. Not in remit.

Prada PJ, Fernandez J et al (2007). Transperineal Injection of Hyaluronic Acid in Anterior Perirectal Fat to Decrease Rectal Toxicity from Radiation Delivered with Intensity Modulated Brachytherapy or EBRT for Prostate Cancer Patients. International Journal of Radiation Oncology Biology Physics.69 (1) 95-102.

Case series

n=27 intermediate and high risk prostate cancer patients

Injecting hyaluronic acid (HA) during external beam radiation therapy (EBRT TO 43 Gy in 23 fractions) with HDR brachytherapy (23 Gy in 2 HDR BT boosts) over 5 week period. HA was injected before the second HDR fraction.

Follow-up: median 13 months.

No toxicity was produced from the HA or the injection. In follow-up CT and MRI the HA injection did not migrate or change in mass/shape for close to 1 year. The mean distance between rectum and prostate was 2.0 cm along the entire length of the prostate. The median measured rectal dose, when normalized to the median urethral dose, demonstrated a decrease in dose from 47.1% to 39.2% (p < 0.001) with or without injection. For an HDR boost dose of 1150 cGy, the rectum mean Dmax reduction was from 708 cGy to 507 cGy, p < 0.001, and the rectum mean Dmean drop was from 608 to 442 cGy, p < 0.001 post-HA injection.

Included in systematic review added.

Prada PJ, Gonzalez H, Menéndez C et al (2009) Transperineal injection of hyaluronic acid in the anterior perirectal fat to decrease rectal toxicity from radiation delivered with low-dose-rate brachytherapy for prostate cancer patients. Brachytherapy; 8(2):210-7.

Pseudo-RCT

N=69 patients with low- and intermediate-risk prostate cancer had BT with I-125 seeds; dose of 145 Gy

Transperineal injection of hyaluronic acid (n=36) versus no transperineal hyaluronic acid injection (n=33)

Follow up median 26 months

No toxicity in fat or in rectal function. Mucosal damage post therapy 5% (2/36) versus. 36% (12/33), p=0.002. Macroscopic rectal bleeding 0 versus 12% (4/23), p=0.047. No side effects related to injection or hyaluronic acid.

Included in systematic review added.

Prada PJ, Jimenez I, Gonzalez-Suarez H et al. (2012) High-dose rate interstitial brachytherapy as monotherapy in one fraction and transperineal hyaluronic acid injection into the perirectal fat for the treatment of favorable stage prostate cancer: Treatment description and preliminary results. Brachytherapy.11(2):105-10.

Case series

N=40 patients with prostate cancer treated with high-dose-rate (HDR) brachytherapy (20.5 Gy) plus transperineal hyaluronic acid injection into the perirectal fat to displace the rectal wall from radiation.

Median follow-up 19 months (range 8-32 months).

All patients tolerated the implantation procedure very well with minimal discomfort. No intraoperative or perioperative complications occurred. Acute toxicity Grade 2 or more was not observed in any patients. No chronic toxicity has been observed after treatment. Logistic regression showed that the late Grade 1 GU toxicity was associated with D(90) (p=0.050). The 32-month actuarial biochemical control was 100% and 88%, respectively (p=0.06) for low- and intermediate-risk groups.

Included in systematic review added.

Prada PJ, Ferri M, Cardenal J et al. (2018) High-dose-rate interstitial brachytherapy as monotherapy in one fraction of 20.5 Gy for the treatment of localized prostate cancer: Toxicity and 6-year biochemical results. Brachytherapy. 17(6):845-51.

Case series

N=60 patients with low- and intermediate-risk prostate cancer were treated with high-dose-rate monotherapy in one fraction (20.5 Gy) and transperineal hyaluronic acid injection into the perirectal space.

Median follow-up was 51 months (range 30–79)

HDR brachytherapy is well-tolerated. No intraoperative or perioperative complications occurred. Grade 1 acute genitourinary toxicity occurred in 36% of patients, Grade 2 or more was not observed, only 1 patient requiring the use of a catheter for 7 days in the immediate postoperative period. No gastrointestinal toxicity or chronic toxicity has been observed after treatment. The actuarial biochemical control was better, 82% (±3%) at 6 years.

Large studies included.

Quinn TJ, Daignault-Newton S, Bosch W et al. (2020) Who Benefits from a Prostate Rectal Spacer? Secondary Analysis of a Phase III Trial. Practical Radiation Oncology 10, 186-194

RCT SpaceOAR phase III trial

Clinical and dosimetric data for the 222 patients enrolled on the original trial were analysed in the present study

218 were assessed for bowel quality of life (QOL) at 15 months, and 140 with a minimum of 3 years of follow-up were assessed for more long-term changes in bowel QOL.

There was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful Therefore, we were not able to identify a subgroup within this population that did not potentially benefit from spacer placement.

Data from the RCT included.

Rossi PJ, Marcus DM, Adrian Hall W et al. (2021) Hydrogel spacers and prostate brachytherapy. Brachytherapy. 21 (1); 75-78.

Review

It is clear that spacing utilized in the setting of brachytherapy, may reduce early or late gastrointestinal side effects, and does not degrade the quality of the treatment. Although toxicities associated with spacers appear to be rare, clinicians should be aware of potential complications and should be trained on appropriate spacer placement. Further study with prospective evaluation is essential.

Review

Repka MC, Creswell M, Lischalk JW (2022). Rationale for Utilization of Hydrogel Rectal Spacers in Dose Escalated SBRT for the Treatment of Unfavorable Risk Prostate Cancer. Frontiers in Oncology; 12; 860848

Review

Outlines a framework and rationale for the utilization of rectal spacers when treating unfavourable risk prostate cancer with dose escalated Stereotactic Body Radiation Therapy (SBRT).

Review

Ruggieri R, Naccarato S, Stavrev P et al. (2015) Volumetric-modulated arc stereotactic body radiotherapy for prostate cancer: dosimetric impact of an increased near-maximum target dose and of a rectal spacer. The British journal of radiology, 88, 20140736.

Prospective cohort study

N=11 patients with low/intermediate risk prostate adenocarcinoma, had VMAT-SBRT 35 Gy in 5 fractions- IMRT

(10 ml of hydrogel spacer versus no spacer)

Patients selected from 2 different trials.

Follow-up not reported.

The increased D2% was associated with improvements in target coverage, whereas spacer insertion was associated with improvements in both target coverage and rectal Vr X . By linear correlation analysis, spacer insertion was related to the reductions in rectal Vr X for X ≥ 28GyA slightly increased D_2% or the use of spacer insertion was each able to improve VPTV 33:2 . Their combined use assured VPTV 33:2 $ 98% to all our patients. Spacer insertion was further causative for improvements in rectal sparing.

Larger studies included.

Rucinski A, Brons S, Richter D, et al. (2015) Ion therapy of prostate cancer: daily rectal dose reduction by application of spacer gel. Radiat;10:56.

Retrospective cohort study

N=19 patients with prostate cancer treated with photons and ions (10 with Hydrogel spacer versus 9 without spacer).

Patients selected from 2 different trials.

The application of spacer gel did substantially diminish rectum dose. Dmax-1 ml on the treatment planning CT was on average reduced from 100.0 ± 1.0% to 90.2 ± 4.8%, when spacer gel was applied. Spacer gel results in a decrease of the daily V90Rectum index, which calculated over all patient cases and CT studies was 10.2 ± 10.4 [ml] and 1.1 ± 2.1 [ml] for patients without and with spacer gel, respectively.

Larger studies included.

Seymour ZA, Daignault S, Bosch W, Gay HA, Michalski JM, Hamstra DA, et al. Long-term follow-up after radiotherapy for prostate cancer with and without rectal hydrogel spacer: A pooled prospective evaluation of quality of life.. BJU Int 2020; 126: 367–372 doi:10.1111/bju.15097

Case series

N=380 men treated with radiotherapy (RT) for prostate cancer (64% with rectal hydrogel spacer and 36% without)

Pooled analysis of two series (a prospective Phase III multi-centred randomised trial and a prospective non-randomised single-institution analysis)

Follow-up (median 39 months)

QOL was examined using the Expanded Prostate Cancer Index Composite (EPIC) and mean changes from baseline in EPIC domains were evaluated.

Treatment with spacer was associated with less decline in average long-term bowel QOL (89.4 for control and 94.7 for spacer) with differences at >24 months meeting the threshold of a MID difference between cohorts (bowel score difference from baseline: control = -5.1, spacer = 0.3, difference = -5.4; P < 0.001). When evaluated over time men without spacer were more likely to have MIDx1 (5 points) declines in bowel QOL (P = 0.01). At long-term follow-up MIDx1 was 36% without spacer vs 14% with spacer (P In this pooled analysis of QOL after prostate RT with up to 5 years of follow-up, use of a rectal spacer was associated with preservation of bowel QOL. This QOL benefit was preserved with long-term follow-up.

Similar study included in HTA added.

Stavrev P, Ruggieri R, Stavreva N et al (2016).

Applying radiobiological plan ranking methodology to VMAT prostate SBRT.

Phys Med 32 (4) 636-641.

Case series

n=11 patients (35Gy-in-five-fractions VMAT prostate SBRT) 4 plans were generated before and after spacer insertion.

The plans without rectal spacer were ranked worse compared to those with rectal spacer except for one set of Hom plans. The use of rectal spacer leads in general to lower risk of rectal complications, as expected, and even to better tumour control. Plans with increased near maximum target dose (D2%40.2Gy) are expected to perform much better in terms of tumour control than those with D2%37.5Gy.

Treatment planning study.

Strom TJ, Wilder RB et al (2014). A dosimetric study of polyethylene glycol hydrogel in 200 prostate cancer patients treated with high-dose rate brachytherapy+/-intensity modulated radiation therapy. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology.111 (1) 126-131.

Retrospective comparative case series

n=200 (100 gel versus 100 no gel) patients with clinically localised prostate cancer who had high dose rate (HDR) brachytherapy with or without intensity modulated radiation therapy (IMRT) and injection of a polyethylene glycol hydrogel spacer (10 ml Duraseal).

Follow-up median 8.7 months.

There was a success rate of 100% (100/100) with PEG hydrogel implantation. PEG hydrogel significantly increased the prostate-rectal separation (mean±SD, 12±4mm with gel vs. 4±2mm without gel, p<0.001) and significantly decreased the mean rectal D2 ml (47±9% with gel vs. 60±8% without gel, p<0.001). Gel decreased rectal doses regardless of body mass index (BMI).

Study included in systematic review added.

Song DY, Herfarth KK et al (2013). 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. International Journal of Radiation Oncology Biology Physics.87 (1) 81-87.

Case series

N=52 patients with localised prostate cancer (T1-T2).

Injection of a prostate-rectum spacer (polyethylene glycol hydrogel [SpaceOAR] during IMRT- 78 Gy in 2 Gy fractions

Follow-up not reported

Injection of hydrogel into the prostate-rectal interface resulted in dose reductions to rectum for >90% of patients treated. Rectal sparing was statistically significant across a range of 10 to 75 Gy and was demonstrated within the presence of significant interinstitutional variability in plan conformity, target definitions, and injection results.

Included in systematic review added.

Sidhom M, Arumugam S et al (2016). Early results of Australian multicentre phase 2 trial of stereotactic "virtual HDR" radiation therapy for intermediate and high risk prostate cancer.

Journal of Medical Imaging and Radiation Oncology (60) 48.

Multicentre case series

n=43 patients with intermediate and high risk prostate cancer who completed

stereotactic body radiotherapy (SBRT) as a "virtual HDR" with stepwise dose escalation of 19 Gy in 2 fractions 1 week apart (in 28), followed by 46 Gy in 23 fractions (in 15).

Median follow-up: 12 months

Treatment was well tolerated. Genitourinary (GU) and gastrointestinal (GI) CTCAEv4 toxicities were minimal with no acute or late grade 3 GU or GI toxicity. At the end of treatment, any grade 1 GU toxicity occurred in 54%, and grade 2 in 31%. Acute grade 1 GI toxicity occurred in 26%, while no patients experienced acute grade 2 GI toxicity. For the 31 patients with 6-month follow-up, at last follow-up the rate of late grade 2 GU toxicity was 10%, while no patients developed late grade 2 GI toxicity. Rectal displacement during SBRT was achieved with an injectable hydrogel spacer (SpaceOAR) in 10 patients, and an external rectal retraction system (Rectafix) in 33 patients. No SpaceOAR patients reported discomfort from rectal displacement, while 39% of Rectafix patients reported moderate discomfort and 11% severe discomfort during SBRT.

Injectable hydrogel spacer inserted in 10 patients only.

Larger studies with longer follow-up included.

Sato H, Kato T, Motoyanagi T et al. (2021) Preliminary analysis of prostate positional displacement using hydrogel spacer during the course of proton therapy for prostate cancer. Journal of Radiation Research. 62, 2, 294–299.

Case series

N=22 patients with intermediate-risk prostate cancer (11 with hydrogel spacer [HS] insertion and 11 without HS insertion).

No significant difference was observed across the groups in the LR and SI directions. Conversely, a significant difference was observed in the AP direction (P < 0.05). The proportion of the 3D vector length ≤5 mm was 95% in the inserted group, but 55% in the non-inserted group. Therefore, HS is not only effective in reducing rectal dose, but may also contribute to the positional reproducibility of the prostate.

Effect of HS insertion on the inter-fraction prostate motion.

Saito M, Suziki T, Suguama Y et al. (2020) Comparison of rectal dose reduction by a hydrogel spacer among 3D conformal radiotherapy, volumetric-modulated arc therapy, helical tomotherapy, CyberKnife and proton therapy. Journal of Radiation Research, 61, 3, pp. 487–493.

Case series (retrospective)

N=20 patients with hydrogel spacer for prostate radiotherapy ( 3D conformal radiotherapy (3DCRT), volumetric modulated arc therapy (VMAT), helical tomotherapy (HT), CyberKnife (CK) and proton therapy).

Significant rectal dose reduction (P < 0.001) between the treatment plans on pre- and post-CT images were achieved for all modalities for D50%, D20% and D2%. The dose reduction of high-dose (D2%) ranges were −40.61 ± 11.19, −32.44 ± 5.51, −25.90 ± 9.89, −13.63 ± 8.27 and −8.06 ± 4.19%, for proton therapy, CK, HT, VMAT and 3DCRT, respectively. The area under the rectum dose–volume histogram curves were 34.15 ± 3.67 and 34.36 ± 5.24% (P = 0.7841) for 3DCRT with hydrogel spacer and VMAT without hydrogel spacer, respectively. Results indicate that 3DCRT with hydrogel spacer would reduce the cost by replacing the conventional VMAT without spacer for prostate cancer treatment, from the point of view of the rectal dose. For the high-dose gradient region, proton therapy and SBRT with CK showed larger rectal dose reduction than other techniques.

Dosimetric outcomes.

Schorghofer A, Drerup M, Kunit T et al. (2019) Rectum-spacer related acute toxicity – endoscopy results of 403 prostate cancer patients after implantation of gel or balloon spacers. Radiat Oncol J; 14 (47): 1–7.

Cohort study

N=403 patients

139 with hydrogel spacer (SpaceOAR) versus 264 with endorectal balloon (prospace) using endoscopy.

IMRT

276 patients were treated with normo-fractionated regimen (78 at 2Gy fraction), 125 treated with moderate hypofractionation (63 at 2 Gy fraction).

116 high risk patients additionally received 50 Gy in pelvic nodes.

12 months follow-up.

Overall rectal toxicity was very low with average VRS scores of 0.06 at the day after implantation, 0.10 at the end of RT, 0.31 at 6 months and 0.42 at 12 months follow up. Acute Grade 3 toxicity (rectum perforation and urethral damage) directly related to the implantation procedure occurred in 1.49% (n = 6) and was seen exclusively in patients who had received the spacer balloon. Analysis of post implant MR imaging did not identify abnormal or mal-rotated positions of this spacer to be a predictive factors for the occurrence of spacer related G3 toxicities.

Included in systematic review added.

Saito M, Suzuki T, Suzuki H et al. (2022) Minimum required interval between

hydrogel spacer injection and treatment planning for stereotactic body radiation therapy for prostate cancer. Practical Radiation Oncology.

Retrospective study

N=15 patients treated with SBRT + hydrogel spacer for prostate cancer.

Pre and post MRI (within 3 days) with spacer were evaluated.

A single day is an acceptable interval between hydrogel spacer injection and treatment planning for SBRT for prostate cancer

Volume of spacer on MRI assessed.

Sturt P, Suh YE, Khoo V et al. (2022) The dosimetric advantages of perirectal hydrogel spacer in men with localized prostate cancer undergoing stereotactic ablative radiotherapy (SABR). Medical Dosimetry.

N=22 patients with hydrogel spacer (SpaceOAR) undergoing stereotactic ablative radiotherapy (SABR) for localized prostate cancer

The use of hydrogel spacer was able to significantly reduce planned dose to the rectum, bladder and penile bulb with SABR techniques associated with the CyberKnife VSI system.

Dosimetry outcome. Larger studies with longer follow-up included.

Sawayanagi S, Yamashita H, Ogita M et al. (2022) Injection of hydrogel spacer increased maximal intrafractional prostate motion in anterior and superior directions during volumetric modulated arc therapy-stereotactic body radiation therapy for prostate cancer.

Radiation oncology. 17 (1); 41

Retrospective study.

N= 38 patients who had definitive volumetric modulated arc therapy (VMAT)-stereotactic body radiation therapy (SBRT) for prostate cancer (8 with spacer and 30 without spacer).

Our findings suggest that maximum intrafractional prostate motion monitoring during VMAT-SBRT was larger in patients with hydrogel spacer injection in the superior and anterior directions. Since this difference seemed not to disturb the dosimetric advantage of the hydrogel spacer, we do not recommend routine avoidance of the hydrogel spacer use.

Prostate motion outcome.

Studies with similar outcomes reported in the overview.

Suziki T, Saito M, Onishi H et al. (2020) Effect of a hydrogel spacer on the intrafractional prostate motion during CyberKnife treatment for prostate cancer. J Appl Clin Med Phys; 21:10:63–68

Case series (retrospective)

N=21 patients with prostate cancer (12 with and 12 without a hydrogel spacer during CyberKnife treatment)

evaluated the effect of a hydrogel spacer on intrafractional prostate motion during CyberKnife treatment.

The offset values (mean ± SD) for the X‐, Y‐, and Z‐axes were −0.04 ± 0.92 mm, −0.03 ± 0.97 mm (P = 0.66), 0.02 ± 0.51, −0.02 ± 0.49 mm (P = 0.50), and 0.56 ± 0.97 mm, 0.34 ± 1.07 mm (P = 0.14), in patients inserted without or with the hydrogel spacer, respectively. There was no effect of a hydrogel spacer on the intrafractional prostate motion in the three axes during CyberKnife treatment for prostate cancer.

Larger studies included.

Su Z, Henderson R, Nichols R et al. (2021) A comparative study of prostate PTV margins for patients using hydrogel spacer or rectal balloon in proton therapy. Physica Medica 81, 47–51.

Retrospective analysis

N=190 prostate patients treated with proton therapy (96 had hydrogel spacer injection and 94 patients had only rectal balloons insertion).

Statistically significant differences were observed in the patient setup and prostate intrafraction motion errors of the two patient groups. However, under the current protocol of bladder preparation and daily marker-based x-ray image-guidance, population PTV margins were comparable between the two patient groups.

Retrospective planning study.

Taggar AS, Charas T, Cohen GN et al. (2018) Placement of an Absorbable Rectal Hydrogel Spacer in Patients Undergoing Low-dose-rate Brachytherapy with Palladium-103. Brachytherapy. 17(2): 251–258

Retrospective cohort study

N=74 patients with prostate cancer had rectal hydrogel spacer inserted following LDR brachytherapy with Pd-103 seed-implant procedure. Brachytherapy was delivered a monotherapy to 26 (35%) patients; as part of planned combination therapy with EBRT to 40 (54%) patients; or as a salvage monotherapy to 8 (11%) patients.

Compared with 136 patients treated with seed implantation (from another cohort).

Follow-up not reported.

(SD 3.81), and112.4% (SD 12.0), respectively. Urethral D20, D5cc and D1cc were 122.0% (SD 17.27), 133.8% (SD 22.8), and 144.0% (SD 25.4), respectively. After completing all treatments, at the time of first the follow up, seven patients reported acute rectal toxicity –six experiencing grade 1 rectal discomfort and one (with pre-existing haemorrhoids) experiencing grade 1 bleeding. (SD 3.81), and112.4% (SD 12.0), respectively. Urethral D20, D5cc and D1cc were 122.0% (SD 17.27), 133.8% (SD 22.8), and 144.0% (SD 25.4), respectively. After completing all treatments, at the time of first the follow up, seven patients reported acute rectal toxicity –six experiencing grade 1 rectal discomfort and one (with pre-existing haemorrhoids) experiencing grade 1 bleeding.

Included in systematic review added.

Tang Q, Zhao F, Yu X, Wu L, Lu Z, Yan S. The role of radioprotective spacers in clinical practice: a review. Quant Imaging Med Surg. 2018;8(5):514-524. doi:10.21037/qims.2018.06.06

Review on different types of spacers and their application in various tumour sites.

Placement-related complications and the cost-effectiveness of the spacers are also discussed. With the increasing use of high-precision radiotherapy in clinical practice, especially the paradigm-changing stereotactic body radiotherapy (SBRT), more robust studies are warranted to further establish the role of radioprotective spacers through materials development and novel placement techniques.

Review

Teyateeti A, Grossman C, Kollmeier, MA et al. (2022) Influence of hydrogel spacer placement with prostate brachytherapy on rectal and urinary toxicity. BJU international. 129 (3); 337-344

Retrospective comparative study.

N= 224 patients with LDR brachytherapy +/-EBRT and hydrogel spacer compared with 139 without spacer.

Follow-up 3 years.

Rectal doses of the spacer cohort were significantly lower compared to the non-spacer cohort. The incidence rates of overall and grade > 2 rectal toxicity were lower in patients with spacer compared non-spacer group: 12% and 1.8% vs 31% and 5.8%, respectively. The 3-year cumulative incidence of overall rectal toxicity was significantly lower with spacer than without (15% vs 33%; P < 0.001), (HR 0.45, 95% CI 0.28-0.73; P = 0.001). None of the urethral dosimetric variables or the presence or absence of spacer was associated with late urinary toxicity.

Studies with similar outcomes included.

Trifiletti DM, Garda AE and Showalter TN (2016). Implanted spacer approaches for pelvic radiation therapy. Expert Review of Medical Devices 13 (7) 633-640.

Review describes the commercially available rectal spacers in pelvic radiation therapy, including prostate cancer and gynaecologic malignancies, and the application, dosimetric effects, and reports clinical outcomes to date.

Several groups have reported significantly reduced rectal doses and decreased rectal toxicity with prostate-rectal spacers, and additional evidence continues to emerge to support this promising approach

Review

te Velde BL, Westhuyzen J et al (2017). Can a peri-rectal hydrogel spaceOAR programme for prostate cancer intensity-modulated radiotherapy be successfully implemented in a regional setting?

Journal of Medical Imaging and Radiation Oncology, 61, 528–533.

Retrospective case series

n=125 patients with localised prostate cancer were treated with 81 Gy prostate intensity-modulated radiotherapy (IMRT).

65 with SpaceOAR 60 without SpaceOAR.

Patients treated with 81 Gy in 45Fx of IMRT over 9 weeks.

Follow-up: 12 weeks

Rectal volume parameters were all significantly lower in the SpaceOAR group, with an associated reduction in acute diarrhoea (13.8% vs 31.7%). There were no significant differences in the very low rates of acute and late faecal incontinence or proctitis, however, there was a trend towards increased haemorrhoid rate in the SpaceOAR group (11.7% vs 3.1%, P = 0.09).

Included in systematic review added.

te Velde BL, Westhuyzen J, Awad N et al (2019). Late toxicities of prostate cancer radiotherapy with and without hydrogel SpaceOAR insertion. Journal of Medical Imaging and Radiation Oncology. 2019.

Case series

N=121 patients with localised prostate cancer (intermediate and high risk patients) treated with 81 Gy in 45 fx of IMRT over 9 weeks were retrospectively compared: 65 patients with SpaceOAR and 56 patients without SpaceOAR.

Follow-up 3 years

The cumulative incidence of low-grade diarrhoea (G1) was significantly higher in the non-SpaceOAR group (21.4% vs 6.2%; P = 0.016). The cumulative incidence of proctitis (grades G1 and G2) was also higher in the non-SpaceOAR group (26.7% vs 9.2%; P = 0.015); the cumulative incidence of G2 proctitis was higher in the latter group (P = 0.043). There were no differences between the treatment groups for cumulative incidences of faecal incontinence and/or haemorrhoids. Three years after IMRT, diarrhoea and proctitis were higher in the non-SpaceOAR group, without reaching statistical significance. This finding was unchanged after correcting for baseline symptoms.

Included in systematic review added.

Teh AYM, Ko H-T et al (2014). Rectal ulcer associated with SpaceOAR hydrogel insertion during prostate brachytherapy. BMJ Case Reports.2014 (no pagination).

Case report

N=1 patient with intermediate risk prostate cancer.

Injection of hydrogel (SpaceOAR) spacer during low dose rate (LDR) prostate brachytherapy

Follow-up 3 years

Rectal ulcer associated with SpaceOAR hydrogel insertion during prostate brachytherapy.

Included in systematic review added.

Uhl M, Herfarth K et al (2014). Absorbable hydrogel spacer use in men undergoing prostate cancer radiotherapy: 12 month toxicity and proctoscopy results of a prospective multicenter phase II trial. Radiation oncology 9:96.

Case series

N=52 patients with localised prostate cancer (T1-T2).

Injection of a prostate-rectum spacer (polyethylene glycol hydrogel [SpaceOAR] during IMRT- 78 Gy in 2 Gy fractions

Follow-up 12 months

19 (39.6%) and 6 (12.5%) patients experienced acute Grade 1 and Grade 2 GI toxicity, respectively. There was no Grade 3 or Grade 4 acute GI toxicity experienced in the study.

45 (95.7%) patients experienced no late GI toxicity (95.7%), with 2 (4.3%) patients experiencing late Grade 1 GI toxicity. There was no late Grade 2 or greater GI toxicity experienced in the study.

20 (41.7%), 17 (35.4%) and 1 (2.1%) patients experienced acute Grade 1, Grade 2 and

Grade 3 GU toxicity, respectively (Table 1). There was no Grade 4 acute GU toxicity experienced in the study.

8 (17.0%) and 1 (2.1%) patients experienced late Grade 1 and Grade 2 GU toxicity, respectively. There was no late Grade 3 or greater GU toxicity experienced in the study.

Larger studies with longer follow-up included. Included in systematic review added.

Uhl M, van Triest B et al (2013). Low rectal toxicity after dose escalated IMRT treatment of prostate cancer using an absorbable hydrogel for increasing and maintaining space between the rectum and prostate: results of a multi-institutional phase II trial. Radiother Ocol 106:215-219.

Case series

n=48 prostate cancer patients with hydrogel spacer injection then had intensity modulated radiotherapy (IMRT).

Hydrogel application was straight forward with minimal patient discomfort. Six patients (12%) had acute GI grade 2 toxicity, with no patients having grade 3 or 4 toxicity. In addition, no patients had early late GI toxicity ⩾ grade 2 after 12 months. The gel was stable during the course of radiotherapy and was not detectable in MRI after 9–12 months because of absorption in 42/43 patients.4 failed implantations occurred before routine implantation under TRUS guidance. 3 reports of focal rectal mucosal necrosis and bladder perforation were reported but were self-limiting without further complications. After TRUS guidance implementation no instances of failed implantations, perforations were reported.

Initial clinical outcomes with acute toxicity results of first 48 patients and late toxicity of 27 patients. Included in systematic review added.

Underwood TSA., Voog JC, Moteabbed M et al. (2017). Hydrogel rectum-prostate spacers mitigate the uncertainties in proton relative biological effectiveness associated with anterior-oblique beams. Acta oncologica (Stockholm, Sweden), 56, 575-581.

Case series

N=10 patients with rectal spacers treated with AO proton beams, SB proton beams and IMRT

29.2 Gy in 1.8 Gy fractions

60 Gy in 3 Gy fractions

36.25 Gy in 7.25 Gy fractions

Rectal spacers enabled the generation of anterior beam proton plans that appeared robust to modelled variation in RBE. However, further analysis of day-to-day robustness would be required prior to a clinical implementation of AO proton beams. Such beams offer almost complete femoral head sparing, but their broader value relative to IMRT and SB protons remains unclear.

Larger and longer follow-up studies included. Toxicity profile not reported.

van Wijk Y, Vanneste BGL, Walsh S, et al. (2018) Development of a virtual spacer to support the decision for the placement of an implantable rectum spacer for prostate cancer SpaceOAR 30 April 16, Technology Assessment Unit, MUHC radiotherapy: Comparison of dose, toxicity and cost-effectiveness. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2017.

Cost effectiveness (using Markov model comparing gains in quality of life versus increases in cost).

Prediction model to identify patients most likely to benefit from SpaceOAR.

Model included real spacers implanted (8 patients with hydrogel spacer and 15 with rectal balloon implant), and a group with virtual spacers (8 hydrogel and 8 balloon spacers) created using computed tomography scans of patients with rectal balloon implants

For a defined threshold of €80,000, the hydrogel spacer resulted in a cost-effective intervention in 2 out of 8 patients. The authors conclude that these devices are not cost-effective for all patients, and that more individual-patient information is needed.

Economic evaluation. Not in remit.

van Gysen K, Kneebone A et al (2014). Feasibility of and rectal dosimetry improvement with the use of SpaceOAR hydrogel for dose-escalated prostate cancer radiotherapy.

Journal of Medical Imaging and Radiation Oncology.58 (4) 511-516.

Case series

n=10 patients had 10ml injection of hydrogel and radiotherapy.

Follow-up: 3 months

In the first 24 h, 2 patients had increase in bowel movement frequency. The comparison plans had identical prescription doses. Rectal doses were significantly lower for all hydrogel patients for all dose endpoints (P < 0.001). Post-treatment MRI showed gel stability. grade 1 bowel toxicity was reported in 6 patients during radiotherapy and 2 patients at 3 months' follow-up. No grade 2 or grade 3 acute bowel toxicity was reported.

Larger and longer follow-up studies included.

Van Gysen K, Kneebone A, Alfieri F, et al. (2013) Feasibility and rectal dosimetry improvement with the use of spaceOAR hydrogel for dose escalated prostate cancer radiotherapy. J Med Imaging Radiat Oncol. 1:59.

Case series

n=10 patients had 10ml injection of hydrogel and radiotherapy.

Follow-up: 3 months

In the first 24 h, 2 patients had increase in bowel movement frequency. The comparison plans had identical prescription doses. Rectal doses were significantly lower for all hydrogel patients for all dose endpoints (P < 0.001). Post-treatment MRI showed gel stability. grade 1 bowel toxicity was reported in 6 patients during radiotherapy and 2 patients at 3 months' follow-up. No grade 2 or grade 3 acute bowel toxicity was reported.

Larger and longer follow-up studies included.

Van Der Meer S, Vanneste BGL et al (2016). A novel decision support method to estimate the value of a rectum spacer: 'Virtual Rectum Spacer'.

Radiotherapy and Oncology (119) S638-S639.

Case series

n=16 prostate cancer patients with CT imaging prior and 3-5 days after a gel RS implantation (SpaceOARTM System, Augmenix Inc.)

Decision support system to predict the CT images with a 'virtual rectal spacers (RS) through non-rigid deformations based on a CT scan without RS to be integrated into a decision support system.

We have developed a novel method to simulate a model based virtual RS that is a useful tool to identify patients with a potentially high benefit of a RS implantation. The volume of the virtual RS can be estimated through the use of different deformation fields. In future, a dose comparison study is necessary to extend into a full decision support system using the virtual RS approach.

Decision support method.

Vassilis K, George M, John G et al (2013). Transperineal implementation of biocompatible balloon in patients treated with radiotherapy for prostate carcinoma: Feasibility and quality assurance study in terms of anatomical stabilization using image registration techniques. Journal of Bioequivalence and Bioavailability.5 (3), 142-148.

Case series

n=10 patients with localised low risk prostate cancer treated with external 3 dimensional radiation therapy (3DCRT with 76-78 Gy in 38-39 daily fractions) combined with biodegradable balloon (ProSpace) implantation

Follow-up: 3 weeks after treatment.

By using registration techniques, the ProSpace device was found stable in sequential CTs with x,y,z-axis displacements up to 2.1 mm, 3 mm and 2.2 mm respectively. The mean VAS score related to ProSpace was 1.4(± 0.5) and the mean score of rectal toxicity according to S-RS score was 1.9(± 0.6). The implementation of PROSPACE is feasible. Implant's position is relative stable. The procedure is minimally invasive with no recorded side effects. The incidence of patient-reported acute Gastrointestinal (GI) and Genitourinary (GU) toxicity as well as findings from flexible rectosigmoidoscopy, following high dose of 3DCRT after the implantation, were low.

Larger and longer follow-up studies included.

Vanneste Ben GL, Hoffmann AL (2016). Who will benefit most from hydrogel rectum spacer implantation in prostate cancer radiotherapy? A model-based approach for patient selection.

Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology (121) 1 118-123.

Case series

n=26 patients with localized prostate cancer a hydrogel rectum spacer injected.

Dose distributions with (IMRT+IRS) and without (IMRT-IRS) IRS were calculated.

IMRT+IRS revealed a significant reduction in V40Gy (p=0.0357) and V75Gy (p<0.0001) relative to IMRT-IRS. For G2-3 acute GI toxicity and G2-3 LRB, the predicted toxicity rates decreased in 17/26 (65%) and 20/26 (77%) patients, and decision rules were derived for 22/32 (69%) and 12/64 (19%) respectively. From the decision rules, it follows that diabetes status has no impact on G2-3 acute toxicity, and in absence of pre-RT abdominal surgery, the implantation of an IRS is predicted to show no clinically relevant benefit for G2-3 LRB.

Larger studies with longer follow-up included.

Vanneste BGL, Buettner F et al (2016).

Localizing the benefit of a hydrogel rectum spacer for prostate IMRT within the ano-rectal wall.

Radiotherapy and Oncology (119) S412.

Case series

n=26 patients with localized prostate cancer a hydrogel rectum spacer injected.

Study assessed spatio-dosimetric differences in Dose-surface maps (DSMs) obtained from planned ano-rectal wall (ARW) dose distributions in patients receiving IMRT with and without implanted rectum spacer (IRS) (IMRT+IRS; IMRT-IRS, respectively).

Significant spatio-dosimetric differences in ARW DSMs exist between prostate cancer patients undergoing IMRT with and without IRS. The IRS particularly reduces the lateral and longitudinal extent of high-dose areas (>50 Gy) in anterior and superior-inferior directions.

Larger studies with longer follow-up included.

Vanneste BG, Pijls-Johannesma M, Van De Voorde L, et al. (2015) Spacers in radiotherapy treatment of prostate cancer: is reduction of toxicity cost-effective? Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2015;114(2):276- 281

Cost-effectiveness study

Patients with prostate cancer who had intensity-modulated radiation therapy and a spacer (IMRT+S) versus IMRT-only without a spacer (IMRT-O).

decision-analytic Markov model constructed to examine late rectal toxicity, costs and quality of life.

IMRT+S revealed a lower toxicity than IMRT-O. Treatment follow-up and toxicity costs for IMRT-O and IMRT+S amounted to €1604 and €1444, respectively, thus saving €160 on the complication costs at an extra charge of €1700 for the spacer in IMRT+S. The QALYs yielded for IMRT-O and IMRT+S were 3.542 and 3.570, respectively. This results in an incremental cost-effectiveness ratio (ICER) of €55,880 per QALY gained. For a ceiling ratio of €80,000, IMRT+S had a 77% probability of being cost-effective.

Costs not in remit of Interventional procedures programme.

Vanneste BG, Buettner F, Pinkawa M et al. (2019) Ano-rectal wall dose-surface maps localize the dosimetric benefit of hydrogel rectum spacers in prostate cancer radiotherapy. Clinical and Translational Radiation Oncology, 14: 17-24.

Case series

n=26 prostate cancer patients receiving intensity-modulated radiation therapy (IMRT) with and without implantable hydrogel rectum spacers (IRS-SpaceOAR).

Spatial differences in dose distributions of the ano-rectal wall (ARW) evaluated using dose-surface maps (DSMs). Dose surface maps are generated for prostate radiotherapy using an IRS.

Local-dose effects are predicted to be significantly reduced by an IRS. The spatial NTCP model predicts a significant decrease in Gr 2 late rectal bleeding and subjective sphincter control. Dose constraints can be improved for current clinical treatment planning.

Comparative dosimetric study. Larger studies included.

Vanneste BGL, Van Limbergen EJ, van de Beek K et al. (2018) A biodegradable rectal balloon implant to protect the rectum during prostate cancer radiotherapy for a patient with active Crohn's disease. Technical Innovations and Patient Support in Radiation Oncology;6:1-4

Case report

Patient with Crohn's disease was implanted with a biodegradable balloon to protect the rectum during prostate cancer radiotherapy

The patient was at high-risk for rectal toxicity and was successfully irradiated to his prostate with only a grade 1 urinary toxicity, no acute rectal toxicity or toxicity flare of the IBD.

Larger studies included.

Vanneste BGL, van Wijk Y, Lutgens LC, Van Limbergen EJ, van Lin EN, van de Beek K, et al. Dynamics of rectal balloon implant shrinkage in prostate VMAT: Influence on anorectal dose and late rectal complication risk. Strahlenther Onkol. 2018;194(1):31-40

Case series

N=15 patients with localized prostate cancer had a rectal balloon implanted during moderately hypofractionated prostate radiotherapy.

Despite significant decrease in rectal balloon implant volume (average 70.4%), the high-dose rectal volume and the predicted late rectal bleeding risk were not significant due to a persistent spacing between the prostate and the anterior rectal wall.

Larger studies included.

Vanneste BGL, Van Limbergen EJ, Marcelissen T et al. (2021) Is prostate cancer radiotherapy using implantable rectum spacers safe and effective in inflammatory bowel disease patients? Clinical and Translational Radiation Oncology,, 27, 121125.

Case report

N= 8 patients with all-risk prostate cancer with the comorbidity of an IBD. 5 patients were treated with external beam RT (70 Gray (Gy) in 28 fractions), and 3 patients were treated with 125I-implant (145 Gy) in combination with a biodegradable prostate-rectum spacer balloon implantation.

Median follow-up was 13 months (range: 3–42 months).

Only one acute grade 2 gastrointestinal (GI) toxicity was observed: an increased diarrhoea (4–6 above baseline) during RT, which resolved completely 6 weeks after treatment. No late grade 3 or more GI toxicity was reported, and no acute and late grade 2 genitourinary toxicity events were observed.

Larger studies included.

Wilton L, Richardson M, Keats S et al. (2017) Rectal protection in prostate stereotactic radiotherapy: A retrospective exploratory analysis of two rectal displacement devices. J Med Radiat Sci 64, 266–273.

Prospective cohort study (retrospective analysis of data from PROMETHEUS trial ACTRN 126150002235380)

N=45 patients with non-metastatic intermediate- or high-risk prostate cancer and treated with stereotactic body radiation therapy (total dose of 19 or 20 Gy in two fractions followed by 46 Gy in 23 fractions).

Centre 1:16 Rectafix and 10 SpaceOAR patients.

Centre 2: 19 Rectafix patients.

dosimetric difference between two methods of rectal displacement compared: (1) centre 1 Rectafix versus centre 1 SpaceOAR; (2) centre 1 Rectafix versus centre 2 Rectafix and (3) centre 1+ centre 2 Rectafix versus centre 1 SpaceOAR

follow up time not reported.

In comparison (1) Rectafix demonstrated lower mean doses at 9 out of 11 measured intervals (P = 0.0012). Comparison (2) demonstrated a moderate difference with centre 2 plans producing slightly lower rectal doses (P = 0.013). Comparison (3) further demonstrated that Rectafix returned lower mean doses than SpaceOAR (P < 0.001). Although all dose levels were in favour of Rectafix, in absolute terms differences were small (2.6–9.0%). In well-selected prostate SBRT patients, Rectafix and SpaceOAR RDD's provide approximately equivalent rectal sparing.

Included in HTA added to table 2.

hydrogel spacers were compared to Rectafix, a plastic rod.

Whalley D, Hruby G, Alfieri F, Kneebone A, and Eade T (2016). SpaceOAR Hydrogel in Dose-escalated Prostate Cancer Radiotherapy: Rectal Dosimetry and Late Toxicity. Clin Oncol 28(10):e148-e54.

Case series

n=30 patients with prostate cancer.

Injection of a prostate-rectum spacer (polyethylene glycol hydrogel (SpaceOAR) during dose escalated intensity modulated radiotherapy (IMRT)

median 28 months (range 24-38)

There were no perioperative complications. Rectal doses were significantly lower for the post-hydrogel plans, especially above 65 Gy (V82 = 0.2% versus 1.3%; V80 = 0.8% versus 5.3%; V75 = 2.2% versus 9.5%; V70 = 3.7% versus 12.3%; V65 = 5.4% versus 14.7%; V40 = 22.9% versus 32% and V30 = 42.7% versus 49.4%). There was no significant difference in acute grade 1 and 2 gastrointestinal toxicity, which was 43% versus 51% and 0% versus 4.5% in the hydrogel and control groups, respectively. Late grade 1 was significantly less frequent in the hydrogel group (16.6% versus 41.8%, P ¼ 0.04).

Included in systematic review added.

Weber DC, Zilli T, Vallee J et al (2012). Intensity modulated proton and photon therapy for early prostate cancer with or without transperineal injection of a polyethylene glycol spacer: A treatment planning comparison study. International Journal of Radiat Oncol Biol Phys. 84: e311-318

Comparative case series

n=8 patients with localised prostate cancer

PEG hydrogel + intensity modulated radiation therapy [IMRT] (78 Gy in 39 fractions), volumetric modulated arc therapy [VMAT] (78Gy) and intensity modulated proton therapy [IMPT] (78 Gy).

Spacer injection significantly decreased the rectal dose in the 60 - 70 Gy range. Mean V70 Gy and V60 Gy with IMRT, RA and IMPT planning were 5.3+/-3.3% / 13.9+/-10.0%, 3.9+/-3.2% / 9.7+/-5.7% and 5.0+/-3.5% / 9.5+/-4.7% after Spacer injection. Spacer injection usually improved the PTV coverage for IMRT. With this technique, mean V70.2 Gy and V74.1 Gy were 100+/-0% - 99.8+/-0.2% and 99.1+/-1.2% - 95.8+/-4.6% with (p = 0.07) and without (p Z0.03) Spacer respectively. As a result of Spacer injection, bladder doses were usually higher but not significantly so.

Comparative dosimetric study. Included in systematic review added.

Wilder RB, Barme GA et al (2010). Cross-linked hyaluronan gel reduces the acute rectal toxicity of radiotherapy for prostate cancer. International Journal of Radiat Oncol Biol Phys. 77(3): 824-830.

Comparative case series with historical controls

n=10 patients with early stage prostate cancer.

Hyaluronan gel injection combined with HDR brachytherapy (4 fractions of twice daily for a total dose of 22 Gy) followed by IMRT to 50.4 Gy in 28 daily fractions over 5.5 weeks.

Dosimetric profiles of these patients were compared with 239 historical controls without gel.

Follow-up: median 3 months

There was 0% incidence of rectal toxicity versus 30% in historical controls (p=0.04). In the HA spacer group, the mean rectal radiation dose V70 Gy was 4% (73Gy) compared with 25% (106 Gy) in the control group (p=0.005) without the spacer.

Included in systematic review added.

Wilder RB, Barme GA et al (2010). Cross-linked hyaluronan gel improves the quality of life of prostate cancer patients undergoing radiotherapy. Brachytherapy.

Case series with contemporary controls

n=30 had cross-linked hyaluronan gel before brachytherapy and IMRT.

controls n=5 without spacer

Follow-up: median 5 months

Acute GI related quality of life: results showed that EPIC bowel bother scores did not change (0±3) pre versus post-treatment for the patients who had implanted pre-radiotherapy (n=30) but scores declined by 11±14 for those who did not have the intervention (p=0.03).

Larger studies with longer follow-up included.

Wei B, See A, El-Hage L et al (2016). Dosimetric and clinical effects of hydrogel insertion in patients receiving dose-escalated prostate radiotherapy: Interim analysis of a phase II trial. Journal of Medical Radiation Sciences (63) 37.

Case series

N=42 men with histologically confirmed adenocarcinoma of the prostate.

Insertion of a hydrogel into the retro prostatic space undergoing dose-escalated prostate radiotherapy.

Increased perirectal space in post hydrogel scans resulted in improvement in rectal dosimetry in all patients. Our early results demonstrated that dose escalation and rectal sparing can be achieved with the application of hydrogel.

Larger and longer follow-up studies included.

Wolf F, Gaisberger C et al (2015). Comparison of two different rectal spacers in prostate cancer external beam radiotherapy in terms of rectal sparing and volume consistency. Radiotherapy & Oncology 116 (2) 221-225.

Comparative case series

N=78 (30 spacer gel group versus 29 balloon spacer group versus 19 control group) patients with prostate cancer.

Total dose was 75.85 Gy in daily fractional doses of 1.85 Gy prescribed to the 95% isodose using multisegmental 7-field and shoot IMRT.

Follow-up 6 months.

Both spacer systems significantly reduced the rectum surface encompassed by the 95% isodose (gel: -35%, p<0.01; balloon -63.4%, p<0.001) compared to a control group. The balloon spacer was superior in reducing rectum dose (-27.7%, p=0.034), but exhibited an average volume loss of >50% during the full course of treatment of 37-40 fractions, while the volume of gel spacers remained fairly constant.

Study included in systematic review added.

Wu SY, Boreta L, Wu A et al. (2018) Improved rectal dosimetry with the use of SpaceOAR during high-dose-rate brachytherapy. Brachytherapy. 17(2):259-64.

Cohort study

N=18 patients with prostate cancer had HDR brachytherapy and underwent transperineal ultrasound-guided placement of 10 cc of SpaceOAR hydrogel.

Then compared with 36 patients treated with HDR brachytherapy without SpaceOAR.

Follow-up 13.3 months.

Patients who received SpaceOAR hydrogel had significantly lower dose to the rectum as measured by percent of contoured organ at risk (median, V80 ! 0.005% vs. 0.010%, p 5 0.003; V75 ! 0.005% vs. 0.14%, p ! 0.0005; V70 0.09% vs. 0.88%, p!0.0005; V60 5 1.16% vs. 3.08%, p!0.0005); similar results were seen for rectal volume in cubic centimetres. One patient who received SpaceOAR developed a perineal abscess 1 month after treatment.

Included in systematic review added.

Yang Y, Ford EC et al (2013).An overlap-volume-histogram based method for rectal dose prediction and automated treatment planning in the external beam prostate radiotherapy following hydrogel injection.

Medical Physics.40 (1) (no pagination)

Case series

n=21 prostate cancer patients

Treatment planning both pre and post hydrogel injection with 5 field IMRT.

Application of the predicted rectum and bladder doses to automated planning produced acceptable treatment plans, with rectal dose reduced for eight of ten plans. The OVH metric can predict the rectal dose in the external beam prostate radiotherapy for patients with hydrogel injection. The predicted doses can be applied to the objectives of optimization in automated treatment planning to produce acceptable treatment plans.

Treatment planning study. Overlap volume histogram for rectal dose prediction evaluated.

Yang DX, Verma V, An Y et al (2020) Radiation dose to the rectum with definitive radiation therapy and hydrogel spacer versus postprostatectomy radiation therapy. Advances in Radiation Oncology, 5, 1225-1231

Retrospective analysis

N=51 patients with prostate cancer who underwent RT with a hydrogel spacer (n=16) versus postoperative RT (n=35)

Follow-up not reported.

Rectal dosimetry is more favourable for definitive RT (79.2 Gy) with a hydrogel spacer compared with postoperative RT (70.2 or 66.6 Gy).

Larger studies included.

Yeh J, Tokia K et al (2015). Rectal Spacer Injection in Postprostatectomy Patients Undergoing High-Dose Salvage External Beam. Oncology April (P141)

Case series

n=32 patients who have had a prostatectomy and had high-dose (>72 Gy) salvage IRMT with the rectal spacer –

Follow-up: 6 months

At the end of treatment, 23 patients (72%) had no change in rectal symptoms. Nine patients (28%) developed grade 1 gastrointestinal (GI) toxicity. No patients developed grade ≥ 2 GI toxicity. At 6 months after treatment, 29 patients (91%) were back to their baseline GI function, with only 3 patients (9%) with residual grade 1 GI toxicity. No patients developed grade ≥ 2 GI toxicity.

Poster presentation. Safety events reported.

Yeh J, Lehrich B et al (2016). Polyethylene glycol hydrogel rectal spacer implantation in patients with prostate cancer undergoing combination high-dose-rate brachytherapy and external beam radiotherapy. Brachytherapy 15(3):283-287.

Case series

N=326 prostate carcinoma patients had high-dose-rate brachytherapy 16 Gy and external beam radiotherapy of 59.4 Gy plus injected with 10 ml of a PEG hydrogel.

Follow-up median 16 months

The mean anterior-posterior separation achieved was 1.6 cm (SD = 0.4 cm). Rates of acute Grade 1 and 2 rectal toxicity were 37.4% and 2.8%, respectively. There were no acute Grade 3/4 toxicities. 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. PEG rectal spacer implantation is safe and well tolerated. Acute and chronic rectal toxicities are low despite aggressive dose escalation.

Included in systematic review added.

Zelefsky MJ, Pinitpatcharalert A, Kollmeier M, et al. Early tolerance and tumor control outcomes with high-dose ultrahypofractionated radiation therapy for prostate cancer. European Urology Oncology. 2019; doi: https://dx.doi.org/10.1016/j.euo.2019.09.006

Case series (retrospective)

N=551 patients with low- or intermediate-risk prostate cancer were treated with 37.5–40 Gy SBRT in 5 fractions.

85% (471/551) received 40 Gy in 8 fractions.

Follow-up 17 months

SBRT

Acute grade 2 gastrointestinal (GI) toxicities occurred in 1.8% of patients, and late grade 2 and 3 GI toxicities were observed in 3.4% and 0.4% of patients, respectively. Acute grade 2 genitourinary (GU) toxicities occurred in 10% of patients, and grade 3 acute GU toxicities were observed in 0.7% of patients. Late grade 2 and 3 GU toxicities were observed in 21.1% and 2.5% of patients, respectively. The use of a hydrogel rectal spacer was significantly associated with reduced late GI toxicity and lower odds of developing late GU toxicity. The median follow-up was 17 months, and 53% of those with at least 2 years of follow up (103/193) had a biopsy performed. The 5-yr cumulative incidence of PSA failure was 2.1%, and the incidence of a positive 2-yr treatment biopsy was 12%. Limitations to this report include its retrospective nature and short follow-up time.

Included in systematic review added.

Zhang H, Wang L, Riegel AC et al. (2022) Biological effective dose in analysis of rectal dose in prostate cancer patients who underwent a combination therapy of VMAT and LDR with hydrogel spacer insertion. Journal of applied clinical medical physics. e13584

Retrospective analysis

Prostate cancer patients who underwent a combination of volumetric modulated arc therapy (VMAT) and low-dose-rate (LDR) brachytherapy

(35 with hydrogel spacer and 30 with no spacer)

Our result suggested a significant reduction of rectal doses in those patients who underwent a combination of VMAT and LDR with hydrogel spacer placement.

Dosimetry impact analysis.

Larger studies with longer follow-up included.