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

Efficacy summary

Placement success

In a prospective multicentre RCT of 222 patients with prostate cancer comparing hydrogel spacer injection (hydrogel, n=148) with no spacer injection as control (n=72) during IG-IMRT, spacer placement success in the spacer group (defined as hydrogel present in the perirectal space) was reported as 99%. Urologists and oncologists rated spacer application as 'easy' and 'very easy' 99% of time (Mariados 2015, Karsh 2018).

In a systematic review and meta-analysis of 7 studies (1 RCT [Mariados 2015] and 6 cohort studies) comparing 486 patients who had a hydrogel spacer with 525 patients who did not have a spacer (controls) before radiotherapy (EBRT, BT with or without EBRT, or combination therapy) for prostate cancer, the hydrogel spacer was successfully placed in 97% (95% CI, 95%-99%) of patients and procedure failure was reported in 3% of patients (data from 5 studies). The reasons for procedure failure include unsuccessful hydrodissection (in 5), inadvertent needle entry into the rectal lumen with no clinical sequelae (in 3), and an unspecified cause (in 1) (Miller 2020).

In a systematic review of 9 studies comparing 671 patients who had hydrogel spacers (of 2 different types) with 537 patients who did not have hydrogel spacers (controls) before brachytherapy for prostate cancer, most studies reported 100% success with hydrogel spacer placement. Procedure failure rate ranged between 4 to 27% (in 12 patients) across 3 studies and was most commonly because of failure of hydrodissection in 9 patients having salvage brachytherapy, unsuccessful hydrodissection of an unknown cause in 1 patient and because of operator inexperience and premature coagulation of the solution during injection in 1 patient. Both these procedures were aborted. There is some slight overlap of studies between the systematic reviews included. (Vaggers 2021).

Perirectal separation distance

In the prospective multicentre RCT of 222 patients, perirectal space (defined as the distance between the posterior prostate capsule and anterior rectal wall on axial mid-gland T2 weighted MRIs) after hydrogel insertion was 12.6±3.9 mm in the spacer group (post application) and 1.6±2.0 mm in the control group respectively (Mariados 2015).

In the systematic review and meta-analysis of 7 studies comparing 486 patients who had a hydrogel spacer with 525 patients who did not have a hydrogel spacer (controls), the pooled results from 5 studies showed that the weighted mean perirectal separation distance was 11.2 mm (95% CI, 10.1 to 12.3 mm) (Miller 2020).

In a HTA report by EUnetHTA on using biodegradable rectal spacers for patients with prostate cancer having curative radiotherapy, they summarise the findings from the RCT (Mariados 2015 with several related studies from the same trial) which reported that the mean perirectal distance (defined as the distance between the posterior prostate capsule and anterior rectal wall on axial mid-gland T2 weighted MRIs) in the hydrogel spacer plus radiotherapy group (n=149) increased by 1.1 cm (from baseline 0.16±0.22 cm to 1.26±0.39 cm after hydrogel insertion and 0.9±0.59 cm at 3 months). Perirectal space in the control group was 1.6±2.0 mm (NIPHNO 2021).

In the systematic review of 9 studies comparing 671 patients who had hydrogel spacers (of 2 different types) with 537 patients who did not have hydrogel spacers (controls) before brachytherapy for prostate cancer, the mean prostate rectum space achieved varied between 7.7 mm to 16 mm in 6 studies that used a variety of techniques to measure the spacing distance (Vaggers 2021).

A systematic review of 11 studies on the use of different rectal spacers during different radiotherapy techniques for prostate cancer reported increased prostate rectum space (ranging from 7 mm to 15 mm with hydrogel spacers in 4 studies, 19.2 mm with biodegradable balloon spacer in 1 study, 13 mm with collagen implant in 1 study, between 9.8 mm to 20 mm with hyaluronic acid in 5 studies) (Mok 2014).

Rectal dose volume

In the prospective multicentre RCT of 222 patients, there was a statistically significant reduction in mean rectal dose volume within the 70 Gy isodose in patients in the spacer group (from baseline, 12.4% to 3.3% after spacer injection, p<0.001) compared with patients in the control group (from baseline, 12.4% to 11.7%) (Mariados 2015).

In the systematic review and meta-analysis of 7 studies comparing 486 patients who had a hydrogel spacer with 525 patients who did not have a hydrogel spacer (controls), at a median follow up of 26 months (range, 3 months to 63 months), the pooled results from 6 studies showed that patients who had the hydrogel spacer before EBRT had 66% less v70 rectal irradiation compared with controls (3.5% versus 10.4%; MD, ‑6.5%; 95% CI, ‑10.5% to ‑2.5%; p = 0.001) (Miller 2020).

In the HTA report by EUnetHTA on using biodegradable rectal spacers for patients with prostate cancer having curative radiotherapy, a RCT (n=220, with 5 companion studies from the same trial) reported that the proportion of patients in the hydrogel spacer plus radiotherapy group who had more than 25% reduction in rectal volume having an isodose of 70 Gy (rV70) was 97%. There was a statistically significant reduction in mean rectal dose volume within the 70 Gy isodose in patients in the spacer group (from 13% at baseline to 3% after spacer injection, p<0.001) compared with patients in the control group (from 13% at baseline to 12%). A nRCT included in the HTA also reported that hydrogel plus radiotherapy (n=29) and balloon spacer plus radiotherapy (n=30) may be effective in reducing the dose to the rectum when compared with radiotherapy alone (n=19), but the evidence is uncertain (p<0.001). Balloon spacer was superior in reducing rectum dose (‑28%, p=0.034) but exhibited an average volume loss of more than 50% during the full course of treatment of 37 to 40 fractions, while the volume of gel spacers remained fairly constant (NIPHNO 2020).

A systematic review of 19 studies (1 RCT, 18 nRCTs; with 3,622 patients) comparing patients who had a perirectal hydrogel spacer with patients who did not have a spacer (controls) across all types of radiotherapy for prostate cancer reported that rectal dose decreased significantly across 13 nRCTs in the hydrogel spacer group regardless of the type of radiotherapy used (all 5 EBRT studies, 1 HDR BT alone, 7 BT plus EBRT studies) and for all dosimetry outcomes (for example, V40 average difference ‑6.1% in high dose-rate brachytherapy plus IG-IMRT [Chao 2019] to ‑9.1% in IG-IMRT [Whalley 2016]). The RCT (Mariados 2015) also showed that hydrogel spacer reduces rectal radiation dose (Armstrong 2021).

In the systematic review of 9 studies comparing 671 patients who had hydrogel spacers (of 2 different types) with 537 patients who did not have hydrogel spacers (controls) before brachytherapy for prostate cancer, the rectal D2 cc was reduced in the spacer group by between 22% and 53% and the median rectal V75% cc was reduced by between 92% to 100% (Vaggers 2021).

A systematic review of 11 studies on using different rectal spacers during different radiotherapy techniques for prostate cancer reported that the mean rectal dose reduced in spacer group when compared with no spacer regardless of dose (with hydrogel spacers, hyaluronic acid) and when comparing preimplantation plans with postimplantation plans (with collagen implants, biodegradable balloons) (Mok 2014).

Rectal and urinary tract toxicity

In the prospective multicentre RCT of 222 patients, acute rectal toxicity was similar between the spacer and control groups (p=0.525), as was urinary tract toxicity (p=0.488). There was statistically significantly less rectal toxicity at 3 to 15 months in patients with a spacer (2% of patients: grade 1 events rectal bleeding, rectal urgency and proctitis, each in 1 patient) compared with patients in the control group (7% of patients: grade 1 events rectal bleeding in 3, rectal urgency in 1 and grade 3 proctitis in 1; p=0.04). There was no late rectal toxicity greater than grade 1 in patients in the spacer group¹. The 3-year incidence of rectal toxicity greater than grade 1 (2.0% versus 9.0%; p=0.28) and greater than grade 2 (0% versus 5.7%; p=0.012) was lower in the spacer group than control group. Urinary toxicity greater than grade 1 was also lower in the spacer arm (4% versus 15%; p=0.046), with no difference in greater than grade 2 urinary toxicity (7% versus 7%; p=0.7) (Mariados 2015, Hamstra 2017).

In the systematic review and meta-analysis of 7 studies comparing 486 patients who had a hydrogel spacer with 525 patients who did not have a rectal spacer (controls), pooled results from 6 studies showed that the risk of early grade 2 or higher rectal toxic effects (at 3 months follow up) was comparable and not statistically significantly different between the hydrogel spacer and control groups (5% versus 4%; RR, 0.82; 95% CI, 0.52 to 1.28; p =0.38). However, in a pooled analysis of 4 studies, at late follow up (median, 38 months; range, 28 to 60 months) the risk of grade 2 or higher rectal toxic effects was lower in the hydrogel spacer group compared to controls (2% versus 6%; RR, 0.23; 95% CI, 0.06 to 0.99; p = 0.05). Another pooled analysis showed that the risk of grade 1 or higher rectal toxic effects was lower in patients treated with the hydrogel spacer compared to controls at early follow-up (21% versus 30%; RR, 0.72; 95% CI, 0.58 to 0.91; p =0.005; 7 studies]; and at late follow-up (median, 40 months; range, 28-60 months) (5% versus 16%; RR, 0.38; 95% CI, 0.22 to 0.65; p < 0.001; 5 studies]; (Miller 2020).

The HTA report by EUnetHTA on the use of biodegradable rectal spacers for patients with prostate cancer receiving curative radiotherapy included 2 prospective comparative studies (1 RCT [Mariados 2015 with 5 related studies, a registry record from the same trial and 1 nRCT) that assessed rectal and urinary or genitourinary toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE). In the RCT (220 patients) the risk of early grade 1 rectal toxicity (at 3 months follow up) was not statistically significantly different (RR 0.77, 95% CI 0.50 to 1.19) and the risk of grade 2 or greater rectal toxicity was also not statistically significantly different (RR 0.91, 95% CI 0.23 to 3.5) in the hydrogel spacer group compared with control group. No grade 3 or 4 toxicities were reported in the spacer group but 1 grade 3 toxicity were reported in the radiotherapy alone group. The risk of grade 1 urinary toxicity and the risk of developing grade ≥2 urinary toxicity were also not statistically significantly different (RR 1.03, 95% CI 0.87 to 1.21, p=0.74 and RR 0.97, 95% CI 0.81 to 1.18, p=0.79, respectively). No grades 3 or 4 were reported.

The risk of late grade 1 rectal toxicity (at 15 months follow up) was not statistically significantly different (RR 0.34, 95% CI 0.08 to 1.48). There was 1 grade 3 case in the radiotherapy alone group and no grades 2 or 4 were reported. At 15 months, the risk of late grade 1 urinary toxicity and the risk of late grade 2 or greater urinary toxicity were also not statistically significantly different (RR 0.65, 95% CI 0.15 to 2.85, p=0.57 and RR 1.57, 95% CI 0.44 to 5.53, p=0.47, respectively). No grade 3 or 4 urinary toxicities were reported.

The cumulative evidence (acute and late rectal toxicity, at a median follow-up of 3 years, n=140), suggests that patients in the hydrogel spacer plus radiotherapy group were less likely to present grade 1 rectal toxicity than the radiotherapy alone group (HR 0.24, 95% CI 0.06 to 0.97, p<0.03). The HR was not presented for grades ≥2. There was 1 case of grade 3 toxicity in the radiotherapy alone group, and no cases of grade 4 reported. The difference between the groups for grade 1 urinary toxicity was HR 0.36, 95% CI 0.12 to 1.1, p=0.046 and for grade ≥2 urinary toxicity was HR 1.22, 95% CI 0.40 to 3.72, p=0.7.

In the nRCT at 3 months follow up, the risk of developing grade 1 rectal toxicity was not statistically significantly different in the radiotherapy alone group when compared with hydrogel spacer plus radiotherapy group (RR 1.58, 95% CI 0.34 to 7.60, p=0.55) or balloon plus radiotherapy group (RR 1.64, 95% CI 0.35 to 7.60, p=0.52). The risk of developing grade 2 GU toxicity was not statistically significantly different in the radiotherapy alone group (RR 1.39, 95% CI 0.57 to 3.38, p=0.46) or in the balloon plus radiotherapy group (RR 0.78, 95% CI 0.28 to 2.22, p=0.64). compared to hydrogel spacer plus radiotherapy group No grades 3 or 4 were recorded (NIPHNO 2020).

The systematic review of 19 studies (1 RCT, 18 comparative nRCTs, with 3622 patients) comparing patients who had a perirectal hydrogel spacer with patients who did not have a spacer (controls) across all types of radiotherapy for prostate cancer reported that GI and GU toxicities reduced but were not statistically significantly different in the hydrogel spacer plus radiotherapy group across 7 included nRCTs regardless of the type of radiotherapy used (5 EBRT studies, 1 HDR BT plus IG-IMRT study [Chao 2019], and 1 LDR BT alone or in combination with EBRT [Taggar 2018]). The RCT (Mariados 2015) included also showed that hydrogel spacer plus radiotherapy significantly reduced late GI and GU toxicities. (Armstrong 2021).

In the systematic review of 9 studies comparing 671 patients who had hydrogel spacers (of 2 different types) with 537 patients who did not have hydrogel spacers (controls) before brachytherapy for prostate cancer, acute GI complications were mainly limited to grade 1 or 2 toxicity. One study (Chao 2019) on HDR BT with EBRT found a significantly lower rate of grade 1 acute GI complications in the spacer group compared with control group (13% versus 31%, p=0.05) but no statistically significant difference in grade 2 acute GI complications (0% versus 2%, p=0.48). Late grade 1 GI toxicity was less in the spacer group compared to control group (0% versus 8%, p=0.11). No late grade 2 or 3 GI toxicities were seen. In another case-control study (Taggar 2018), at a median follow up of 3 months, grade 1 or 2 rectal or GI toxicity was seen in 20% (n=15) patients in the spacer cohort and 24% (n=33) patients in the non-spacer cohort (p= 0.95) (Vaggers 2021).

Quality of life

In the prospective multicentre RCT of 222 patients, at 15‑month follow up, 12% of patients in the spacer group and 21% of patients in the control group reported a 10-point decline (p=0.087) in bowel quality-of-life scores (assessed using the Expanded Prostate Cancer Index Composite self-assessment questionnaire)¹. Bowel QoL consistently favoured the spacer group from 6 months (p=0.002), with the difference at 3 years (5.8 points; p<0.05) meeting the threshold for a minimally important difference (MID, 5 points). At 3 years, more patients in the control group than in the spacer group had experienced a MID decline in bowel QoL (5 point decline: 41% versus 14%; p=0.002; OR 0.28, 95% CI 0.13- 0.63) and even large declines at twice the MID (10 point decline: 21% versus 5%, p=0.02, OR 0.30, 95% CI 0.11-0.83) (Mariados 2015, Hamstra 2017).

At 6‑month follow up, 9% of patients in the spacer group and 22% of patients in the control group reported 10-point decline in urinary QoL scores (p=0.003). At 12- and 15‑month follow up, the declines in urinary QoL scores were similar for both groups¹. At 3-year follow up, the control group had a 3.9-point greater decline in urinary QoL compared with the spacer group (p<0.05), but the difference did not meet the MID threshold (6 points). At 3 years, more patients in the control group than in the spacer group had experienced a MID decline in urinary QoL (6 point decline: 30% versuse 17%; p=0.04; OR 0.41, 95% CI 0.18 to 0.95) and even large declines at twice the MID (12 point decline: 23% versus 8%; p=0.02; OR 0.31, 95% CI 0.11 to 0.85) (Mariados 2015, Hamstra 2017).

In the systematic review and meta-analysis of 7 studies comparing 486 patients who had a hydrogel spacer with 525 patients who did not have a spacer (controls), pooled analysis of 2 studies showed that changes in bowel-related QoL were similar between the 2 groups at 3-month follow up (MD, 0.2; 95% CI, ‑3.1 to 3.4; p = 0.92). At late follow up (median, 48 months; range, 36 to 60 months), the changes showed an improvement in QoL in the hydrogel spacer group and exceeded the threshold for a minimal clinically importance difference (MD, 5.4; 95% CI, 2.8 to 8.0; p <0.001) (Miller 2020).

In the HTA report by EUnetHTA, a RCT (Mariados 2015) that assessed QoL according to the EPIC 50 item scale (in which higher values indicate better QoL) and summarised on 3 domains (bowel, urinary, and sexual QoL) reported that the proportions of patients experiencing minimally important differences (declines) in all three QoL summary domains at 36 months were 2.5% with hydrogel spacer plus radiotherapy group compared with 20% in radiotherapy group (p=0.002). Results also indicate that hydrogel spacer plus radiotherapy group may improve bowel QoL (p=0.002), may have little to no effect on urinary QoL (p=0.13) over the entire follow-up period (n=140) but the evidence is uncertain (NIPHNO 2021).

The systematic review of 19 studies (1 RCT, 18 comparative nRCTs, with 3622 patients) comparing patients who had a perirectal hydrogel spacer with patients who did not have a spacer (controls) across all types of radiotherapy for prostate cancer reported that improvements were seen after perirectal spacer implantation in most EPIC QoL domains across 4 nRCTs but not statistically significant (in 3 EBRT studies with up to 60 months follow up). For example, in 1 study with EBRT plus LDR BT, bowel function score decreased at 3 and 6 months: average change of 0 versus ‑6.25 and ‑3.57 respectively. Another included study reported clinically meaningful differences in EPIC–bowel bother scores at 18 and 60 months (6-point and 5-points respectively, p>0.05). The RCT also showed that hydrogel spacer significantly improves urinary, bowel and sexual QoL (MID declines in all 3 QoL domains, p=0.002) (Armstrong 2021).

Spacer absorption

In the prospective multicentre RCT of 222 patients, hydrogel absorption was confirmed at 12 months (on MRI scans) in all the patients in the spacer group, with 2% (3/148) of them having small water density remnant cysts in unremarkable perirectal tissues (Mariados 2015, Hamstra 2017).

The systematic review of 11 studies on using different rectal spacers during different radiotherapy techniques for prostate cancer reported that time to complete absorption is variable among the spacers (with PEG hydrogels and biodegradable balloons reporting complete absorption after 6 months, collagen implants and hyaluronic acid at 12 months) (Mok 2014).

Prostate motion or displacement

In a systematic review of 21 studies evaluating the role of the biodegradable rectal spacers on prostate motion, hydrogel spacer placement (in 4 studies) was not associated with statistically significant changes in prostate motion, compared with no spacer or endorectal balloons but significantly reduces rectal wall doses and GI toxicities. Endorectal balloon (ERB) placement (in 12 studies) significantly decreases intra-fractional prostate motion. This reduces planning target volume (PTV) margins and additional rectal dose sparing. Even with an ERB, inter-fractional prostate displacements are seen. (Ardekani 2021).