Depth of Hydrogel Spacer Rectal Wall Infiltration Was Not Associated With Rectal Toxicity: Results From a Randomized Prospective Trial

Abstract

Purpose

Rectal spacers have gained popularity as a dose-sparing material for prostate cancer radiation therapy (RT). However, the procedure can be associated with unintended rectal wall infiltration (RWI) of the spacer gel. We therefore classified RWI severity as a function of depth and explored its association with rectal toxicity using a data set from prostate cancer patients treated with RT on a prospective randomized clinical trial (RCT).

Methods and Materials

Postimplant T2-weighted magnetic resonance images of 149 subjects randomized to the hydrogel spacer arm of a published multicenter RCT were assessed for the presence and depth of RWI. All implants were assigned a score of 0 (no rectal wall signal changes), 1 (rectal wall edema/signal change), 2 (partial RWI), or 3 (full-thickness RWI); RWI was defined as a score of 2 or 3. Correlations were made between RWI score and physician-reported procedure, acute, and late rectal toxicity.

Results

Although 62.4% of implants had no rectal wall signal abnormalities, 24% [scores of 2 (20.1%) and 3 (4.0%)] of procedures exhibited radiographic evidence of RWI. Full-thickness RWI was associated with both a longer length (22.8 ± 7.0 mm, P = .008) and a larger circumferential percentage (35.8% ± 9.2%, P = .045) of rectal infiltration. Although 7 subjects (5%) experienced transient procedure-related rectal toxicities (most commonly perineal/rectal pain), only one had RWI (score of 2, National Cancer Institute's Common Terminology Criteria for Adverse Events grade 1). Consequently, no correlation was observed between procedural rectal toxicity and the presence/extent of RWI (P = .64). Similarly, no difference in acute (P = .64) or late (P = .85) rectal toxicity incidence or grade was detected between RWI categories; none of the 6 men with a RWI score of 3 developed late rectal toxicity by 15 months.

Conclusions

Based on data from an RCT, RWI did not contribute to increased rectal toxicity prior and up to 15 months after conventional prostate cancer RT.

Introduction

With the recognition that higher biologically effective radiation doses lead to superior biochemical control of prostate cancer,¹ strategies have been fashioned to improve sculpting of doses around the prostate gland and mitigate incidental radiation to neighboring radiosensitive organs such as the rectum. Biodegradable rectal spacers have become adopted into practice owing to their ability to displace the rectum away from the tumoricidal radiation doses targeting the prostate gland. This, in turn, manifests as reduced physician-reported rectal toxicity and smaller declines in patient-reported bowel quality of life, as established in 3 multi-institutional randomized controlled trials (RCTs) of prostate cancer patients treated with image-guided intensity modulated radiation therapy (RT) with or without a rectal spacer.2, 3, 4 Besides this clinical benefit, rectal spacers appear to be cost effective for prostate cancer patients undergoing external beam RT in the United States⁵ and Europe.⁶

Although placement of a rectal spacer is typically well-tolerated without long-lasting sequelae, some have called into question its true benefit and safety.⁷ A review of adverse events associated with the hydrogel rectal spacer reported to the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database identified 25 patient cases between 2015 and 2019, some with such level III (severe) and IV (life-threatening) complications as perineal or prostatic abscess, rectal fistula, rectal ulcer, colostomy, urosepsis, and severe anaphylaxis.⁸ With heightened popularity of the hydrogel rectal spacer in community practice, an updated query of the MAUDE database through 2022 cited a total of 574 cases of adverse events; this was primarily attributed to an improperly implanted spacer.⁹ Interestingly, most of these inadvertent placements were ascribed to injection of the gel into the rectal wall, termed rectal wall infiltration (RWI), which was only symptomatic in 28% of cases. Although the incidence of adverse events still appears to be exceptionally low, given the widespread use of the Food and Drug Administration-approved hydrogel spacer (SpaceOAR) in 280,000 patients as of 2023,¹⁰ some claim that the anonymous voluntary reporting by health care providers to the MAUDE database may underestimate the real-world complication rate.

Attempts have been made to describe the quality of the rectal spacer implant,11, 12, 13 of which only 1 group designed a metric that was associated with late rectal toxicity following prostate RT.¹⁴ However, none of these instruments included such procedural complications as RWI in their evaluation system, which should also be accounted for when characterizing the quality of a rectal spacer implant, given its serious potential clinical implications. An effort was made to create a semiqualitative RWI scoring system,¹¹ which was applied retrospectively to the 149 men randomized to the rectal spacer arm of the phase 3 RCT evaluating the clinical and dosimetric impact of the hydrogel spacer.² However, they were unsuccessful at demonstrating a correlation with toxicity in the 6% of subjects with variable degrees of RWI based on the percentage of involved rectal wall circumference. This lack of association can be possibly explained by the metric's failure to account for the depth of gel penetration into the 4 layers of the rectal wall; one would expect a greater likelihood of injury to the highly proliferative mucosal epithelium and stem cells with deeper infiltration of the gel, which would manifest with clinical symptoms.

We therefore characterized the depth of hydrogel rectal spacer RWI in the same prospective cohort of prostate cancer patients treated with conventional RT in the previously published RCT.² An expert genitourinary radiologist, blinded to study details and outcomes, evaluated and scored RWI on the postimplant T2-weighted magnetic resonance (MR) images, and subsequent associations with rectal sequelae were examined.

Materials and Methods

Patient cohort

A secondary analysis was conducted on 149 men with low- and intermediate-risk prostate cancer who were randomized to the hydrogel rectal spacer arm of a 20-center phase 3 trial.² All were treated with image-guided intensity modulated RT to a dose of 79.2 Gy in 1.8 Gy daily fractions prescribed to ≥98% of the planning target volume (PTV) and 100% of the clinical target volume (CTV), delivered 5 days weekly to the prostate with or without the seminal vesicles. Prior to RT, the hydrogel rectal spacer was inserted transperineally under ultrasound guidance into the perirectal space between Denonvilliers’ fascia and the anterior rectal wall by users credentialed by the study sponsor.

As previously described,³ MR imaging (MRI) of the pelvis was performed preimplantation, and then, 5-10 days following the spacer procedure, the latter was used for treatment planning and for the purposes of this secondary analysis. Subjects were followed weekly during RT, and at 3, 6, 12, and 15 months postenrollment. Physician-reported adverse events attributed to RT were documented using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and reviewed centrally by an independent Clinical Events Committee who was blinded to randomization. Because the aim of this secondary analysis was to assess complications ensuing from the depth of iatrogenic breachment of the rectal wall by the hydrogel spacer, only rectal toxicities were considered. Rectal adverse events were classified as “procedure-related” toxicities if they transpired prior to initiation of RT, “acute” if they developed within 90 days of the implant procedure, and “late” if they occurred after 90 days from enrollment through the 15-month follow-up visit. Consequently, the total number of procedural-related rectal toxicities was reduced from the 15 men reported in the original RWI publication of this cohort¹¹ to only 7 subjects who were deemed to have genuine rectal adverse events (ie, omitting such toxicities as flatulence, tachycardia, and hematospermia). Deidentified data, including MRIs, were provided by the study sponsor (XXXX) under a data transfer agreement, and all attempts to ensure data integrity were maintained.

Derivation of hydrogel RWI metric

In all 149 subjects who had an implanted rectal hydrogel spacer, transverse T2-weighted MR images were reviewed in correlation with other multiplanar MR images (when available) by an expert genitourinary cancer radiologist (OA) who was blinded to subject demographic and adverse event data. RWI was delineated based on the following categorical scoring system illustrated in Fig. 1: “0” represented no rectal wall signal changes; “1” denoted rectal wall edema/signal changes, but no breaching of the rectal wall; “2” indicated disruption of the outer T2 hypointense muscularis propria layer (ie, partial infiltration of the rectal wall); and “3” was designated as a disturbance of the inner mildly T2 hyperintense mucosa and submucosa (ie, full-thickness infiltration into all 4 rectal wall layers). A RWI score of 2 or 3 was defined as the existence of RWI, whereas a score of 1 was attributed to reactive changes of the outer rectal wall because of presumed trauma from the implant procedure. In the case of equivocal full-thickness RWI because of poor image quality, the radiologist chose a conservative approach and assigned a score of 2. When present, the degree of both partial or full-thickness RWI was further described by measuring the length and circumferential percentage (reported in 5% increments) of the involved rectal wall in the transverse plane.

Figure 1.

Representative T2-weighted magnetic resonance (MR) images of a hydrogel spacer implant RWI score of (A) 0, (B) 1, (C) 2, (D) 3 (axial), and (E) 3 (sagittal).

Statistical analysis

Using standard procedures, we computed descriptive statistics, including median and ranges for continuous parameters, as well as percentages and frequencies for categorical variables. Correlations of the RWI score with hydrogel spacer procedure attributes or toxicity outcomes of the 149 subjects were explored using Kruskal-Wallis tests for continuous factors and Fisher exact tests for categorical factors. Ordinal univariable logistic regression modeling was implemented to evaluate the association between the independent variable, RWI score, and ordered categorical dependent variables. All statistical computations were performed and generated using STATA software version 18.0 (StataCorp LLC).

Results

Although the majority (62.4%, n = 93) of the 149 men with a hydrogel spacer did not have any rectal signal changes on T2-weighted MRIs (score of 0) performed within 5 to 10 days after the implant (Table 1), 20.1% (n = 30) and 4.0% (n = 6) exhibited radiographic changes consistent with RWI (defined as RWI scores of 2 and 3, respectively); the remaining 13.4% had radiographic findings suggestive of inflammatory changes without gel infiltration into the rectal wall (score of 1). Ninety-seven percent of the subjects with RWI (categories 2-3) had a component of involvement at the level of the prostate mid-gland (Table 2).

Table 1.

Rectal wall infiltration score

Category	Description	Frequency (%)
0	No rectal wall signal changes	93 (62.4%)
1	Rectal wall edema/signal change	20 (13.4%)
2	Partial infiltration of rectal wall	30 (20.1%)
3	Full-thickness infiltration of rectal wall	6 (4.0%)

Table 2.

Location of rectal wall infiltration (scores 2-3) relative to prostate gland

Location of RWI	Frequency (%)
Base	1 (2.8%)
Base to Mid-gland	12 (33.3%)
Base to Apex	4 (11.1%)
Mid-gland	8 (22.2%)
Mid-gland to Apex	11 (30.6%)

As Table 3 reveals, men with a RWI score of 3 had a much longer length of disrupted rectum (22.8 ± 7.0 mm, P = .008) compared with categories 2 (14.1 ± 4.5 mm) or 1 (15.1 ± 4.5 mm). Similarly, there was a greater percentage of violated rectal circumference in subjects with a category 3 RWI (35.8% ± 9.2%, P = .045) versus categories 2 (24.5% ± 8.5%) or 1 (27.3% ± 9.7%). The size of the prostate did not appear to impact the incidence of RWI.

Table 3.

Associations between rectal wall infiltration score and hydrogel spacer procedure attributes

	RWI score
Parameter*	0 (n = 93; 62.4%)	1 (n = 20; 13.4%)	2 (n = 30; 20.1%)	3 (n = 6; 4.0%)
Prostate volume (mL) (P = .24)
Mean ± SD	46.2 ± 15.2	55.8 ± 19.8	44.7 ± 10.5	44.3 ± 11.7
Median (range)	42.2 (18.5-94.7)	53.2 (24.0-91.7)	42.7 (25.2-80.4)	42.7 (30.1-61.5)
Sagittal length (mm) of involved rectum (P = .008)	N/A
Mean ± SD		15.1 ± 4.5	14.1 ± 4.5	22.8 ± 7.0
Median (range)		15 (8-24)	14 (5-24)	21 (16-36)
Percent (%) affected rectal circumference (P = .045)	N/A
Mean ± SD		27.3 ± 9.7	24.5 ± 8.5	35.8 ± 9.2
Median (range)		25 (10-50)	25 (5-40)	35 (25-50)
Location of RWI relative to prostate (P = .45)	N/A	N/A
Base			1 (3.3%)	0
Base to Mid-gland			10 (33.3%)	2 (33.3%)
Base to Apex			2 (6.7%)	2 (33.3%)
Mid-gland			7 (23.3%)	1 (16.7%)
Mid-gland to Apex			10 (33.3%)	1 (16.7%)
User-rated ease of implant procedure (P = .42)
Very easy	68 (73.1%)	11 (55%)	20 (66.7%)	5 (83.3%)
Easy	23 (24.7%)	9 (45%)	10 (33.3%)	1 (16.7%)
Difficult	2 (2.2%)	0	0	0

Abbreviation: SD = standard deviation.

^⁎Kruskal-Wallis or Fisher exact test, or overall ANOVA.

To gauge whether the depth of RWI was associated with rectal toxicity, the relationships between rectal adverse events and RWI categories were examined (Table 4). Although 7 of the 149 subjects (5%) had procedure-related rectal toxicity, only one of them had genuine RWI (RWI score of 2, with a grade 1 CTCAE toxicity). Four of the 7 men with a procedure-related rectal adverse event had a RWI score of 0, implicating the lack of correlation (P = .64) between rectal toxicity and presence/extent of RWI. Perineal/rectal pain was the most frequently reported procedure-related rectal toxicity (6 of 7 men), with rectal bleeding reported in just 1 subject. The worst procedure-related rectal adverse event had a CTCAE grade of 2 (observed in 3 of 7 subjects). Although 4 of the 7 men with procedural-related rectal toxicity continued to experience acute rectal toxicity during RT, these rectal toxicities did not translate into late rectal adverse events; all 7 men had resolution of their rectal toxicity within 90 days of the implant procedure.

Table 4.

Relationship between rectal wall infiltration score and rectal toxicity

	RWI score
Outcome*	0	1	2	3
Procedure-related rectal toxicity
Presence of procedure-related rectal toxicity (P = .64)
No	89 (95.7%)	18 (90%)	29 (96.7%)	6 (100%)
Yes	4 (4.3%)	2 (10%)	1 (3.3%)	0
Procedural-related rectal toxicity event type (P = .65)
Rectal bleeding	1 (25%)	0	0	0
Perineal/rectal pain	3 (75%)	2 (100%)	1 (100%)	0
Procedure-related rectal toxicity CTCAE grade (P = .63)
0	89 (95.7%)	18 (90%)	29 (96.7%)	6 (100%)
1	2 (2.2%)	1 (5%)	1 (3.3%)	0
2	2 (2.2%)	1 (5%)	0	0
Day of procedure-related rectal toxicity relative to implant (P > .9)				N/A
Mean ± SD	1 ± 0	1 ± 0	1
Median (range)	1 (1-1)	1 (1-1)	1
Duration (days) of procedure-related rectal toxicity (P = .11)				N/A
Mean ± SD	4 ± 2.9	52 ± 53.7	7
Median (range)	4 (1-7)	52 (14-90)	7
Acute rectal toxicity	n = 93 (62.4%)	n = 20 (13.4%)	n = 30 (20.1%)	n = 6 (4.0%)
Presence of acute rectal toxicity (P = .64)
No	66 (71.0%)	17 (85%)	21 (70%)	5 (83.3%)
Yes	27 (29.0%)	3 (15%)	9 (30%)	1 (16.7%)
Acute rectal toxicity CTCAE grade (P = .54)
0	66 (71.0%)	17 (85%)	21 (70%)	5 (83.3%)
1	22 (23.7%)	2 (10%)	9 (30%)	1 (16.7%)
2	5 (5.4%)	1 (5%)	0	0
Late rectal toxicity†	n=92 (62.2%)	n=20 (13.5%)	n=30 (20.3%)	n=6 (4.1%)
Presence of late rectal toxicity (P = .85)
No	90 (97.8%)	20 (100%)	29 (96.7%)	6 (100%)
Yes	2 (2.2%)	0	1 (3.3%)	0
Late rectal toxicity CTCAE grade (P = .73)
0	90 (97.8%)	20 (100%)	29 (96.7%)	6 (100%)
1	2 (2.2%)	0	1 (3.3%)	0
2	0	0	0	0
Day of late rectal toxicity relative to implant (P > .9)		N/A		N/A
Mean ± SD	259.5 ± 125.2		180
Median (range)	259.5 (171-348)		180
Outcome of late rectal toxicity (P = .33)
Resolved	2 (100%)	0	0	0
Persistent	0	0	1 (100%)	0
Duration (days) of late rectal toxicity (P > .9)		N/A	N/A	N/A
Mean ± SD	15.5 ± 2.1
Median (range)	15.5 (14-17)

Abbreviations: CTCAE = National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0; SD = standard deviation.

^⁎Kruskal-Wallis, Fisher exact test, or overall ANOVA.

^†One patient from the initial hydrogel rectal spacer cohort was not included in the analysis of late rectal toxicities because of early study withdrawal.

Among the 40 men who developed acute rectal toxicity, 96% had a CTCAE grade of 1 and 4.0% had a CTCAE grade of 2. The presence of an acute rectal adverse event was distributed similarly across RWI categories. All 10 of the acute rectal toxicities occurring in men assigned a RWI score of 2-3 had a CTCAE grade of 1. All 6 men with a CTCAE grade 2 acute rectal toxicity did not appear to have RWI (5 had a RWI score of 0 and one had a RWI score of 1); this subject with a CTCAE grade 2 acute rectal toxicity and category 1 RWI was the only case in the entire cohort of 149 men who had a persistent toxicity that developed immediately following the implant (which resolved within 90 days of the procedure). Only 3 of the 148 men (2.0%) followed up to 15 months from the spacer implant procedure developed a late rectal toxicity (all CTCAE grade 1), reported as rectal bleeding, rectal urgency, and proctitis. Two occurred in men with a RWI score of 0, and one transpired in a subject with a category 1 RWI, further demonstrating no relationship between the presence/severity of RWI and late rectal adverse events.

Discussion

Analyzing the T2-weighted MR images performed 5 to 10 days following hydrogel rectal spacer implantation from a well-conducted RCT, we reported a RWI rate of 24% according to depth of infiltration into the rectal wall. RWI scores of 2 or 3 did not correlate with higher frequencies of physician-reported symptomatic rectal toxicity, whether before the commencement of prostate cancer RT or up to 15 months later. This lack of correlation was similarly observed by others¹¹ in the same patient cohort using involved rectal circumference as the measure of RWI.

We surmise that the lower RWI rate of 6% reported in the prior classification system only considered implants with unequivocal RWI owing to distinct penetration through the entire rectal wall, regardless of the amount of rectal circumference involved. Because we observed greater circumferential involvement in implants with full-thickness RWI, this may account for the differences in RWI rates between studies as we only recorded 4% of implants with a score of 3. Another explanation for the discrepancy in RWI rates may be attributed to those who interpreted the scans: radiation oncologists in the previous publication versus an expert genitourinary radiologist in our study. Because T2-weighted diagnostic MRIs at best can anatomically differentiate the rectal wall into 2 layers using rectum-specific protocols,¹⁵ the variable quality of the postimplant treatment-planning MR images made it frequently challenging for our expert radiologist to interpret. Consequently, the ambiguity in MR signal changes may have been overlooked by the screening radiation oncologists in the original RWI study, thereby leading to lower rates of observed RWI than we report. Likewise, the 46% RWI rates reported in a retrospective review of 395 prostate cancer patients with a hydrogel implant at Johns Hopkins Medical Center¹⁶ may be high, as scans were appraised only by radiation oncologists.

We believe that grading RWI according to whether the gel has penetrated superficially just below the serosa/adventitia versus entirely through all 4 rectal wall layers is a better classification scheme, as the mechanism contributing to rectal injury is likely because of (1) direct tissue damage from leakage of the spacer into the rectal wall layer(s), thereby triggering an inflammatory response, and/or (2) the mechanical pressure of the gel on the mucosal and submucosal layers that results in direct cell death and indirect injury from ischemic changes.¹⁷ It is postulated that with gel infiltration deep into the well-vascularized and cellular-rich submucosal and mucosal layers, vascular injury can ensue and lead to a situation with reversible or irreversible mucosal epithelial damage and submucosal edema.^17,18 Another group speculated that RWI-induced ischemia may arise if the rectal wall vasculature is consequentially displaced toward the prostate and thereby inadvertently exposed to higher radiation treatment doses.¹⁹ Such an ischemic-like colitis from direct vascular and/or tissue injury, mechanical pressure, and/or radiation effects may be asymptomatic or manifest clinically as cramping abdominal pain, tenesmus, rectal bleeding, diarrhea, or in the most severe forms, transmural ulceration/necrosis with rectal perforation, fistulization, peritonitis, and/or sepsis.^18,19

Regardless of the criteria to characterize RWI, the incidence of unintended gel injection into the rectal wall may be underreported in the literature, as few cases are symptomatic or of severe nature.¹⁶ One group observed a reduced likelihood of RWI if the interval between prostate biopsy and spacer placement was greater than 70 days (odds ratio, 0.42), hypothesized to result from improved needle guidance once inflammation from the violated tissue planes has subsided.¹⁶ We were unable to investigate this, as such data were unavailable for our analysis. Although patients with rectal spacers implanted by less proficient users seem to develop more severe adverse events,²⁰ RWI is the most common type of spacer procedural complication irrespective of experience; the majority are asymptomatic.^9,20,21 The infrequent rectal adverse events in our data set are likely, in part, owing to the clinical trial requirement for all participating investigators to have prior experience with transperineal procedures and complete a study-sponsored hydrogel spacer credentialing program before enrolling subjects.^2,4

Out of caution, the typical practice in the case of RWI has been to delay prostate RT until the gel is fully resorbed, and the rectum is completely healed. However, there have been numerous instances in which treatment proceeded despite known20, 22, 23 or retrospectively discovered RWI on MRI.^19,24 As standard practice, we advise routinely performing a postimplant MRI to inspect for misplaced spacers and rectal injury. A straightforward MRI-based RWI classification system such as ours can be implemented into the clinic to evaluate and improve on a user's technique to reduce iatrogenic gel infiltration into the rectum. A published pictorial MR and CT atlas of misplaced rectal spacers²⁵ may be especially helpful to the radiologist and radiation oncologist less familiar with this procedure. In men with postprocedure rectal sequelae and/or a RWI score of 3, we suggest conservative management with serial imaging for approximately 6 months until near complete gel dissolution to minimize causing further treatment-related complications. In those asymptomatic patients postimplant with a RWI score of 0 to 2, proceeding with definitive RT may be considered, as only one of the 36 cases of RWI treated with RT in our study developed a late rectal toxicity.

A strength of this secondary analysis is the use of meticulously collected and unbiased long-term toxicity data that had been previously adjudicated by an independent Clinical Events Committee. Additionally, all men had an MRI performed 5 to 10 days following the implant, providing qualitative radiographic information to characterize RWI and any clinical manifestations prior to initiation of RT. This study is not without its weaknesses. Besides inadequate power owing to infrequent toxicity events and minimal RWI, our findings may lack generalizability outside a clinical trial performed by experienced users of the spacer hydrogel. If complete penetration of the gel into the rectal wall damages the highly cellular and vascular mucosa and submucosa, then the few cases of “severe” (ie, a score of 3) RWI may have contributed to the lack of an association with rectal toxicity. Our conclusions may only be valid for men treated with a conventional course of RT, as moderately or ultrahypofractionated RT may have more of an impact on rectal wall vasculature, thereby resulting in a higher risk of toxicity in the presence of RWI. Furthermore, in those men who received prior pelvic RT or surgery, it is conceivable that ensuing fibrosis could limit the ability to introduce a spacer and therefore result in greater rates of RWI with more frequent and severe complications. Because we did not evaluate the reproducibility of our classification system, we recommend validation by multiple expert genitourinary radiologists using a large data set of diagnostic-quality MR images.

Conclusion

Applying a revised classification system accounting for depth of RWI (which may offer advantages over the originally proposed measure that was based on rectal circumference), we observed hydrogel spacer gel RWI in 24% of men with prostate cancer treated on a multicenter RCT with conventionally fractionated RT; however, none of the RWI cases developed clinically meaningful rectal complications (CTCAE grade 3 or higher). Although patients with RWI did not have increased rates of rectal toxicity in this study data set, caution should still be exercised to avoid the spacer penetrating the rectal wall.