Major Complications and Adverse Events Related to the Injection of the SpaceOAR Hydrogel System Before Radiotherapy for Prostate Cancer: Review of the Manufacturer and User Facility Device Experience Database

Abstract

Purpose:

SpaceOAR^® is a Food and Drug Administration-approved hydrogel injection used to create space between the prostate and rectum during prostate radiotherapy. It has shown to significantly reduce the rectal radiation dose with lower rates of rectal toxicity. Despite a high safety performance in initial trials, SpaceOAR remains in early clinical use. Thus, we examined emerging safety reports as the system becomes more widely utilized.

Methods:

We reviewed the SpaceOAR manufacturer website for the safety profile and complications associated with the SpaceOAR hydrogel. We then compared this with reports submitted to the Manufacturer and User Facility Device Experience (MAUDE) database.

Results:

The manufacturer website reported risks including pain, needle penetration, and/or gel injection into a nearby organ or blood vessel, local inflammation, infection, urinary retention, and local rectal injury or symptoms. There were 22 unique reports discussing 25 patient cases in the MAUDE database from January 2015 to March 2019, with an increasing number of reports each year up through 2018. Unique major complications including acute pulmonary embolism, severe anaphylaxis, prostatic abscess and sepsis, purulent perineal drainage, rectal wall erosion, and rectourethral fistula were reported.

Conclusion:

Despite well-documented clinical benefits of the SpaceOAR System, there are a number of severe and debilitating complications recently reported in proximity to gel injection. This highlights the need for further study of device complications in light of its increasing clinical use.

Introduction

Radiation therapy is widely utilized for management of prostate cancer as a primary or salvage/adjuvant modality. Despite advances in radiation technology such as intensity-modulated platforms, inadvertent radiation to vital pelvic structures (e.g., rectum) remains a great concern. Even after implementation, strict rectal dose constraints may not be met in up to 25%, especially with regard to hypofractionated dose-escalation radiotherapy.¹ In recent years, injectable synthetic agents and space-making devices have been developed to increase the distance between the prostate and rectum in an effort to reduce potential rectal toxicity.^2,3

The SpaceOAR^® system (Augmenix, Inc., Bedford, MA) is a Food and Drug Administration (FDA)-approved, absorbable polyethylene glycol hydrogel that is designed to reduce rectal radiation, resulting in improved bowel and genitourinary quality-of-life measures.^4,5

Through a transperineal approach, the SpaceOAR hydrogel is injected under ultrasound guidance into the space between Denonvillier's fascia and the anterior rectal wall. After injection, the liquefied components immediately polymerize to form a hydrogel spacer that remains in place for ∼3 to 6 months before undergoing spontaneous decomposition and natural renal excretion.^1

–5

Randomized trials showed a significant 25% relative reduction in rectal radiation dose and a subsequent significant decrease in grades I to III clinical rectal toxicity as well as improvements in bowel quality of life in short- (15 month) and intermediate-term (3 years) follow-up periods.^4,5 Interestingly, these trials reported no device-related adverse events directly related to hydrogel injection, only transient symptoms such as fullness or tenderness at the site of injection have been described.^4,5 There are only anecdotal reports of rectal complications associated with the injected SpaceOAR hydrogel, with minimal literature supporting the subject.^6,7

Despite a high apparent safety performance in initial studies, SpaceOAR remains in early clinical use. In this study, we examined emerging safety reports as the system becomes more widely utilized.

Methods

We reviewed the SpaceOAR manufacturer website (www.spaceoar.com) for the safety profile and currently accepted complications associated with the SpaceOAR hydrogel. In addition, we queried the Manufacturer and User Facility Device Experience (MAUDE) database for reports associated with SpaceOAR injection-related complications.

The MAUDE database is an FDA-maintained archive for anonymous report of device-related adverse events during procedures. The database is public and may be freely queried with unrestricted access. The terms “SpaceOAR” and “Augmenix” were utilized to search for hydrogel spacer reports within the period of January 2015 to March 2019. Obtained reports were then examined for aspects including potential device malfunction, postmalfunction manufacturer assessment, and potential changes to patient management. All included reports and adverse events were classified and stratified according to the previously established MAUDE complication classification system.⁸

Results

The manufacturer website reported possible adverse events associated with the SpaceOAR injection, including pain, needle penetration, and/or gel injection into the rectum or blood vessel, local inflammation, infection, and local rectal injury or fistula formation. With regard to the MAUDE database, 22 unique reports discussing 25 patient cases were submitted between January 2015 and March 2019.

With each passing year through 2018, the number of cases increased (2015, 1 patient; 2016, 2 patients; 2017, 3 patients; 2018, 14 patients). Table 1 demonstrates all registered adverse events and classifies their severity. Complications ranged from mild (Levels I and II—minimal harm/minor intervention) to severe (Levels III and IV—significant harm/life threatening event).

Table 1.

Adverse Events Related to the Injection of SpaceOAR Device Before Radiotherapy for Prostate Cancer Reported to the Manufacturer and User Facility Device Experience (MAUDE) Database

MAUDE complication level ^a	Year of report	Reported event	No. of patients (n = 25)
I	2015	Venous injection—No sequelae	n = 1
	2017	Venous injection—No sequelae	n = 1
	2017	Tenesmus with air in rectal wall—No sequelae	n = 1
	2018	Venous injection—No sequelae	n = 1
	2018	Rectal wall erosion—No sequelae	n = 1
II	2018	Purulent drainage from perineum requiring antibiotics	n = 1
II	2018	Diagnosed pulmonary embolism requiring anticoagulant	n = 4
III	2016	Perineal abscess requiring drainage	n = 1
	2016	Proctitis requiring colostomy	n = 1
	2017	Rectourethral fistula requiring colostomy	n = 1
	2018	Rectal ulcer and hemorrhage requiring surgery	n = 1
	2018	Perineal abscess requiring drainage	n = 1
	2018	Perirectal fistula requiring surgical intervention	n = 1
	2018	Rectourethral fistula requiring colostomy	n = 1
	2019	Rectourethral fistula requiring colostomy	n = 1
	2019	Perineal abscess requiring drainage	n = 1
	2019	Urinary tract infection and prostatic abscess requiring drainage	n = 1
	2019	Rectourethral fistula requiring colostomy	n = 1
IV	2018	Perineal abscess—subsequent death from alcoholic cardiomyopathy	n = 1
	2018	Severe urosepsis—ICU care	n = 1
	2018	Severe anaphylactic reaction	n = 1
	2019	Dizziness/nausea postprocedure leading to unresponsiveness and death	n = 1

Manufacturer and user facility device experience classification system: Level I (none/mild)—no harm occurring to the patient, Level II (moderate)—harm to the patient requiring minor intervention and deviation from the initial plan but without change in the outcome, Level III (severe)—harm to the patient requiring major/procedural intervention(s) and deviation from the initial plan, Level IV (life threatening)—ICU admission/death.

ICU = Intensive Care Unit.

Surgical intervention was required in 11 patients with infectious complications (i.e., proctitis and abscesses), perirectal fistulae, and significant bleeding from the procedure. In addition, there were two life-threatening complications including serious anaphylactic reaction and an intensive care unit (ICU) admission for sepsis. Unfortunately, two deaths associated with the hydrogel injection were reported as well. In one case, a patient became dizzy and nauseous postprocedure and proceeded to become unresponsive and subsequently died; at the time of the published report, the cause of mortality was still unclear. However, in the other fatality, the death was unrelated to the hydrogel injection and actually was determined to be related to baseline patient comorbidity.

Discussion

Rectal toxicity is one of the major concerns when radiation is considered as primary or salvage treatment for prostate cancer. Radiation-induced proctitis may occur even with low dose pelvic radiation (i.e., early sessions).⁹ The condition typically presents with acute symptoms such as rectal pain, urgency, cramping, and bleeding a few weeks after radiation or with more chronic symptoms, including bloody diarrhea, fistula formation, bowel obstruction, and fecal incontinence 6 to 18 months post-therapy.¹⁰

Prior advances in radiotherapy planimetry such as intensity-modulated or volumetric-modulated templates have offered improved safety profiles by reducing collateral damage.¹¹ Parallel to these developments, there has been an emerging interest regarding the use of rectal/pelvic spacer systems for rectal protection during radiotherapy in recent years.

A retrospective analysis of two commonly used rectal displacement systems (i.e., hydrogel spacer vs endorectal balloon) showed equal efficacy of both modalities for reducing the dose of inadvertent radiation to the rectum.¹² Reducing rectal toxicity is critical as high-grade rectal and genitourinary toxicities remain the main source of costs of complications after pelvic radiation.¹³ To this point, cost analysis studies also documented the cost-effectiveness of rectal protection systems, seemingly further encouraging their application.¹⁴ Spacer administration has been shown to result in adding an average of ∼12 mm prostate-to-rectum distance, accompanied with the reduced rectal dose (>25% in >97% of patients).¹⁵ Furthermore, in a pivotal phase III prospective multicenter randomized controlled trial, the continued benefit of the use of spacer before radiation was shown up to 3 years after radiation therapy; no spacer-related adverse events were reported in this trial (n = 222 subjects).⁴

In contrast to the promising results of these recent studies, our study showed that the use of the rectal spacer may inadvertently be associated with new safety issues. Most notably, major complications (Level III and IV) including severe anaphylaxis, rectourethral fistula, abscess formation, and sepsis were reported (Table 1). Major interventions such as ICU admission, abscess drainage, or diverting colostomy were required for management of these complications. Two specific reports highlighted the deaths of patients undergoing the procedure, although association with the device and/or injected hydrogel is at best unclear. Although the SpaceOAR website does identify many of the direct potential complications, the site does not specifically recognize more severe complications, including the need for secondary procedures, prolonged hospitalization, and reported deaths. Overall, we believe that these findings highlight a discrepancy with previous reported side effects that had only been described as minimal or mild.

Previously, it has been reported that the protective efficacy of spacers may be reduced in certain circumstances. For instance, the presence of extraprostatic extension would be associated with a larger radiation field and/or a higher radiation dose as well as potentially more severe rectal toxicity. In the salvage setting, the presence of scar tissue in the perirectal space after prior radiation, surgery, or cryotherapy may also interfere with uniform and symmetrical placement of the spacer and its subsequent efficacy.^4,5 Most relevant studies examined the use of spacer in the setting of conventional fractioned dose-escalated radiotherapy.^4,5 Understandably, the treatment plan and radiation dose are independent predictors of the collateral energy absorbed by the rectum.¹⁶

Although newer radiotherapy modalities such as stereotactic body radiotherapy, proton therapy, or brachytherapy boost radiation may be associated with a higher treatment efficacy, their rectal toxicities may be difficult to control because of the increased radiation dose.¹⁶ For example, up to 10% of patients undergoing high-dose stereotactic body radiotherapy may eventually have to have a colostomy placed because of associated rectal toxicity.¹⁷

Rectal injuries associated with spacer placement have been reported anecdotally. Among their experience with 55 SpaceOAR injections, Teh et al. reported a case of rectal ulcer documented by sigmoidoscopy 2 months after implementation of brachytherapy seeds and SpaceOAR hydrogel.⁷ Similarly, Klotz et al. reported gel penetration into the rectal submucosa in 1 of 47 patients, leading to a rectal mucosal lesion.⁶ In both circumstances, the patients were managed conservatively. However, in our study of the MAUDE database, we noted more complicated rectal injuries as well requiring further intervention such as colostomy formation.

According to the interdisciplinary consensus statement on the application of hydrogel spacer, currently the main indication for this system is before dose-escalation conventional radiotherapy for low–intermediate risk disease. Regarding locally advanced disease, there is still no consensus currently. Several technical points are indeed offered to help avoid rectal wall erosion: creation of perirectal space before SpaceOAR insertion, limiting the amount of injected hydrogel to 10 mL, and utilizing proper needle angle and direction of entry.¹⁸

Although the role of learning curve may appear to logically play a role for proper insertion of SpaceOAR in the perirectal space, the learning curve may not actually be steep.¹⁹ Te Velde and colleagues showed that at the regional hospital level with low volume SpaceOAR placement per urologist (one procedure per urologist per month), a significantly lower rate of radiation-induced rectal toxicity can be achieved even in their initial cohort of 65 patients.²⁰ Nonetheless, in our study we identified several cases of vascular, rectal, and infectious side effects with varying severity. Thus, both proceduralists and patients should be aware of potential adverse events before administration of the SpaceOAR hydrogel. As SpaceOAR is used more widely in clinical practice, there is a need for rigorous follow-up and documentation of complications for further investigations.

The limitations of this study also deserve mentioning. The inherent shortcomings of the MAUDE database include being reliant on voluntarily reporting of complications (i.e., risk of under-reporting), having limited data about the physician experience and case volume, as well as lacking detailed patient and disease characteristics. As a result, determining the exact culprit for the occurrence of an adverse event (surgeon/facility or device related) is difficult. In addition, certain events (e.g., pulmonary emboli or anaphylactic reactions) may be potentially related to disease process, patient comorbidities, or the injection itself. True incidence of adverse events related to this system is also unknown; therefore, it is still difficult to statistically analyze the risk factors associated with these “seemingly” rare events. Lastly, as the SpaceOAR hydrogel represents a relatively new innovation, further time is required to allow for continued accrual and, therefore, further study of this modality.

Conclusion

As a cost-effective procedure, the use of SpaceOAR system before radiotherapy for prostate cancer can significantly reduce the rate of rectal toxicity. Contrary to most contemporary literature, there are a number of severe and debilitating complications recently reported in association with the hydrogel injection. This study highlights the need for further knowledge about potential rare but serious complications of this procedure.

In addition to enhancing physician training, this information may be useful for optimizing patient selection and counseling. As the adverse event profile continues to be developed, it is essential that potential complications are balanced against the benefits of the procedure to ensure optimal patient outcomes.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Abbreviations Used

References

Berlin

, Di Tomasso

, Ballantyne

, et al. 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, 2017; 11:373–375.

Mahal

, O'Leary

, Nguyen

. Hydrogel spacing for radiotherapy of prostate cancer: A review of the literature. Urol Pract, 2014; 1:79–85.

Quarrier

, Matloubieh

, Wu

. Robot-assisted placement of pelvic tissue expander for radiation after prostatectomy and cystectomy for treatment of prostate cancer biochemical recurrence. Urology, 2019; 124:292–296.

Hamstra

, Mariados

, Sylvester

, 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; 97:976–985.

Mariados

, Sylvester

, Shah

, 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; 92:971–977.

Klotz

, Mathers

, Lazar

, Gagel

. Use of hydrogel as spacer in Denovier's space: Optimization of IMRT radiotherapy of localized prostate cancer. Urologe A, 2013; 52:1690–1697.

Teh

, Ko

, Barr

, Woo

. Rectal ulcer associated with SpaceOAR hydrogel insertion during prostate brachytherapy. BMJ Case Rep, 2014; 2014. pii: bcr2014206931.

Gupta

, Schomburg

, Krishna

, et al. Development of a classification scheme for examining adverse events associated with medical devices, specifically the DaVinci surgical system as reported in the FDA MAUDE database. J Endourol, 2017; 31:27–31.

Bansal

, Soni

, Kaur

, Chauhan

, Kaushal

. Exploring the Management of Radiation Proctitis in Current Clinical Practice. J Clin Diagn Res. 2016 Jun;10(6):XE01–XE06.

10.

PDQ^® Supportive and Palliative Care Editorial Board. PDQ Gastrointestinal Complications. National Cancer Institute, Bethesda, MD, 2018 (Updated 05/09/2018). Available at https://www-cancer-gov/about-cancer/treatment/side-effects/constipation/GI-complications-hp-pdq (Last accessed December, 24 2018).

11.

Bucci

, Bevan

, Roach

3rd . Advances in radiation therapy: Conventional to 3D, to IMRT, to 4D, and beyond. CA Cancer J Clin, 2005; 55:117–134.

12.

Wilton

, Richardson

, Keats

, et al. Rectal protection in prostate stereotactic radiotherapy: a retrospective exploratory analysis of two rectal displacement devices. J Med Radiat Sci. 2017; 64:266–273.

13.

Hutchinson

, Sundaram

, Folkert

, Lotan

. Decision analysis model evaluating the cost of a temporary hydrogel rectal spacer before prostate radiation therapy to reduce the incidence of rectal complications. Urol Oncol, 2016; 34:291.e19–e26.

14.

Vanneste

, Pijls-Johannesma

, Van De Voorde

, van Lin

, van de Beek

, van Loon

, Ramaekers

, Lambin

. Spacers in radiotherapy treatment of prostate cancer: Is reduction of toxicity cost-effective?. Radiother Oncol, 2015; 114:276–281.

15.

Uhl

, Herfarth

, Eble

, et al. Absorbable hydrogel spacer use in men undergoing prostate cancer radiotherapy: 12 month toxicity and proctoscopy results of a prospective multicenter phase II trial. Radiat Oncol, 2014; 9:96.

16.

Price

, Stone

, Stock

. Predictive factors and management of rectal bleeding side effects following prostate cancer brachytherapy. Int J Radiat Oncol Biol Phys, 2013; 86:842–847.

17.

Kim

, Cho

, Straka

, et al. Predictors of rectal tolerance observed in a dose-escalated phase 1–2 trial of stereotactic body radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys, 2014; 89:509–517.

18.

Müller

, Mischinger

, Klotz

, Gagel

, Habl

, Hatiboglu

, Pinkawa

. Interdisciplinary consensus statement on indication and application of a hydrogel spacer for prostate radiotherapy based on experience in more than 250 patients. Radiol Oncol, 2016; 50:329–336.

19.

Pinkawa

, Klotz

, Djukic

, et al. Learning curve in the application of a hydrogel spacer to protect the rectal wall during radiotherapy of localized prostate cancer. Urology, 2013; 82:963–968.

20.

Te Velde

, Westhuyzen

, Awad

, Wood

, Shakespeare

. Can a peri-rectal hydrogel spaceOAR programme for prostate cancer intensity-modulated radiotherapy be successfully implemented in a regional setting?. J Med Imaging Radiat Oncol, 2017; 61:528–533.