Comprehensive review of hydrogel spacers prior to radiation therapy for prostate cancer

Abstract

Introduction:

Radiation therapy is a curative intent treatment option for men with prostate cancer. Despite advancement in radiation therapy delivery, rectal toxicity still occurs. Hydrogel spacers offer the potential to reduce rectal toxicity for prostate cancer patients receiving radiation therapy. Since its introduction, numerous studies have confirmed their safety and efficacy in reducing rectal complications. The concept is elegantly simple whereby a hydrogel compound is injected under ultrasound guidance during routine fiducial marker insertion or as a standalone procedure prior to radiotherapy. After radiation therapy the body naturally reabsorbs the hydrogel material. We aimed to provide a comprehensive narrative review and outline the practicalities of inserting hydrogel spacers and published data on the impact of hydrogel spacers on rectal dosimetry and toxicity.

Results:

A growing body of evidence suggests the administration of hydrogel spacers is safe and associated with limited perioperative morbidity. The impact on rectal dosimetry has been clearly established and hydrogel spacers are associated with resulting reduces rectal morbidity. These results have been corroborated by several Phase II and III clinical trials and subsequent meta-analysis. Several future research questions exist, including the role of hydrogel spacer in prostate stereotactic beam radiotherapy or post-radiotherapy local recurrence.

Conclusions

Hydrogel spacers provide a low morbidity method potentially reducing rectal toxicity following radiation therapy in men with prostate cancer. Data outlining sexual function and oncologic outcomes are limited to date. No doubt future studies, currently being conducted, may provide further clarification of the role of hydrogel spacers in prostate cancer management.

INTRODUCTION

Prostate cancer remains as one of the commonest soft tissue malignancies in the developed world [1]. In the setting of localized prostate cancer, radiation therapy represents a curative treatment option that provides similar oncologic control to radical prostatectomy [2] [3], [4]. Radiation therapy to the prostate is also recommended in the setting of locally advanced, and low volume metastatic disease [5]. Due to the proximity of the rectum to the prostate, rectal irradiation is unavoidable [6, 7]. Unintentional radiation may result in early or late adverse effects, the latter occurring after 3 months of the treatment date [8]. Late rectal adverse effects, such as chronic radiation proctitis may be characterised by symptoms of frequency, incontinence, diarrhea and rectal bleeding [9]. In some severe cases, severe proctitis and ulceration may occur, even rectourethral fistula formation [10]. These toxicities still exist, despite the advancement in technologies and techniques in radiation therapy delivery, through beam modulation and image guidance, such as intensity-modulated radiation therapy (IMRT), and image-guided radiation therapy (IGRT). Meta-analyses of conventional fractionation of image modulated radiotherapy (IMRT) suggests long term grade 2 and 3 rectal toxicity of up to 14 to 25% [11]. Further, for every 8 to 10 Gray increase in radiation dose, the risk of toxicity doubles [12]. The need to further reduce rectal toxicity is especially important in the era where moderately hypofractionated radiation therapy is gradually becoming the standard of care – multiple Phase 3 randomised trials have consistently showed that compared to conventional fractionated regimen (of 1.8–2Gy per fraction), hypofractionated radiation therapy is associated with small increased risk of acute rectal toxicity [13].

Over the past decade, various strategies have been employed to reduce long-term radiation-related rectal toxicity. The use of spacing devices to reduce the dose received by adjacent healthy tissues were first utilized in the 1980s with radiation therapy for treatment of abdominal neoplasms [14]. More recently, various rectal displacement devices have been assessed, with the intention of increasing prostate-rectal distance to mitigate radiation exposure to the rectum. The earliest of such spacers was a hyaluronic acid spacer reported by Prada et al [15]. Subsequent iterations include the use of hydrogel tissue spacers and rectal retractors [16]. Rectal spacing using inflatable balloons is also under development but yet to be approved by FDA or international counterparts - several trials are currently investigating their safety and efficacy (NCT00918229 and NCT00462124).

Hydrogels are injectable viscous semiliquid compounds comprised mostly of water with a hydrophilic polymer matrix giving structure to the substance[17]. Hydrogels have been used extensively in the medical and cosmetic industries including breast implants, contact lenses, burns treatments and as slow-release drug delivery systems [18–21]. In the setting of radiotherapy treatment for prostate cancer, hydrogel is inserted between the prostate and rectum under ultrasound guidance prior to radiation therapy to reduce the rectal radiation dose by increasing the physical distance between prostate and rectum due to the inverse square law [22, 23].

This narrative review outlines the process of insertion and aims of insertion of hydrogel spacers. We discuss the evidence supporting the use of hydrogel spacer in reducing the radiation dosimetry to the rectum (and other neighbouring organs at risk) which translates into reduce toxicities. We also discuss the current areas of controversies with regards to hydrogel spacer use, which may offer opportunities for future research and trials.

TYPES OF HYDROGEL SPACERS

Various types of injectable hydrogels have been reported. These include polyethylene glycol (PEG), hyaluronic acid, and collagen-based products. PEG hydrogels include SpaceOAR (Aumenix, Waltham, MA, USA) and DuraSeal (Covidien, Irvine, CA, USA). Although poisoning may occur with PEG hydrogels, it has been shown to be safe at low quantities and is routinely used in many commercial products including packaged dried foods, soaps, cosmetics and injectable medications [24]. Augments to the PEG hydrogels have been produced, including iodinated cross-linked PEG that introduces radio-opacity, enabling easy visualisation during computerised tomography [25].

Hyaluronic acid- based spacers exist such as Barrigel (Palette Life Sciences, California, USA), Hyalgan (Sanofi Aventis, Paris, France), and Hyalaform (Genzyme Corporation, Cambridge, MA, USA). It should be noted that at present, Duraseal, Hyalgan and Hyalaform use in the setting of prostate cancer is considered off-label. To date, no comparative analysis has occurred based on the pharmacological, tolerability, efficacy or financial properties of the various hydrogel spacers. The properties of these agents enable gradual metabolism and subsequent absorption. In general, complete absorption occurs within 12 months [12].

INSERTION TECHNIQUE

Interdisciplinary consensus suggests hydrogel spacer is suitable for patients undergoing dose-escalated radiation therapy for prostate cancer. Patients undergoing hypofractionated courses or brachytherapy may also be considered [26]. Typically, trials have limited the use to patients with glands under 80cc, however several groups have reported safety and efficacy in larger prostate glands [23, 27]. Contraindications for hydrogel spacer insertion includes: locally advanced disease with adjacent organ invasion (T4 disease); bleeding diathesis and coagulopathy [26].

The insertion technique for hydrogel spacers is a relatively simple procedure that is typically performed under general anaesthetic, as outlined in Figure 1. Pre-operative prophylactic antibiotics is recommended to allow coverage for standard skin organisms, such as a first-generation cephalosporin. A transrectal ultrasound probe is inserted with the patient in the lithotomy position and a biplanar view of the prostate and rectum is achieved. Using a freehand technique, the injecting needle (18G, 15cm) is passed through the perineal region, 1–2cm anterior to the TRUS probe under ultrasound guidance to the rectoprostatic plane (the perirectal fat between Denonviliers fascia and the rectal wall). The sagittal view provides optimal visualization of the needle location. The needle penetrates transperineally through the rectourethralis muscle and entry posterior to Denonviliers fascia is achieved. The needle tip should be advanced to the mid-gland or the base of the seminal vesicles. A small volume of saline may be administered to allow hydrodissection and confirm the needle position within the perirectal fat.

Figure 1:

Technique for hydrogel spacer insertion, (a) insertion of needle under ultrasound guidance (b) hydrodissection with saline injection (c) introduction of hydrogel spacer

Upon hydrodissection, the needle tip position is maintained, and empty syringe is removed. At this point, the hydrogel solution is suitable for introduction. In the setting of the PEG hydrogel spacer (SpaceOAR) system, a single use system whereby the hydrogel forms during injection of two solutions concurrently (the precursor and the accelerator are contained within a dual lumen syringe) [28]. Conversely, the Barrigel system is ready for injection and is delivered within a glass syringe barrel. The hydrogel precursors is then attached to the needle via a Luerlock system and the hydrogel compound is then injected via a transperineal approach. The needle tip may be slowly removed under ultrasound guidance to ensure adequate spacing to the prostatic apex.

Post administration rectal examination is performed to ensure appropriate placement and distribution of the spacer device and to exclude gross rectal injury. Inappropriate placement of hydrogel may be determine on rectal examination by the identification of unevenly distributed or focussed administration of the hydrogel, as opposed to a correctly placed hydrogel which is characterised by even, homogenous distribution.

The operative time is short, estimated at 4.1 minutes (range: 3.1 – 12.5 min) based on a recent report[29]. With minimal impact on anaesthesia time, this procedure can safely be performed with concurrent insertion of fiducial markers for radiation therapy target verification if required. A follow up procedure or imaging is not required to remove the hydrogel as it is reabsorbed and excreted by the body (see Figure 2).

Figure 2:

(a) MR image from patient one week after SpaceOAR insertion post completion of radiotherapy. (b) Six months after SpaceOAR application shows the hydrogel completely absorbed. (Modified from [70]). P: Prostate, H: hydrogel, R: rectum

COMPLICATIONS FROM HYDROGEL SPACER INSERTION

Procedural complications following hydrogel spacer insertion are rare, and any reported adverse events were mild. In the RCT by Mariados et al, mild procedural perineal discomfort was reported in 10% [30]. A recent systematic review and meta-analysis by Miller and colleagues demonstrated in over 1000 patients, approximately half of whom received a hydrogel spacer, a low rate of predominantly minor and transient procedural complications [31]. A review of the SpaceOAR® Manufacturer and User Facility Device Experience database published by Aminsharifi, et al. reported a range of potential adverse events that may be associated with hydrogel spacer insertion [32]. Although this review included major complications such as pulmonary embolism or anaphylaxis alongside more common side effects, event rates were not investigated and not definitively linked to device insertion. Although rare, there have been reported cases of serious adverse events due to hydrogel spacer insertion, such as rectal or urethral injuries [33]. Several case reports of rectal injury or ulceration have been published following hydrogel spacer insertion [34–36]. Table 1 summarises frequent complications associated with hydrogel insertion.

Table 1:

Complications associated with hydrogel insertion [32]

Complication	Frequency
Mild discomfort	10–50%
Failed insertion	3–18%
Infective complication (eg. abscess)	~1%
Venous injection (no sequele)	~1%
Rectal injury/erosion	~1%
Urethral injury	~1%
Anaesthetic risks	Rare
Anaphylaxis	Rare

Limited reports of long term adverse effects following hydrogel spacer exist. Though, despite the biodegradable nature of these devices, the resulting fibrosis of Denonviliers fascia must be considered. This is particularly pertinent in patients with disease recurrence, planned for salvage prostatectomy. Intuitively, increased fibrosis along Denonviliers fascia may increase difficulty of the posterior prostatic dissection. Hout et al reported performing a robotic prostatectomy 6-months after hydrogel insertion with operative safety and limited concern over fibrosis [37].

IMPACT OF HYDROGEL SPACERS ON RECTAL SEPARATION, DOSIMETRY AND TOXICITIES

The aim of hydrogel spacer insertion is to increase spatial separation between prostate and rectum, with the intention of reducing rectal dosimetry during radiation therapy, in hope that this will translate into reduced patient reported symptoms of rectal toxicity. However, it is important to consider the type of radiation therapy techniques (i.e. external beam radiation therapy alone [23, 38–41], brachytherapy alone [29, 42–45], or external beam radiation therapy in combination brachytherapy boost [29, 44–46], or proton beam radiation therapy [47]) as well as the dose-fractionation [48, 49] used when evaluating these outcomes.

Prostate-rectal separation:

While most series reported prostate-rectal separation of approximately 10–12mm following spacer insertion [31, 50], it is important to recognise that the degree of symmetry varies over the length of prostate, and is also operator-dependent. Pinkawa et al reported that the degree of separation is influenced by learning curve, with the mean prostate-rectal separation at base/mid-gland/apex increasing from 8mm/11mm/8mm in the first 32 spacer insertions, to 13mm/15mm/11mm for the subsequent 32 spacer insertions [51]. Accordingly, given the respective learning curve, appropriate supervised experience should be sought prior to performance of the procedure unaccompanied. It should be noted that the region that experiences the least separation tends to be at the level of the prostatic apex – this is likely due to the fixed nature of the prostatic apex due to the surrounding musculofascial suspension system [52].

Rectal dosimetry:

All studies have reported that the increased prostate-rectal separation results in reduced rectal dosimetry, although varying dosimetry parameters have been reported [53, 54], which may result in issues comparing dosimetry changes between studies. In studies using image-guided intensity-modulated external beam radiation therapy alone to total dose of 74–80Gy in 1.8–2Gy per fractions, one of the more consistently reported parameters is V70Gy (i.e. volume of rectum receiving 70Gy of radiation). In one of the earliest pooled pilot studies of 52 patients from 4 institutions, Song et al reported that 96% of patient achieved reduction in V70Gy of more than 25% (mean V70Gy reduced from 13.0 to 5.1, p<0.001) [41]. In the only published Phase 3 prospective RCT, the primary endpoint was more than 25% reduction in V70Gy and this was achieved in 97% of patients who had spacer insertion in the trial [50]. In a pooled analyses of 6 studies (including one study with external beam radiation therapy and brachytherapy boost), Miller et al reported a mean reduction in rectal V70Gy from 10.4% in patients who did not have hydrogel spacer to 3.5% in patients who had hydrogel spacer inserted [31]. These results have been corroborated in alternate series [54].

Rectal toxicity:

Several studies have reported on the rectal toxicity outcomes following spacer insertion for radiation therapy for prostate cancer, and of these studies, toxicities have been varyingly reported using a mix of Common Terminology Criteria for Adverse Events (CTCAE) [39, 47, 55, 56] and Radiation Therapy Oncology Group (RTOG) grading [38, 48]. Overall, proportion of Grade 2+ rectal toxicities are low. In a Phase 3 prospective RCT, Mariados et al reported non-statistically significant reduction in acute rectal toxicities (within 3 months of radiation therapy) between patients who had spacer vs no spacer insertion – Grade 0, 1, 2+ rectal toxicities of 73%, 23% and 4% in patients who had spacer insertion vs. 68%, 28% and 4% in patients who did not have spacer insertion (P=0.5) [50]; however, with longer follow-up, the 3-year Grade 2+ rectal toxicities were markedly lower in patients who had spacer insertion (0% vs. 6%, P<0.015) [56]. In a pooled analysis of 4 studies with median follow-up of 38 months, Miller et al reported 77% relative reduction in Grade 2+ rectal toxicities (RR = 0.23; 95%CI = 0.06–0.99; P=0.05) [31].

Data on the impact of spacer on rectal toxicity in the setting of moderately hypofractionated, or stereotactic body radiation therapy (SBRT) is limited. There was a single-arm study that evaluated the use of spacer with hypofractionated radiation therapy (62Gy in 20 fractions) in 36 patients between 2010 and 2013. In the study, there were 4 (12%) Grade 2 rectal toxicities (3 rectal bleeding and 1 diarrhea), with no Grade 3 and above rectal toxicities [49]. Only one study evaluated rectal toxicity with the use of spacer in men treated with SBRT of 36.25Gy in 5 fractions). Of the 50 men in the study, 16% had Grade 1 rectal toxicities during treatment, 4% had Grade 2 rectal toxicity within 4 weeks post-treatment, and no rectal toxicities were reported beyond 1 month post-treatment [48].

Only a few studies have outlined patient-reported bowel bother outcomes, and all used the Expanded Prostate Cancer Index Composite (EPIC) questionnaire [40, 56]. In the Phase 3 prospective RCT, Hamstra et al reported that at 3-year follow-up, the mean differences in EPIC bowel quality of life score between those who had spacer vs no spacer to be 5.8, favouring patients who had spacer, and meeting the threshold for minimally important differences [56]. In a separate study, Pinkawa et al reported EPIC bowel bother score change of <10 from baseline in 6% vs 32% at 17 month (P<0.01) and 5% vs. 14% at 63 months (P=0.2) for patients who had spacer vs. no spacer [40].

IMPACT OF HYDROGEL SPACERS ON OTHER ORGANS-AT-RISK DOSIMETRY AND TOXICITIES

The insertion of spacer into the perirectal fat - between the Denonvillers fascia and the rectal wall, is unlikely to impact on the radiation dosimetry to the neighbouring organs at risk. Several studies have investigated the impact of spacer insertion on dosimetry to these neighbouring organs, such as bladder [40, 46], penile bulb [46, 57], and urethra [29, 44, 46] – most did not show significant changes to the organs-at-risk dosimetry with spacer insertion. However, a secondary analyses of Phase 3 RCT showed lower penile bulb dose in patients who had spacer insertion compared to those who did not–mean dose 11Gy vs. 21Gy, maximum dose 36Gy vs 46Gy (P<0.05) [57].

Two studies have specifically evaluated patient-reported urinary and sexual toxicities using EPIC questionnaires in patients who have had spacer insertion [40, 57]. In the secondary analyses of a prospective RCT, Hamstra et al reported that patients who did not have spacer have statistically significant greater decline in EPIC urinary score at 3 years compared to patients who had spacer (3.3 versus 0.6, p=0.04), but the difference did not meet the minimally important difference threshold (5–7 points) [56]. In the subgroup of patients who had adequate baseline sexual function, patients who had spacer had better sexual function at 3-year compared to patients who did not have spacer (P=0.03), and the authors suggested that this may be correlated to the penile bulb dose [57]. The aforementioned randomised trial by Pinkawa et al, reported better sexual function in patients who had spacer – 24% patients who had spacer reported erection firm enough for erection compared to 3% in patients who did not have spacer (P<0.01) [40]. Given the randomised nature of the trial, both groups demonstrated no difference in baseline sexual function prior to radiotherapy. Overall, it is not entirely clear as to whether the lower dosimetry to the penile bulb or possibly other organs at risk (e.g. neurovascular bundle) may have been the primary driver for the observed sexual function differences between patients who had spacer vs. no spacer.

FUTURE DIRECTIONS

One area for future research is to better integrate the use of hydrogel spacer with prostate SBRT [54]. Folkert et al have recently completed a Phase II trial that examines the use hydrogel spacers in 44 patients planned for SBRT, with the primary outcomes being reduction in the rate of rectal ulceration (NCT02353832). A currently recruiting Phase 2 trial (POTEN-C) aims to evaluate the impact of spacer use in neurovascular-sparing prostate SBRT on erectile function preservation (NCT03525262). Cury et al are leading a Canadian Phase I trial looking into the impact of hydrogel spacer on urinary and rectal toxicities in men treated with single-fraction SBRT (NCT04004312). There is also a planned industry-led trial that aims to evaluate the use of spacer in patients receiving prostate SBRT (NCT04905069).

Research focussed on modifications on administration techniques may be of value. While antibiotic prophylaxis is typically recommended, comparable procedures performed via the transperineal route, such as prostate biopsy, is frequently performed without antibiotic prophylaxis [58]. However, it should be noted that spacing devices may be considered a prosthesis and may be of higher infective risk. Moreover, consideration may be given to performance under local anaesthesia, in the outpatient setting. Potential barriers to such strategies include difficulty in performance of an acceptable regional block and the lack of complete patient immobility that may be required for precise administration.

Future research may include expanding the use of spacer in patients who have local recurrence following previous prostate radiation therapy, whereby the rectum is often a dose limiting organ in the re-irradiation setting. While there is clear benefit in rectal dosimetry and toxicities by increasing the spatial separation of rectal wall from high dose region with spacer insertion, with significant tissue fibrosis from previous radiation therapy, there is also a theoretical risk of displacement of prostate cancer cells posteriorly in the process of hydrodissection for spacer insertion. This may lead to under-treatment of prostate cancer posterior to the spacer, and hence compromise on oncological outcomes. This risk is not insignificant if there is obvious extra-prostatic extension with tumour abutting or invading the rectal wall. Another area for future research, which may be potentially controversial, is the use of hydrogel spacer in the post-prostatectomy settings [59–61]. In contrast to spacer insertion with intact prostate in-situ, the plane for spacer insertion in the post-prostatectomy setting is less well-defined. Hence, patient selection in such a trial will be crucial. A pre-requisite for the use of rectal spacers in this setting will be a preserved Denonvillier’s fascia and with it, the perirectal fat. As such it will only be limited to patients who undergo an intrafascial or interfascial dissection.

The role of regulation and monitoring of such implantable devices is unclear in contemporary practice, however, consideration into regional, state or national registries may be of value [62]. Such practices may assist with monitoring of adverse effects or beneficial effects on prostate cancer survivorship [63].

COST EFFECTIVENESS OF HYDROGEL SPACER

An important consideration is device cost and availability [64–66]. Published data to date is dependant on model simulation cost, such as use of Markov decision analysis, rather than actual cost data. For example, Hutchinson et al performed decision-tree model for cost-benefit analysis by estimating costs of hydrogel spacer use versus the cost of rectal toxicity over a 10 year period. The resulting analysis determined that hydrogel spacer usage was associated with marginal increased in radiation therapy costs [64]. Although, this study acknowledges the short follow-up period, and thus cost savings are likely to increase with time after EBRT. Conversely, using a Markov decision analysis model, Vanneste et al demonstrated that in patients with hydrogel spacers a reduced cost was associated with mitigated complication costs [65]. Variation in analytical methods may, in part, contribute to the subtle discrepancies in these results. Jones et al, based on Markov modelling, suggested maximal cost-benefit would occur when spacing devices were used selectively rather than whole cohorts [66]. The subjective question of cost to benefit ratio remains but increasing availability and range of commercial products will likely see a great shift to cost reductions with hydrogel spacers.

Alternative devices that provide similar function are currently under development and may provide even greater benefits compared with currently available products. One example is the BioProtect rectal balloon, a saline filled biodegradable polymer balloon. Such products are yet to be approved by regulatory bodies pending further research [33].

RECOMMENDATIONS

Due to its naïve history, limited guides by authoritative guidelines exists. The National Institute for Health and Care Excellence (NICE) suggests that safety and efficacy data exists to support the use of biodegradable devices in both external beam radiotherapy and brachytherapy [67]. The European Urologic Association (EAU) and American Urological Association (AUA) do not have recommendations specifically pertaining to the use of biodegradable spacer devices [68, 69]. Nevertheless, in line with the NICE guidelines, currently evidence supports the use of biodegradable spacing devices, and should only be performed by experienced clinicians.

CONCLUSION

Hydrogel spacers provide a surgical method with low morbidity to potentially reducing rectal toxicity following radiation therapy in men with prostate cancer. Current data suggests a robust effect on bowel toxicity and bowel quality of life after radiation therapy. A growing body of evidence supports this in the setting of conventional EBRT and now more conformal techniques such as IMRT. Data outlining sexual function and oncologic outcomes are limited to date. No doubt future studies, currently being conducted, will provide further clarification of the role of hydrogel spacers in prostate cancer management.