RADIATION ONCOLOGY—ORIGINAL ARTICLE

Feasibility of and rectal dosimetry improvement withthe use of SpaceOAR® hydrogel for dose-escalated prostatecancer radiotherapyKirsten van Gysen,1 Andrew Kneebone,1,2 Florencia Alfieri,1 Linxin Guo1 and Thomas Eade1,2

1Northern Sydney Cancer Centre, Royal North Shore Hospital, and 2University of Sydney, Sydney, New South Wales, Australia

K van Gysen MBChB; A Kneebone FRANZCR;

F Alfieri BAppSc(MRS)RT; L Guo BSc, MHSc;

T Eade FRANZCR.

CorrespondenceThomas Eade, Northern Sydney Cancer Centre,

Royal North Shore Hospital, Pacific Highway, St

Leonards, NSW 2065, Australia.

Email: teade@nsccahs.health.nsw.gov.au

Conflict of interest: None.

Submitted 18 September 2013; accepted 07

December 2013.

doi:10.1111/1754-9485.12152

Abstract

Introduction: The aim of this study was to investigate the feasibility of injectinga temporary spacer between the rectum and the prostate and to quantify thedegree of rectal dosimetric improvement that might result.Methods: Ten patients underwent CT and MRI before and after injection of10 cc of hydrogel and at completion of radiotherapy. Hydrogel was injectedunder general anaesthetic using a transperineal approach. The primary end-points were perioperative toxicity and rectal dosimetry (V80, V75, V70, V65,V40 and V30). Secondary endpoints were acute gastrointestinal toxicityduring and 3 months following radiotherapy and the stability of the hydrogel.Treatment for all patients was planned incorporating volumetric modulatedarc therapy with a D95 of 80 Gy in 40 fractions to the prostate and proximalseminal vesicles on both the pre- and post-hydrogel scans. Toxicity wasscored with the Common Terminology Criteria, v. 3.0.Results: In the first 24 h, two patients described an increase in bowel move-ment frequency. The comparison plans had identical prescription doses.Rectal doses were significantly lower for all hydrogel patients for all doseendpoints (V80 = 7% vs. 0.1%, V75 = 10.3% vs. 1.1%, V70 = 13.2% vs.2.7%, V65 = 15.8% vs. 4.6%, V40 = 35.2% vs. 23.3%, V30 = 52.6% vs.38.5%; P < 0.001). Post-treatment MRI showed gel stability. Grade 1 boweltoxicity was reported in six patients during radiotherapy and two patients at3 months’ follow-up. No Grade 2 or Grade 3 acute bowel toxicity was reported.Conclusion: SpaceOAR hydrogel was successfully injected in 10 patients withminimal side effects. Rectal dosimetry was significantly improved in allpatients. This study has been extended to 30 patients with longer follow-upplanned.

Key words: prostate cancer; radiation therapy; spacer gel; toxicity; treatmentplanning.

Introduction

Randomised trials and single-institution series havedemonstrated a dose response to radiotherapy for pros-tate cancer.1–4 However, due to the close association ofthe prostate and the rectum, delivering higher doses canbe at the cost of increased rectal toxicity.5 More recently,hypofractionated treatments have proven to be effec-tive,6,7 although this technique may be limited by poten-tial rectal toxicity.8,9 There have been numeroustechnical advances in radiotherapy treatment, including

image-guided radiotherapy (IGRT) and volumetricmodulated arc therapy (VMAT); the latter is an arc-based dose delivery approach that produces highly con-formal dose distributions, similarly to static-gantryintensity-modulated radiotherapy (IMRT). Both aim toaccurately deliver radiation to the target and sparenormal tissues; however, irrespective of the treatmenttechnique, the anterior wall of the rectum cannot bespared from high doses, as it is directly adjacent to theprostate. A promising technique is the injection of asynthetic gel into the space between the rectum and

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Journal of Medical Imaging and Radiation Oncology 58 (2014) 511–516

© 2014 The Royal Australian and New Zealand College of Radiologists 511

prostate, increasing the distance between the twoorgans and aiming to reduce radiation delivery to therectum and improve the toxicity profile during prostateradiotherapy. Clinical data available on this techniqueare limited.

Synthetic polyethylene-glycol-based (PEG) hydrogelsare composed of approximately 90% water by weight,with the remaining solids being cross-linked polyethyl-ene glycol. They are injected as a thin liquid into theanterior perirectal fat, where they polymerise in situ toform a soft hydrogel after the two precursor solutionsmix. There is a high degree of tissue compatibility, andthe gel is tissue-dense on CT scan. The gel maintainsorgan separation for 3 months and then dissolves, beingabsorbed by the body within 4 to 5 months. The PEGhydrogel used in this study (SpaceOAR®) is manufac-tured by Augmenix Inc. (Waltham, MA, USA), whoprovided the information in this paragraph, and hasbeen approved by the Australian Therapeutic GoodsAdministration.

The aim of this study was to investigate the feasibilityof injecting a temporary spacer between the rectum andthe prostate and to quantify the degree of rectaldosimetric improvement.

Methods

Following ethics approval, 10 patients were recruited tothe study between March and July 2012. All patients hadhistologically proven prostate cancer and were eligiblefor prostatic radiotherapy.

Hydrogel implant

After informed written consent was obtained from par-ticipants, the PEG hydrogel was injected at the sametime as the prostatic fiducial gold seeds were inserted,with patients under a general anaesthetic. The hydrogelwas injected after insertion of the fiducial seeds, as thehydrogel causes elevation of the prostate and degrada-tion of the prostatic image, which may affect seed

insertion via the transperineal approach. Undertransrectal ultrasound guidance, a needle was advanced,via the transperineal approach, into the space betweenthe prostate and the rectum. Hydrodissection with salinecreated a distance of 3–4 mm between the prostate andthe rectum. Following confirmation of the correct posi-tioning of the needle, 10 cc of the hydrogel precursorswas injected, filling the perirectal space and then poly-merising (see Fig. 1).

Planning and treatment

To determine the dosimetric effect of the hydrogel, twotreatment plans were created for each patient. An initialplanning CT scan was performed prior to the hydrogelinjection, followed by a second scan 7 days following thehydrogel injection. (There was a time interval of 1–2weeks between the two scans.) Hydrogel is clearly visibleon MRI scans but not on CT scans, as it is tissue-dense.Therefore, patients underwent three pelvic MRI scans.The first two scans occurred at the same time as theplanning CT scans, and the third was at the end oftreatment (approximately 3 months post-injection). TheMRI scans were used to determine the maximumanterior–posterior dimensions of the hydrogel at themid-plane of the prostate and whether the degree ofseparation was constant for the duration of the treat-ment. In addition, the MRI scans were fused to theplanning CT scans to aid voluming.

Patients underwent standard prostate cancer planningand treatment using image-guided dose-escalated VMATaccording to the Royal North Shore Hospital departmentprotocol and guidelines.10 The same prescription wasplanned for all patients: D95 of 80 Gy in 40 fractions tothe prostate and proximal seminal vesicles. For both CTscans, patient preparation was identical, using the samebladder filling (patients emptied their bladders 1 h priorto the scan before drinking 500 mL of water, aiming fora comfortably full bladder) and rectal emptying proto-cols. The bladder was contoured from apex to base, andthe bladder volume was determined from the bladder

a bFig. 1. (a) Pre-hydrogel MRI. Prostate gland (pink)

resting against rectum (blue) (b) Post-hydrogel

MRI. The same patient after hydrogel (white)

insertion; note increased distance between pros-

tate and rectum.

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© 2014 The Royal Australian and New Zealand College of Radiologists512

contours. The rectum was contoured as a solid organfrom the rectosigmoid junction to the lower border of theischial tuberosities. The prostate and the proximal 1 cmof the seminal vesicles were included in the planningtarget volume high dose (PTVHD). The same radiationtherapist created both treatment plans to reduce incon-sistency. Plans were created and dose–volume histo-grams constructed for both the pre- and post-hydrogelCT scans. Mean rectal doses were calculated for thetreatment. The rectal volumes receiving 80 Gy, 75 Gy,70 Gy, 65 Gy, 40 Gy and 30 Gy were compared. Pros-tate volume, rectal volume, bladder volume and meandose to PTVHD were also compared between thehydrogel and non-hydrogel groups. Patients weretreated according to the hydrogel plan, with the initialprehydrogel plan for comparison purposes only.

Patient assessment

To determine if there were any adverse events related tothe hydrogel injection, patients were assessed immedi-ately post-injection and were contacted by telephone24 h and 1 week later. During treatment, patients wereassessed weekly in the clinic, and their toxicity wasrecorded using the modified Radiation Therapy OncologyGroup and National Cancer Institute Common Terminol-ogy Criteria (v. 3.0) for adverse events. They werereviewed in the clinic 3 months after completion of treat-ment.

Statistical analysis

The Wilcoxon rank-sum test was used to evaluate thelevel of significance of the observed differences betweenthe two plans. A P value of <0.05 was considered statis-tically significant.

Results

All 10 patients were able to undergo the procedureperformed. In the first 24 hours, two patients describedan increase in bowel movement frequency, which settledon ceasing aperients. One patient reported tenesmus,

which was managed with Buscopan® and resolved com-pletely after 2 days. No patients reported bleeding orinfection following the procedure. There were no allergicreactions to the product and no reports of urinary reten-tion. (One patient had grade 1 rectal bleeding that wasthought to be due to haemorrhoids; another patient hadgrade 1 haematuria for a week, thought to be due to thefiducial markers.) The two plans were comparable, withno significant difference between the prostate volumes(P = 1), the rectal volumes (P = 0.76), the bladdervolumes (P = 1) and the mean dose to the PTVHD(P = 0.67). In all patients, the mean and maximumdoses received by the rectum were lower with thehydrogel plan. The mean rectal dose was 34.4 Gy in thenon-hydrogel plan vs. 27 Gy in the hydrogel plan. Con-versely, as seen in Table 1, there was no notable differ-ence between the two plans in the dose received by thebladder, the clinical target volume (CTV) prostate or thePTVHD.

For all rectal dose endpoints, there was a significantimprovement with the hydrogel plan, as seen in Fig. 2and Table 2. This difference was more notable at higherdoses: for hydrogel versus non-hydrogel, V80 = 7.0%versus 0.1% (P < 0.001); V75 = 10.3% versus 1.1%(P < 0.001); V70 = 13.2% versus 2.7% (P < 0.001);V65 = 15.8% versus 4.6% (P < 0.001); V40 = 35.2%versus 23.3% (P < 0.001); and V30 = 52.6% versus38.5% (P < 0.001). The bladder dose endpoints showedlittle discrepancy between the two plans.

A comparison between the post-hydrogel MRI and thepost-treatment MRI showed that the prostate rectalseparation distance remained stable throughout treat-ment. The mean anterior–posterior diameter of thehydrogel was 1.6 cm at the start of treatment and1.5 cm at the end. In two patients, however, there wasevidence on the post-treatment MRI of changes inkeeping with gel resorption. Despite these changes, theprostate–rectum distance was maintained at >1.0 cm(see Fig. 3).

Grade 1 bowel toxicity was reported by six patientsduring radiotherapy and two patients at 3 months’ followup. There was no Grade 2 or Grade 3 acute bowel toxicityreported.

Table 1. Structure volumes and doses delivered to each structure in the hydrogel and non-hydrogel plans

Rectum Bladder CTV prostate PTVHD

NHG HG NHG HG NHG HG NHG HG

Structure volume (cc) 70.41 68.62 311.2 316.82 46.37 47.08 137.6 140.17

Mean dose (Gy) 34.38 27.06 26.87 26.24 82.81 82.65 82.24 82.16

Median dose (Gy) 30.34 22.85 17.81 15.87 82.80 82.66 82.41 82.38

Maximum dose (Gy) 82.79 80.02 83.81 83.58 84.59 84.47 84.69 84.47

SD 24.02 18.31 22.96 23.19 0.55 0.51 1.14 1.06

CTV, clinical target volume; PTVHD, planning target volume high dose; NHG, non-hydrogel; HG,

hydrogel.

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© 2014 The Royal Australian and New Zealand College of Radiologists 513

Discussion

In recent years there have been studies published dem-onstrating a definite benefit of the use of a spacer gel:increasing the distance between the rectum and theprostate and consequently reducing the rectal dose.11–15

These results have not previously been validated in anAustralian setting.

During prostate radiotherapy, rectal toxicity is associ-ated with the dose delivered to the rectum as well as thevolume of rectum receiving a particular dose.16–18 Astudy by Pinkawa et al. demonstrated that the injectionof a spacer gel between the prostate and the anteriorrectal wall was associated with a 56% reduction in therelative rectal volume within the 70-Gy isodose.11 Susilet al. analysed dosimetric effects of injecting hydrogelinto cadaveric specimens and found that the averagerectal volume receiving 70 Gy decreased from 20% to4.5%.12 This is very similar proportionally to our results,with the average rectal volume receiving 70 Gy decreas-ing from 13.2% to 2.7%. The benefit was particularlyevident at higher doses (60 Gy and above). Due to thedesign of VMAT treatment, the pelvic tissues are exposedto a low-dose wash of radiation, and therefore thehydrogel spacer is less effective at reducing the rectalvolumes receiving lower doses. Our results showed asubstantial reduction in mean rectal dose (by 20%),which is in keeping with previous studies, Wilder et al.reported a reduction in daily mean rectal dose from106 ± 20 cGy to 73 ± 13 cGy with a gel spacer inpatients receiving high-dose-rate brachytherapy fol-lowed by IMRT.13 Weber et al. reported that followingspacer insertion the prostate was moved anteriorly, andthis resulted in bladder doses that were usually higher,although not significantly.14 In our study dose to thebladder, CTV prostate and PTV high dose remainedunchanged, indicating that the hydrogel did not compro-mise dose delivery to the treatment field or increasebladder dose.

The hydrogel is thought to be slowly absorbed overtime, and prior to this study there were concerns that thedegree of separation might be reduced over the durationof treatment. Prada et al. reported a separation distanceof 2 cm along the entire length of the prostate that wasmaintained throughout treatment.15 Two reports haveobserved that with the use of a different gel, cross-linkedhyaluronan gel, the irradiated gel is absorbed slightlymore quickly than reported for non-irradiated gel.13,19 Inour study, the prostate–rectum separation distance

a

b

0

20

40

60

80

100

0 20 40 60 80 100

Vo

lum

e (%

)

Dose (Gy)

0

20

40

60

80

100

0 20 40 60 80 100

Vol

ume

(%)

Dose (Gy)

Fig. 2. Cumulative dose–volume histograms for (a) the rectum and (b) the

bladder in 10 prostate cancer patients planned for volumetric modulated arc

therapy, before (blue curve) and after (red curve) hydrogel spacer injection.

Table 2. Percentage rectal volume receiving a particular dose in each plan

Rectal dose endpoint† Non-hydrogel plan (% volume),

mean (range)

Hydrogel plan (% volume),

mean (range)

V80 7.0 (2.3–23.7) 0.1 (0–0.5)

V75 10.3 (7.1–12.8) 1.1 (0–3.0)

V70 13.2 (9.1–16.3) 2.7 (0.7–5.3)

V65 15.8 (11–19.4) 4.6 (1.6–8.7)

V40 35.8 (31.3–41.1) 23.3 (17.3–28.5)

V30 52.6 (40.2–60.4) 38.5 (32.7–49.4)

P < 0.001 for all endpoints. †Vx, percentage rectal volume receiving x Gy of radiation.

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© 2014 The Royal Australian and New Zealand College of Radiologists514

remained consistent during the period of planning andtreatment; however, there was evidence of changes inthe gel in two of our patients on post-treatment MRI.This observation will require further investigation.

The potential adverse effects associated with theinjection and use of hydrogels include infection (antibi-otics were administered prophylactically); allergic reac-tions such as itching; injection site reactions includingbleeding and pain; urinary retention; tenesmus, rectalpressure or a sensation of rectal filling; systemicembolisation if the gel or air is injected into a bloodvessel; needle penetration of the rectal wall or urethraduring injection; and injection of the hydrogel into therectum, prostate or bladder. In previous hydrogelstudies, none of these adverse events have beenobserved.11–13,15 Based on the results in our studyand previous studies, we believe that the benefitsachieved from the procedure should outweigh the poten-tial risks.

One of the main indications for the use of hydrogel inprostate radiotherapy is to reduce rectal toxicity. In thereport by Wilder et al., patients who had the spacer fortheir treatment with high-dose-rate brachytherapy fol-lowed by IMRT had significantly reduced acute rectaltoxicity compared with patients treated without gel. Nopatients who received gel had acute diarrhoea, com-pared with 30% of those who did not.13 Patients withacute rectal toxicity are more likely to have late rectaltoxicity.20,21 For the use of hydrogel in our study, nograde 2 or grade 3 acute rectal toxicity was reportedduring treatment or at 3 months’ follow-up. Patients willhave ongoing reviews to determine any chronic rectaltoxicity.

A possible limitation of this study is that the dose hasbeen compared in two separate planning CT data sets.Despite identical setup protocols and similar meanvolumes for the rectum and bladder, the variation involume could have an impact on dose–volume histogramanalysis and the conclusion of the study. The sameradiation therapist planned for all patients to reduceinconsistency and interobserver variability; however,this may have resulted in potential bias whereby the

hydrogel CT was favourably planned to show a reductionin rectal dose. As this was a feasibility study, only 10patients were included, but the study has now beenextended to include more patients with longer follow-up.

SpaceOAR hydrogel was successfully injected into all10 patients with minimal toxicity. Our dosimetric resultsindicate that the hydrogel spacer significantly reducedthe rectal dose during prostate radiotherapy, and thisrectal dose sparing may translate into reduced ratesof rectal toxicity. Despite the expected advantages ofthis technique, a randomised prospective study isrequired to determine whether the hydrogel spacer willresult in a therapeutic benefit for prostate radiotherapypatients.

Acknowledgements

SpaceOAR was provided for the study by MD Solutions(Newport, Victoria, Australia). Special thanks to Dr PhilipMcCloud for his statistical contribution.

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a bFig. 3. Resorption of the hydrogel. (a) Axial T2

MRI showing hydrogel (red arrow) prior to the

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therapy, 3 months post-injection. Note the fuzzier

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