Radiotherapy is an established curative treatment method for prostate cancer. Optimal tumor control rates can only be achieved with high local doses, associated with a considerable risk of rectal toxicity. Apart from already widely adapted technical advances, as intensity-modulated radiation therapy, the application of spacers placed between the prostate and rectum has been increasingly used in the last years. Biodegradable spacers, including hydrogel, hyaluronic acid, collagen or an implantable balloon, can be injected or inserted in a short procedure under transrectal ultrasound guidance via a transperineal approach. A distance of about 1.0-1.5 cm is usually achieved between the rectum and prostate, excluding the rectal wall from the high isodoses. Several studies have shown well tolerated injection procedures and treatments. Apart from considerable reduction of rectal irradiation, a prospective randomized trial demonstrated a reduction of rectal toxicity after hydrogel injection in men undergoing prostate image-guided intensity-modulated radiation therapy. The results are encouraging for continuing evaluation in dose escalation, hypofractionation, stereotactic radiotherapy or re-irradiation trials in the future.

Radiotherapy is an established curative treatment method for prostate cancer. Prospective randomized trials evaluating dose escalation have consistently shown significantly higher biochemical control rates for higher doses. However, significantly higher rectal toxicity rates resulted[1]. Rectal toxicity is regarded as the dose-limiting toxicity[2]. Rectal toxicity has been evaluated in a large number of studies and dose-volume correlations have been clearly established[3-5]. Apart from higher dose and larger volumes within specific isodoses, risk factors for toxicity after radiotherapy include history of prior abdominal surgery, advanced age, diabetes mellitus, concomitant use of androgen deprivation, hemorrhoids, and inflammatory bowel disease[6].

Most of the randomized dose escalation studies applied three-dimensional conformal techniques[1]. Several further technical advances have been introduced in the last years. Intensity-modulated radiotherapy (IMRT) techniques, currently regarded as a standard for prostate cancer treatment in an increasing number radiation oncology departments, result in improved dose conformality[7]. Image-guided radiotherapy (IGRT) is applied to show the prostate position before or even during each fraction, so that treatment margins and volumes can be reduced[8]. Using these techniques, new concepts as hypofractionated treatments or even stereotactic radiotherapy treatments have been introduced in the past, resulting in a considerable shortening of the external beam radiotherapy (EBRT) treatment period[9].

As the prostate is usually situated without a relevant distance to the rectal wall and EBRT requires safety margins around the prostate of about 4-10 mm (depending on several factors as patient positioning and IGRT method), the anterior rectal wall is always included in the planning target volume and thus the prescription isodose. The insertion of a spacer between the prostate and rectum is an increasingly used method to create a considerable distance between the prostate and rectum and thus exclude the rectum from the high dose volume. A high dose can be delivered safely with adequate margins[10].

Requirements for a spacer are a well tolerated insertion, a stable position during up to two months of radiotherapy and biodegradation. A spacer should not be allergenic or toxic. Studies in prostate cancer patients evaluated the effects of hyaluronic acid, human collagen, inflatable balloon or hydrogel as different spacer materials[11-14]. Hyaluronic acid is a natural polysaccharide component in connective tissue and extracellular matrix[15]. Human collagen is known from injections into the perineum to treat urinary incontinence[16]. An inflatable biodegradable balloon (PLCL, polylactide-co-ε-caprolactone) has been specifically introduced to be used as a spacer[17]. In the past absorbable polyethylene glycol (PEG) hydrogels have been applied in surgical procedures as lung, dural and vascular sealants[14]. Hydrogels are injected as liquids and polymerize in situ within < 10 s following the mixture of two precursor solutions.

A transperineal approach with transrectal ultrasound (TRUS) guidance is used for spacer implantation/ injection under local, spinal or light general anaesthesia. The actually selected anaesthesia will be chosen depending on the procedures planned (length and depth needed for incision, gold marker implantation, brachytherapy) and the respective local protocol. The approach is well known from prostate brachytherapy or gold marker implantation for IGRT. A needle is placed about 1-2cm anteriorly to the TRUS probe and forwarded to the prostatic apex. Prior hydrodissection facilitates spacer insertion. The spacer must be positioned between the rectal wall and the Denonvilliers’ fascia[18]. In a series including 243 prostatectomy specimens, Villers et al[19] reported that prostate cancer invaded Denonvilliers’ fascia in 19% of cases, but no patients presented a tumour progression through the full thickness of the fascia. Thus, the risk of tumour cell displacement can be regarded to be minimal.

Prada et al[13] performed hyaluronic acid injections without hydrodissection. Hydrogel or human collagen are injected following prior hydrodissection - the same-18 gauge spinal needle is used for hydrodissection and spacer injection[12,18]. Injection of fluid spacers is less invasive in comparison to the balloon implantation. However, a balloon can be deflated and repositioned if required.

An incision of 3-5 mm is required before implantation of a biodegradable balloon. The incision allows the dilatator and the introducer sheath to be inserted into the perineum. The dilatator is advanced towards the prostate base over the needle and the needle removed subsequently. The introducer sheath acts as a working channel for the introduction of the balloon. The balloon is filled with warm saline and sealed with a biodegradable plug following a full inflation[11,20].

As demonstrated in several studies, the injection or insertion of a spacer results in a distance of about 1.0-1.5 cm between the prostate and rectum, so that the rectal wall and planning target volume do not overlap[11-13,21]. The largest study included 100 patients after hydrogel injection[22]. A higher injected volume can result in a larger separation. Hydrogel is usually inserted in standardized 10-15 mL systems[14,22]. Comparably to the hydrogel studies, a mean separation of 12.7 mm was achieved with 20 mL human collagen injections in a pilot study[12]. The inflation of a balloon with nearly 20 mL of saline can result in mean prostate-rectum separation > 1.5 cm[11]. Though different injection volumes have not been compared in studies, an increasing volume can be potentially associated with toxicity related to the pressure on the rectal wall or even the prostate. A volume of 10-15 mL and a resulting distance of 1.0-1.5 cm appear to be very effective and well tolerable for the patients[11-14,22].

This separation results in a considerable dosimetric advantage for the rectum. In EBRT studies, relative rectal wall volume reductions of > 70% within the 90% isodose levels have been shown comparing treatment plans prior and following spacer insertion, i.e., only < 5% of rectal volume is included in the 70Gy isodose when a prescription dose of 78-79Gy is used[11,15,21]. Guidelines recommend to limit this volume to 20%[23], so that these recommendations can be met without problems. Thus, to reach an optimal dose distribution, treatment planning after spacer insertion must include much lower objectives for the rectum. The information from the dose-volume histogram indicates a low risk of rectal toxicity. On the other hand, it implicates the potential for safe delivery of new hypofractionated and stereotactic treatments or re-irradiation concepts without a relevant risk of higher grade rectal toxicity.

Spacer studies have been reported after several different treatment concepts, as low-dose rate[24] and high-dose rate (HDR) brachytherapy[22,25] with or without additional EBRT, hypofractionated EBRT concepts[26] or proton and heavy ion concepts[27,28]. Rare spacer-related complications have been reported in the literature, as focal rectal necrosis or ulceration as a result of unintentional injection of hydrogel into the rectal wall or urinary retention, usually resolving within a short time[14].

Vanneste et al[29] calculated the cost-effectiveness of treating prostate cancer patients with and without a spacer, using a decision-analytic Markov model. According to the Dutch health costs, the spacer was found to be cost-effective for prostate cancer patients due to less severe toxicity and a reduction in treatment costs associated with side effects.

Taking into account a lack of long-term clinical experience with spacers, radiobiological models can be used to estimate long-term toxicity. They correlate prior data from the treatment plan and long-term toxicity[30]. Mean normal tissue complication probability (NTCP) for severe proctitis, necrosis, fistula or ≥ grade 2 rectal bleeding was found to be reduced by ≥ 50% comparing data before vs after hydrogel spacer injection. A clear advantage was shown for conventional and IMRT techniques[31].

The vast majority of published clinical studies have used hyaluronic acid or hydrogel. Studies with hyaluronic acid included smaller patient groups. Prada et al[25] did not observe grade 2 or higher toxicity after HDR brachytherapy as monotherapy (single 19Gy fraction) in an analysis of 40 patients and a median follow-up of 18 mo. Chapet et al[26] reported the acute toxicity of a hypofractionated IMRT with 3.1Gy fractions up to 62Gy total dose in 36 patients, without any grade 2 or higher toxicities.

PEG hydrogel stability during treatment has been shown in studies, so that a constant prostate-rectum separation can be expected[32]. Hydrogel starts to liquify about 3 mo after injection, is absorbed within about 6 mo and cleared via renal filtration. Prostate position variability is similar with or without hydrogel, so that IGRT is still required with a spacer to keep safety margins small. However, in contrast to patients without a spacer, larger posterior displacements were not found with a spacer[32].

A learning curve has been reported in a study including 64 patients, showing an increasingly symmetrical hydrogel distribution and significantly larger prostate-rectum distances with the same hydrogel volume. As a consequence, an improved dosimetric rectum protection and smaller acute bowel quality of life changes resulted[10].

Gastrointestinal toxicity (GI) was analyzed in a study including 48 patients in a multi-institutional prospective study. Grade 2 acute GI toxicity was reported in only 12% of patients (no grade 3-4 toxicity). Grade 1 late GI toxicity was found in 7% of patients within 12 mo after treatment (corresponding to two patients, one of them with grade 1 at baseline; no patients with grade 2-4 toxicity)[14].

In a prospective randomized multicenter study 222 patients were randomized between a treatment with and without hydrogel (149 patients with and 73 without spacer). Patients were treated after fiducial marker placement (IGRT) with 1.8Gy fractions up to a total dose of 79.2Gy, using an IMRT technique. There were no device-related adverse events, rectal perforations, serious bleedings or infections within either groups[21]. Mean rectal volume within the 70Gy isodose was reduced from 12% to 3%. As also reported in a prior case control study[33], similar acute rectal toxicity was observed in both patient groups. However, a significant reduction in late (3-15 mo) rectal toxicity in the spacer group was observed (2% vs 7%). There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 mo, 12% and 21% of spacer and control patients experienced 10-point declines in bowel quality of life (EPIC questionnaire, Expanded Prostate Cancer Index Composite)[21].

The number of published studies reporting clinical data with spacer materials for prostate cancer radiotherapy is increasing. Hydrogel, hyaluronic acid, collagen or an implantable balloon, can be injected or inserted under transrectal ultrasound guidance. Most studies, including several studies with more than 50 patients treated with a spacer and a recently published prospective randomized study, evaluate the effects of a hydrogel spacer (Figure 1). A distance of about 1.0-1.5 cm is usually achieved between the prostate and rectum, excluding the rectal wall from high isodoses. Procedure or spacer related complications are rare and treatments well tolerated. Reduced late toxicity rates have been shown in a prospective randomized study. Long-term results with a follow-up > 2 years are not available yet. Presently available results are encouraging for the design of further clinical studies.

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Figure 1 T2 weighted magnetic resonance imaging without (left) and with (right) a hydrogel spacer. Spacer hyperintense, resulting in > 1 cm separation between prostate and rectum.