Interdisciplinary consensus statement on indication and application of a hydrogel spacer for prostate radiotherapy based on experience in more than 250 patients

Dose escalated intensity-modulated radiation treatment (IMRT with radiation doses ≥ 76 Gy) is a highly effective, curative treatment option for localized prostate cancer. Biochemical control is directly related to radiation dose with a dose effect per each additional Gy.¹ For example, escalation from 70 to 80 Gy is connected with a 15% increase in PSA control. This dose effect is described for all risk groups. However, an increased radiation dose is also associated with rising levels of grade ≥ 2 acute and chronic toxicity.¹ Lower gastrointestinal toxicity rates can result from smaller posterior safety margins or even no safety margins², potentially compromising local tumour control.

A novel method to reduce rectal toxicity during dose-escalated IMRT is the insertion of a hydrogel spacer between the Denonvilliers’ fascia and anterior rectal wall to separate these structures.³ The created space generates a distance of 10 – 15 mm between both organs.⁴-⁶ Recent studies unequivocally demonstrated a significant reduction in high-dose areas on the anterior rectal wall.⁴,⁵,⁷,⁸ As expected, better rectal sparing from higher radiation doses was associated with only mild toxicity from the dose-escalated treatment.⁴,⁹,¹⁰

The application technique³, dosimetric studies⁴,⁸ and some early toxicity data⁴,¹⁰, as mentioned above, were all published within the last two years. However, despite rising numbers of hydrogel injections, reports on practical aspects or pitfalls of hydrogel application as well as frequency and management of side effects of the administration were not or were only provided for single cases.¹¹ Therefore, the first consensus meeting was held in July 2013 to discuss this practical issue and to generate answers for users on the indication, application and management of side effects of a hydrogel spacer for dose-escalated radiotherapy. Thereafter, toxicity data of the injection technique was collected from > 250 patients of four centres to better balance the benefit and potential risks of this new method.

The aim of this consensus report is to offer new users of this technique easy access to relevant information on practical application and patient management to shorten the learning curve⁷ and to carefully balance potential benefits against potential risks of this technique.

The interdisciplinary meeting was attended by radiation oncologists and urologists, each with experience of 23 – 138 hydrogel injections (SpaceOAR®) in prostate cancer patients before dose-escalated IMRT. In the first part of the meeting, user experiences were discussed and questions were defined to comprise practical information relevant for successful gel injection and treatment. In the second part, answers to the defined key questions

were developed. Prospective data from the multi-institutional clinical trial¹⁰, prospective mono-institutional data (German Clinical Trials Register DRKS00003273)⁴ and data collected retrospectively from patient files were considered in this interdisciplinary process to evaluate hydrogel application in current practice. The prospective studies were approved by each institution’s ethics committee. With regard to the participating centres approvals were given by the University of Aachen¹⁰, the University of Heidelberg¹⁰ and the University of Tübingen.⁴ All of these patients (n = 62) gave their written informed consent to participate in these studies.⁴,¹⁰ After discussing the intended analysis of retrospectively collected data (n = 196) the institutional review board (Ethics Committee of the University of Tübingen) had no objections (266/2015BO2). Patients gave informed consent to standardized data documentation and evaluation of treatment related toxicity.

After the meeting, participants were asked to state the incidence of side effects to better balance risks and beneficial effects. Finally, the statement was revised and consented. Recommendations derived from prospective studies were indicated as level of evidence (LOE) 2a (evidence obtained from at least one well-designed controlled study without randomisation). Consensus statements based on expert opinions were indicated as LOE 4.

The SpaceOAR® System (resulting in 10 mL hydrogel) is FDA cleared and CE Mark approved, and commercially available in the US and most countries of Western Europe.

The following key questions were developed with regard to practical aspects of hydrogel application and patient management:

The following key answers were developed:

Injection technique

Hydrogel injection can be performed under local (possibly additional sedation), spinal or general anaesthesia. Additional procedures that are planned at the same time (i.e. brachytherapy, marker implantation etc.) determine the selected anaesthesia and should be performed in advance or a few days later since hydrogel injection might worsen visibility by air contamination. For preparation of the patient see also 3. Prophylaxis. Generally, the patient is placed in the lithotomy position. The injection is performed transperineally under transrectal ultrasound (TRUS) guidance using a linear side-fire TRUS probe and a stand-off balloon to optimize visibility. A stepper unit stabilizes the probe, so that both hands are free for the procedure.³,¹⁸ The transperineal route is well known for procedures such as prostate biopsies, fiducial placement or prostate brachytherapy.¹⁹

All centres involved in this consensus used the hydrodissection technique before spacer injection to separate Denonvilliers’ fascia and the anterior rectal wall. This fluid-mediated tissue separation technique is also used in other settings like cataract surgery and carpal tunnel syndrome treatment.²⁰,²¹

In short, an 18 gauge needle is inserted 1 – 2 cm above the patient’s anus through his perineum. The needle is advanced either parallel to the probe or slightly angled towards the prostate apex. The correct needle position is below the prostatic apex in midaxial and midsagital position of prostate (so called midgland position). Lowering the probe before hydrodissection might facilitate the procedure. Hydrodissection is performed with 10 – 20 ml of saline or lidocaine (as local anaesthesia) diluted in saline. A slow injection of the fluid is necessary to ensure later a symmetric distribution of the spacer. Only in case of a successful hydrodissection, the hydrogel can be applied.

Hydrogel is formed during the simultaneous injection i.e. mixing of the precursor (polyethylene glycol powder) and accelerator solutions (diluent). The solutions are mixed as they pass through a Y-connector prior to passing through the injection needle. Both solutions polymerise to a soft PEG-based gel within 10 seconds. An injection of 10 mL hydrogel results in a separation of about 9 – 10 mm between the prostate and rectal wall (Figure 1).⁶ The injection procedure can be completed within a few minutes.

Figure 1

The most relevant practical aspects of hydrogel injection after 258 applications were summarized in this consensus statement. A detailed description of indications, prophylaxis and management of side effects should provide new users with a fast and comprehensive introduction to the successful application of this new method. After a short learning period, the procedure can be performed to a high standard, ensuring low toxicity. Most data used are derived from well-defined controlled but not randomized studies or prospective investigations, leading to Level IIA evidence for indication and application of the hydrogel spacer.

In the multi-institutional phase II trial (52 patients recruited, 49 patients after successful spacer injection), patients were informed of higher probability of grade 2+ toxicity, as no experience existed. With a carefully estimated probability of 6 – 20%, it included an injection into the rectal wall, bladder wall and urethra, ulceration and necrosis of the rectal wall, bleeding and urinary retention. Three patients who were initially treated within this study experienced procedure-related events after hydrogel injection including focal rectal necrosis due to inadvertent injection of hydrogel into the rectal wall, bladder piercing during injection with hydrogel leak into the bladder, urinary retention and a device-related proctitis.⁶ All of these events occurred during the initial experience (learning curve in the first patient cohort) and resolved completely. Adaptations of the injection procedure (side-fire TRUS probe, stepper, stand-off balloon) were conducted which facilitated handling of the needle and hydrogel insertion. A learning curve has been reported for the application and treatment with a hydrogel, again stressing several technical aspects to achieve homogenous hydrogel distribution. This report summarizes important issues that need to be considered to achieve satisfactory spacer distribution.

Radiotherapy planning should not include the usual objectives for the dose to the rectal wall. A dose of 70Gy can be allowed for 20% of the rectal wall volume according to RTOG (Radiation Therapy Oncology Group) recommendations.²³ With a prescription dose of 76–78Gy, mean rectum volumes within the 70Gy isodose can range by about 1% with good spacer placement and adequate treatment planning.⁷

However, the findings of this multi-institutional evaluation of spacer-related toxicity (no G3+ event) were based on conventional fractionated dose-escalated IGRT and cannot be simply adopted to other radiation treatment schedules (hypofractionation) or treatment with other ionizing radiation sources. In a study with hypofractionation using particle beam therapy (without CT-image guidance) two cases (2/92; 2%) of G3-toxicity (colostomy) occurred, a relation to the hydrogel spacer injection cannot be excluded.²⁴

Therefore, it is extremely important that patients are closely followed up at their centre after hydrogel injection. As the hydrogel is not tissue-toxic or allergenic, conservative management in case of inaccurate injection should be initiated as described above. Patience is required in case of inadvertent injection to the rectum or bladder wall, or in case of rectal wall penetration or ulceration. All cases in this analysis where this occurred healed without long-term sequelae. A currently published randomized trial demonstrated well toleration of spacer application (10% mild transient procedural perineal discomfort) in 149 patients suggesting safety of this method with conventional fractionated dose-escalated IGRT, too.²⁵

For optimized injection results, one expert in each centre was trained by another expert. The procedure was performed by only one or two experts at each centre, guaranteeing a high degree of experience. Last but not least, correct patient selection is essential. The optimal patient for this new method is at low risk of adhesions (inflammation, tumour spread due to locally advanced disease) and has a low risk of bleeding. The risk of tumour displacement by hydrodissection is very small, since prostatectomy series with limited pT3 stages reported in less than one fifth of patients an invasion and in no case a progression through the full thickness of the Denonvilliers’ fascia.²⁶

After successful injection, the benefit for the patients was measured by acute toxicity scores and by radiation planning parameters (dose-volume histograms). In brief, the theoretical benefit of an additional space between prostate and rectum translated into improved radiation treatment plans with approximately 10% reduction in relevant high-dose areas (dose level from 40–70Gy).⁸ These improved radiation treatment plans with lower rectal doses converted into reduced acute toxicity rates. Grade 2 proctitis resulting from radiotherapy was a rare event compared to standard conformal or intensity-modulated radiotherapy, for example 12.5% acute toxicity in the multicenter phase II trial¹⁰ in comparison to occasionally 50% or more in studies without a spacer.²⁷,²⁸ The prevention of acute proctitis with this procedure is a benefit for the patient. Further benefits for the patients are conceivable. Consequential late side effects derive from persisting acute toxicity²⁹ and reduced acute toxicity will usually be associated with a lower risk of late toxicity. However, the evaluation of this potential long-term benefit needs longer follow-up. Another beneficial effect of improved rectum protection is the facilitation of dose escalation to the prostate. Since increased radiation doses improve outcome in the range of approximately 1.5% better biochemical control per Gy after a mean follow-up of five years¹, these dosimetric changes are relevant for improved tumour control with a lower risk of toxicity.

This spacer consensus focuses on the use of Polyethylene-glycol (PEG) hydrogel spacers in dose-escalated radiotherapy of prostate cancer. However, at least four different bio-resorbable spacer materials (PEG-hydrogel, balloon of copolymer of polylactic acid or similar poly (α-hydroxy acids), hyaluronic acid and collagen) are currently evaluated. PEG hydrogel spacers and bio-resorbable balloons have demonstrated an excellent biocompatibility profile in humans compared to other spacers made of hyaluronic acid or collagen.³⁰

Direct comparison of PEG hydrogel spacer and bio-resorbable balloon demonstrated the following. PEG spacers were less invasive (smaller needle diameter with 1.3 vs. 2 – 3mm). The balloon spacer was superior in reducing rectum dose (-28%), but exhibited an average volume loss of > 50% during the full course of treatment (37–40 fractions), while the volume of gel spacers remained fairly constant.³¹

Displacement of radiosensitive organs by spacers is not limited to primary prostate cancer alone. Further applications being investigated include treatment of recurrent prostate cancers³², gynecological malignancies³³ and esophageal gel-shifting facilitating treatment of mediastinal nodes.³⁴ The principle to displace radiosensitive organs from high dose areas is also used in case of adhesions of small intestinum and radiation targets. For such special situations are invasive surgical techniques available like laparoscopic mesh placement.³⁵

We conclude that hydrogel injection can be considered for dose-escalated radiotherapy. Well trained physicians, correct patient selection and knowledge of the management of potential side effects are essential for optimal application. The benefit for the patient is improved protection of the rectal wall, which is associated with low radiation related proctitis rates. This allows dose-escalation associated with improved tumour control. However, a very low rate of a potential serious adverse event cannot be excluded and should carefully be discussed with the patient and be balanced against potential benefits. The evaluation of this potential long-term benefit needs longer follow-up.

The consensus meeting was supported by CSDiagnostics, Neuss, Germany. Augmenix, Inc., Waltham, Massachusetts, United States is the sponsor of the multicentre-study and sponsored with CSDiagnostics, Neuss, Germany additional hydrogels for patients treated outside the multicentre study. TK reports grants from CSDiagnostics, Neuss, Germany for another meeting.