- Published in Everyday Urology - Oncology Insights: Volume 3, Issue 4
Nonetheless, improved and extended long-term survival following prostate radiotherapy raises the concern of late-onset radiation-induced toxicity.7 Sequelae such as chronic diarrhea, rectal stricture, tenesmus, rectal bleeding, urinary obstruction, urgency, incontinence, and sexual dysfunction may seriously undermine a patient’s quality of life and also contribute substantially to healthcare costs.8,9,10,11
These toxicities are still encountered despite our ability to render more precise radiotherapies such as IMRT and IGRT.5 In a meta-analysis of five randomized trials, every 8 to 10-Gy increase in radiation dose to the prostate approximately doubled the odds of severe late-onset gastrointestinal or genitourinary toxicities and led to a 63% increase in the likelihood of more moderate toxicities.7 In other recent trials of prostate radiotherapy, rates of late-onset grade 2 or worse toxicities were 14% to 25% for rectal sequelae and 12% to 46% for genitourinary sequelae.4,12,13,14
PROTECTING THE ORGAN AT RISK
The rectum is the radiation dose-limiting anatomical structure within the pelvis because of its fixed position immediately adjacent to the prostate.5,6,15 Indeed, some studies suggest that as many as 75% of patients who undergo prostate radiotherapy develop acute proctitis, and some 20% develop chronic symptoms.15 These risks further increase in the presence of conditions that predispose patients to vascular injury and ischemia, such as smoking, hypertension, diabetes, and atherosclerosis.15 Studies using three-dimensional imaging show a strong correlation between rates of late rectal bleeding after prostate radiotherapy and the volume of rectal tissue receiving more than 70 Gy radiation.6,16,17 More moderate radiation doses (40 to 50 Gy) also can lead to substantial late-onset gastrointestinal toxicities if a larger surface area of the rectum is exposed.6
Given these findings, investigators have tested various strategies for shielding the organ at risk (OAR), the rectum, during prostate radiotherapy. For example, endorectal balloons have been used to immobilize the prostate, and in some studies, they also appeared to reduce rectal irradiation during three-dimensional conformal radiotherapy (3DCRT).6 However, endorectal balloons showed no significant dose-sparing effect during IMRT, which in many settings has replaced 3DCRT for prostate radiotherapy.6,18 In addition, an improperly placed endorectal balloon can potentially decrease the efficacy of radiotherapy.6,19 In one real-world study, researchers reported an average placement error of 0.5 cm, enough to partially shift the prostate outside the planned radiation effective treatment area.19
More recent work has focused on administering transperineal injections of various materials into Denonvilliers’ space in order to shift the anterior rectal wall away from the prostate during radiotherapy.20,21 Hyaluronic acid, blood patches, and collagen all have been tested; all were found to be well-tolerated, relatively easy to position under transrectal ultrasound guidance, and protective regarding rectal irradiation.22,23,24,25 However, the deployment of these materials was not uniform. Untoward effects included the creation of too limited a perirectal space (buffer), material shift after placement, or too rapid biodegradation after deployment.21,26
In contrast, studies of off-label injections of DuraSeal® polyethylene glycol (PEG), a spinal sealant, showed excellent tolerability, ease of use, and significant rectal sparing during IMRT and low- and high-dose brachytherapy.27,28
DEVELOPMENT OF SPACEOAR®
SpaceOAR® (Augmenix, Bedford, MA, USA) was developed as an absorbable perirectal spacer made of biodegradable PEG-based hydrogel that is injected transperineally between the prostate capsule and the rectum under transrectal ultrasound guidance.29
In a multicenter single-arm phase II trial of 52 men with localized prostate cancer, CT simulation scans performed before and after placement of this spacer revealed decreases in rectal radiation that were consistent across investigative institutions.30 Significant rectal sparing was observed across a radiation treatment range of 10 to 75 Gy.30 The mean decrease in rV70 was 8.0% (standard deviation 4.2 %), and the median decrease was 7.8% (95% confidence interval, 0.3% to 19.5%).
In this phase II trial, initial and 12 month follow-up results demonstrated no grade 3-4 gastrointestinal toxicities and no grade 4 genitourinary toxicities, while only 2.1% of patients developed grade 3 genitourinary toxicities.31 At 12 months, gastrointestinal toxicities were uncommon (4.3%) and were always grade 1, with no cases of gastrointestinal ulcer, stricture, or necrosis.31 The incidence of late genitourinary toxicities was 17% for grade 1 events, 2.1% for grade 2 events, and 0% for grade 3 or worse events.31
PHASE III TRIAL
Based on the phase II results, researchers evaluated SpaceOAR in a 3-year, multicenter, randomized, controlled trial of 222 men with stage T1 or T2 prostate cancer (NCT01538628).32 After undergoing CT and MRI-based radiation treatment planning and fiducial marker placement, participants were randomly assigned on a 2:1 basis to the spacer or control (no spacer) arm. Men in the spacer arm had the hydrogel spacer placed under intravenous anesthesia. Patients in both arms then received another set of planning scans followed by dose-escalated (79.2 Gy) IMRT of the prostate (with or without the seminal vesicles) in 44 fractions.32
The results of the phase III trial supported those from the phase II study. Spacer placement increased the perirectal space by a mean of 11.0 mm.32 In the spacer arm, 97.3% of men had at least a 25% decrease in average projected volume of rectal tissue receiving at least 70 Gy (rV70).32 Mean rectal v70 values were 3.3% after spacer placement versus 12.4% at baseline (P < .0001).32 Rates of acute rectal toxicities generally were similar between groups, but men who received the spacer reported significantly less acute rectal pain compared with controls (P = .02).32
From 3 months onward, no patients in the spacer arm and 5.7% of controls developed grade 2 or worse rectal toxicities such as fecal incontinence, proctitis, or bleeding (P = .012).33 Rates of late-onset grade 1 or worse rectal toxicities also favored the spacer arm (2% vs. 9.2% in the control group; P = .028). Men who received the spacer also had a significantly lower rate of grade 1 or worse urinary incontinence (4% versus 15%; P = .046), although rates of grade 2 or worse urinary toxicity were identical (7%) between arms.33
Secondary analyses of the phase III trial correlated SpaceOAR placement with significantly improved long-term patient-reported quality of life.33 From 6 months onward, men who had received the spacer reported significantly better post-radiotherapy bowel quality of life compared with controls (P = .002), and the difference remained statistically significant at 3 years.33 Additionally, 41% of controls reported long-term declines in bowel quality of life that met a predefined threshold for minimally important difference (MID), compared with only 14% of spacer recipients (P = .002). Men who received the spacer also reported significantly improved 3-year urinary quality of life versus controls (P < .05). Furthermore, 30% of controls reported declining urinary quality of life that met the MID threshold, versus only 17% of spacer recipients (P = .04).
Preliminary data also have correlated SpaceOAR placement with preserved sexual function after prostate radiotherapy.5,34 In the phase III trial, the spacer reduced the average and maximum radiation doses to the penile bulb, as well as the volume of the penile bulb receiving 10 to 30 Gy (all P < .05).34 Most (59%) men in this trial had low baseline sexual function, scoring below 60 on the Expanded Prostate Cancer Index Composite (EPIC).34 However, among men with adequate baseline sexual quality of life, those who received the spacer reported better sexual function at 3-year follow-up versus controls (mean EPIC scores, 57.7 vs. 44.6, respectively; P = .1). Furthermore, among baseline-potent men, 66.7% of spacer recipients retained erections sufficient for intercourse at 3 years compared with only 37.5% of controls (P = .046).
SpaceOAR placement in the phase III trial also demonstrated similar safety and tolerability as that seen in the phase II trial. The rate of successful spacer deployment in the pivotal trial was 99%, and nearly all investigators reported that placing the spacer was easy or very easy.32 There were no rectal perforations, serious bleeding events, or rectal infections in either study arm.
In order to further characterize real-world experiences with SpaceOAR, a single-arm trial was prospectively conducted of 99 men with prostate cancer who received the spacer at 16 urology group practices.35 A total of 95% of cases were performed within the office-clinic setting, while 5% were performed at ambulatory surgery centers. The average postprocedural perirectal space created was 10.7 mm, and 80% of urologists described the procedure as easy or very easy, while the rest described it as moderately easy. Fully 94% of patients said the would recommend the SpaceOAR procedure to other patients. Furthermore, 97% of patients said that they were less anxious about their pending radiation therapy knowing that they had SpaceOAR in place during treatment.
Figure 1. SpaceOAR Clinical Trial Patient, MRI Images: Normal Anatomy, During Prostate RT and 6 months Following
Placing SpaceOAR is technically straightforward for urologists who are familiar with ultrasound-guided transperineal injections. The spacer can be deployed at the same time that fiducial markers are placed.
Patients are placed in a lithotomy position and may receive either conscious sedation, local anesthesia with oral anesthesia or general anesthesia.36 Under stepper-mounted side-fire transrectal ultrasound guidance, 18-gauge needle is advanced through the perineal midline into the perirectal fat posterior to Denonvilliers’ fascia and anterior to the rectal wall. 36
Proper placement of the transperineal needle within the midline of Denonvilliers’ space is key. It must be advanced at the prostate midline to prevent lateral injection of the hydrogel precursor and accelerator solutions.36 If the needle enters the rectal lumen at any time during injection, the procedure should be abandoned to prevent infection.36
After confirming that the needle has been placed correctly, mid-gland hydrodissection with a sterile saline solution is performed to expand the space between Denonvilliers’ fascia and the anterior rectal wall. The needle is aspirated to confirm it is not intravascular. Then, without moving the needle, 10 ml of PEG hydrogel precursor and accelerator solutions are injected into the expanded perirectal space.31 These solutions polymerize within 10 seconds to form a soft hydrogel spacer approximately 1 cm in diameter.36 The spacer persists for 3 months and is completely absorbed and cleared by renal filtration within 6 months.30,36
In the phase III trial, SpaceOAR was placed under intravenous sedation.32 In my practice, I now use local anesthesia. I pre-medicate patients with an oral anxiolytic and wait 30 to 45 minutes before injecting any perineal local anesthetic. Next, I perform a perineal subcutaneous block, fan out the anesthetic along the skin, and then perform a diffuse block around the prostatic apex. I avoid injecting anesthetic along the right or left lateral aspects of the prostate to avoid creating any ultrasound artifact. The learning curve for SpaceOAR is fairly rapid. Urologists who have experience with transperineal procedures and transrectal ultrasound should be very comfortable performing SpaceOAR insertions after just a few cases. Those who are comfortable with transrectal ultrasound, but not with transperineal needle placement, may consider using more anesthesia for their first few SpaceOAR cases in order to become comfortable with the technique. SpaceOAR procedures require a side-fire transrectal ultrasound probe and a stepper. A floor-mounted stepper is more mobile and may be preferable to a table-mounted or bedmounted stepper, but individual preferences will vary. Although a template grid often is useful for placing fiducial markers, it is not necessary and can impede proper angling of the needle when placing SpaceOAR.
REIMBURSEMENT AND TREATMENT PLANNING
Spacer placement can be performed in an outpatient setting or in a hospital surgery center. For patients with Medicare coverage, reimbursement is approved under CPT code 55874 (transperineal placement of biodegradable material, peri-prostatic single or multiple injections, including image guidance, when performed).37 Reimbursement in clinic settings is favorable. As of 2018, the national Medicare reimbursement averages were $3,797.24 for physician office-based spacer placement and $3,706.03 for hospital outpatient procedures.38
Based on this reimbursement rate, urologists whose practices purchased a side-fire transrectal ultrasound probe and stepper may achieve revenue neutrality after approximately 40 SpaceOAR cases.35 Further efforts are underway to approve Medicare reimbursement of SpaceOAR placement in ambulatory surgery facilities.
Repeat imaging should occur about 5-10 days after placing the spacer to allow post-injection swelling to resolve.39,40 This prevents overestimation of the prostate volume, which will presumably be coordinated by our radiation oncology colleague.
Some radiation oncologists elect to obtain a T2-weighted MRI and fuse to the repeat planning CT in order to better distinguish the hydrogel from the rectal wall.39,40 The addition of MRI also helps confirm that the spacer was properly injected. It is not necessary to further monitor the spacer volume during radiotherapy in the pivotal multicenter trial, the spacer consistently retained a stable volume for 3 months after placement.39
TOXICITIES AND CAUTIONS
SpaceOAR has been well tolerated in studies to date. There have been no reports of local irritation or allergic reactions. However, several contraindications should be considered. First, use of SpaceOAR is not recommended for locally advanced prostate cancer because it may not be possible to create an effective perirectal space, and also because a transperineal needle could potentially disseminate tumor cells within the pelvis.39 Men who have previously undergone high-intensity focused ultrasound, cryotherapy, or radiotherapy of the prostate may have adhesions that could impede the injection of SpaceOAR.39 SpaceOAR also is contraindicated for patients with clinically significant coagulopathies or active bleeding disorders. For other patients on anticoagulants, it may be possible to discontinue anticoagulants temporarily for the purpose of SpaceOAR placement.39 Finally, SpaceOAR may not be appropriate for patients with prostatitis or anorectal inflammatory diseases for which there is increased risk of ulceration, fistula, or bleeding, such as ulcerative colitis or Crohn’s disease.39
Although transient perineal discomfort has been reported, there have been no reports of rectal perforation, rectal infection, or serious rectal bleeding after placing SpaceOAR.39 However, there has been a single report of a necrotic 1-cm rectal ulcer occurring 2 months after a patient underwent SpaceOAR placement prior to I-125 prostate brachytherapy.41 This was the first case of rectal ulceration that the reporting physicians had observed in 55 SpaceOAR procedures.41 The patient and physicians closely monitored the ulcer, and sigmoidoscopy showed complete resolution 3 months after the SpaceOAR procedure.41
After reviewing the case, the physicians reported that SpaceOAR had been placed under sterile conditions with routine antibiotic prophylaxis consisting of perioperative intravenous cephazolin plus 5 days of postprocedural norfloxacin (400 mg twice daily).41 The only unusual aspect of this case was that the hydrogel had solidified prematurely within the SpaceOAR delivery system, requiring the system to be replaced mid-procedure.41 The physicians concluded that mechanical injury might have been the cause of this ulcer. Since then, these physicians have begun tilting patient beds “head up” before inserting SpaceOAR to reduce downward angling of the needle and premature leaking of the precursor and accelerator solutions.41 This is an appropriate precaution to consider. These physicians also remove the brachytherapy template to improve maneuverability of the SpaceOAR needle, advance the needle with the bevel away from the rectum to avoid perforation, take care to reduce pressure of the transrectal ultrasound probe against the anterior rectal wall, hydrodissect with normal saline to expand the perirectal space, inject no more than 10 mL of the precursor and accelerator solutions, and stop if they encounter resistance.41
Research continues to evaluate the safety and efficacy of SpaceOAR across a range of prostate radiotherapies. One such modality is stereotactic ablative radiotherapy, an emerging external beam technique that delivers fewer but larger radiation fractions to the tumor target over an abbreviated treatment schedule.42
Earlier this year, oncologists in Ireland reported their experience with the first six participants in a clinical trial of SpaceOAR placement prior to stereotactic ablative radiotherapy.43 All spacers were placed successfully, the only acute toxicity was grade 1 proctitis, spacer placement did not significantly alter clinical target volume dose coverage, and rectal irradiation dropped substantially: for example, by at least 42% for the volume of rectum receiving 36 Gy radiation.43 Furthermore, the probability of grade 2 or worse rectal bleeding fell from 4.9% to 0.8% (P = .03).43
Unfortunately, late-onset rectal ulceration is common after patients undergo stereotactic ablative radiotherapy. To understand whether placing a hydrogel spacer can meaningfully reduce this risk, a phase II trial (NCT02353832) at the University of Texas Southwestern Medical Center has enrolled 44 patients with low-risk prostate cancer. Planned follow-up time is 5 years, and secondary outcome measures include acute toxicities, at least a 50% reduction in the circumference of rectum receiving 24 and 39 Gy radiation, and the stability of the spacer during treatment.
Additionally, a post-marketing surveillance trial (NCT01999660) in Germany is recruiting an estimated 250 patients with T1 to T2, N0, M0 prostate cancer. The primary endpoint is late rectal complications for up to 5 years after IMRT, 3DCRT, or brachytherapy. The secondary outcome is quality of life based on the EPIC questionnaire in combination with the Short Form Health Survey (SF-12). The investigators also are evaluating the immediate feasibility and safety of hydrogel injection. Primary results are expected in January 2019. The results of this study will help clarify the effects of SpaceOAR placement on late toxicities and quality of life across a range of radiotherapy modalities for prostate cancer.
Injecting a transperineal spacer prior to radiotherapy can help prevent rectal adverse events by protecting the organ at risk (OAR) from radiation toxicity. Currently, the only FDA-approved prostate cancer spacing device available for use in the United States is SpaceOAR, a polyethylene glycol (PEG) hydrogel spacer. In clinical trials, SpaceOAR placement significantly reduced irradiation of the rectum and penis during prostate radiotherapy. Long-term follow-up of the pivotal phase III trial also showed significant reductions in late gastrointestinal and genitourinary toxicities, with corresponding improvements in bowel, urinary, and sexual quality of life.5, 32, 33,34 The spacer is well tolerated, inserting it is straightforward, and the risk of postprocedural adverse events is low. It is becoming an important component of prostate radiotherapy. Additional studies of hydrogel spacers are ongoing. Urologists and radiation oncologists can work in tandem in order to further benefit prostate cancer patients who elect to proceed with radiation therapy.
Written By: Neal Shore, MD, FACS
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