Use of a Hyaluronic Acid Spacer May Effectively Mitigate Rectal Toxicity

Can using a hyaluronic acid spacer mitigate rectal toxicity and reduce the gastrointestinal toxicity that can be associated with radiation therapy? According to a recent paper published in JAMA Oncology, there is prospective data that support this approach.¹

Radiation therapy is a common treatment option for prostate cancer, and the use of hypofractionated radiation therapy has become increasingly more common over the last few years. Hypofractionated radiation therapy is convenient and cost-effective² and can be given to patients over a 4-to-6-week period as opposed to conventional fractionated radiation therapy, which must be given over an 8-to-9-week period. The authors report that several randomized trials have shown hypofractionated radiation therapy has similar biochemical control for both low-risk and intermediate-risk prostate cancer when compared with conventional fractionated radiation therapy. However, hypofractionated radiation therapy is associated with a nearly 10% greater absolute risk of acute grade 2 or higher gastrointestinal (GI) toxic effects compared with conventional fractionated radiation therapy.³

This risk of GI toxicity has led to the innovation of rectal spacers, which lengthen the distance between the prostate and rectum to reduce the high radiation doses effecting the rectum.⁴ Studies have investigated whether this approach improves GI toxicity, and the authors suggest rectal spacers “have been associated with reduced risk of acute GI toxic effects for hypofractionated radiation therapy.”

Rectal spacers using polyethylene glycol hydrogel were studied in a randomized, prospective trial with longer follow-up prior to conventional fractionated radiation therapy,^5,6 and a single-arm study in 2015 found that only 1 out of 36 patients experienced GI toxicity when a rectal spacer was placed prior to receiving hypofractionated radiation therapy.⁷ That result formed the basis for this study, which was “to report end points of a randomized clinical trial evaluating hyaluronic acid spacers (Palette Life Sciences) for hypofractionated radiation therapy,” with a primary end point of more than 70% of patients achieving a ≥25% reduction in rectal volume receiving 54 Gy (hypofractionated radiation therapy delivers 60 Gy in 20 fractions with IG-IMRT). The study’s secondary end point was showing noninferior acute grade 2 or higher GI toxic effects in patients who received the rectal spacer prior to being administered hypofractionated radiation therapy compared with those who did not.

The prospective, randomized, single-patient, blinded, multicenter clinical trial included patients who had biopsy-proven prostate cancer, cT1 or cT2 disease, and a Gleason score of 7 or less, with a prostate-specific antigen level ≤20 ng/mL. Patients who had allergies to hyaluronic acid, had prostate volume <15 cc or >90 cc, had undergone a transurethral resection of the prostate within 1 year, or had inflammatory bowel disease requiring steroids, lupus, scleroderma, an active bleeding disorder, or bilateral hip implants were excluded from the study.

A total of 201 patients met the study’s eligibility criteria. They were randomized 2:1 to receive a hyaluronic acid spacer plus fiducial markers (67%) or fiducial markers alone (32.3%) prior to receiving hypofractionated radiation therapy.

Patients were blinded to treatment assignment. Those who received the spacer underwent fiducial marker placement and transrectal ultrasound-guided, transperineal placement of the hyaluronic acid spacer. The spacer was injected between the Denonvilliers’ fascia and the anterior rectal wall under local anesthesia or conscious sedation. The average time to place was close to 14 minutes, and more than 90% of surgeons who placed the spacer found it easy or very easy to use. No intraoperative adverse events were reported. The authors noted that “post-injection, mean (SD) volume of the injected spacer as well as the mean prostate-rectum separation were 10.9 (2.1) mL and 12.9 (3.5) mm, respectively.”

Treatment with radiation therapy began within 30 days after placement of the fiducial marker plus hyaluronic acid spacer or fiducial marker alone. A total of 31% of patients received androgen deprivation therapy (ADT) and needed to initiate treatment within 30 to 60 days before fiducial marker placement and continue treatment for 4 months. Patients were monitored weekly while receiving radiation therapy and were assessed for toxic effects at 3 and 6 months. Patients also received repeat magnetic resonance imaging at 3 months to measure changes in spacer volume and prostate-rectum distance.

At the 3-month follow-up, spacer volume had decreased to 8.8 mL, and the prostate-rectum separation remained approximately the same at 12.6 mm. Nearly all (98.5%) patients experienced at least a 25% reduction in rectum V54, with a mean reduction of 85%.

A total of 4 (2.9%) patients in the spacer group experienced an acute grade 2 or higher GI toxic event within 3 months of treatment compared with 9 (13.8%) patients in the control group. Event symptoms included proctitis, diarrhea, constipation, and hemorrhoids. One patient experienced a grade 3 GI toxic event, severe diarrhea, which required suspension from receiving radiation and ultimately resulted in early termination of treatment. No acute grade 4 GI toxic events were noted in the control group. Grade 2 GI toxic events experienced by the 9 patients in the control group included proctitis, diarrhea, hemorrhoids, and rectal hemorrhage. All symptoms resolved by 6-month follow-up.

The authors concluded that use of the hyaluronic acid spacer demonstrated noninferior acute grade 2 or higher GI toxic events and “superior acute grade 2 or higher GI toxic effects.”

This is an important study and the first randomized clinical trial evaluating the utilization of a rectal spacer for hypofractionated radiation therapy. Study results indicate a significant reduction in GI-related toxic effects and are consistent with the previous literature for both the control and treatment cohorts. The authors hope to continue follow-up to characterize long-term effects and quality-of-life outcomes, including implications on sexual function at 3 years with the use of a hyaluronic acid spacer.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

 

References:

1. Mariados NF, Orio PF, Schiffman Z, et al. Hyaluronic acid spacer for hypofractionated prostate radiation therapy:a randomized clinical trial. JAMA Oncol. doi:10.1001/jamaoncol.2022.7592
2. Zhou K, Renouf M, Perrocheau G, et al. Cost-effectiveness of hypofractionated versus conventional radiotherapy in patients with intermediate-risk prostate cancer: an ancillary study of the PROstate Fractionated Irradiation Trial—PROFIT. Radiother Oncol. 2022; 173:306-312. doi: 10.1016/j.radonc.2022.06.014
3. Datta NR, Stutz E, Rogers S, Bodis S. Conventional versus hypofractionated radiation therapy for localized or locally advanced prostate cancer: a systematic review and meta-analysis along with therapeutic implications. Int J Radiat Oncol Biol Phys. 2017;99(3):573-589. doi:10.1016/j. ijrobp.2017.07.021
4. Prada PJ, Fernández J, Martinez AA, et al. Transperineal injection of hyaluronic acid in anterior perirectal fat to decrease rectal toxicity from radiation delivered with intensity modulated brachytherapy or EBRT for prostate cancer patients. Int J Radiat Oncol Biol Phys. 2007;69(1):95-102. doi:10.1016/j.ijrobp.2007.02.034
5. Mariados N, Sylvester J, Shah D, et al. Hydrogel spacer prospective multicenter randomized controlled pivotal trial: dosimetric and clinical effects of perirectal spacer application in men undergoing prostate image guided intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2015;92(5):971-977. doi:10.1016/j.ijrobp.2015.04.030
6. Hamstra DA, Mariados N, Sylvester J, et al. Continued benefit to rectal separation for prostate radiation therapy: final results of a phase III trial. Int J Radiat Oncol Biol Phys. 2017;97(5):976-985. doi:10.1016/j.ijrobp.2016.12.024
7. Chapet O, Decullier E, Bin S, et al. Prostate hypofractionated radiation therapy with injection of hyaluronic acid: acute toxicities in a phase 2 study. Int J Radiat Oncol Biol Phys. 2015;91(4):730-736. doi:10.1016/j.ijrobp.2014.11.027