To overcome this potential toxicity, prostate-rectum spacers have been developed to push the rectum out of the high dose region throughout radiotherapy, and then to allow for these spacers to fully absorb within 6 months’ time. The only FDA cleared spacer, SpaceOAR® System, is a soft PEG hydrogel placed between Denonvilliers’ fascia and the rectal wall, where it allows for enhanced anatomic separation of the rectum and prostate during radiotherapy. This spacer was the focus of a prospective, randomized, patient-blinded, multicenter, Phase 3 prostate IG-IMRT clinical trial conducted between 2012 and 2016. The results of that study have been previously published in Radiation Oncology journals.[5]–[7] The objective of this paper is to review and summarize these clinical results.
Study Design
A total of 222 men with low-intermediate risk prostate cancer were included in the 20-center trial. Using either local, general or MAC anesthesia all patients underwent transperineal fiducial marker placement concomitantly and were immediately randomized 2:1 to receive Spacer hydrogel (n=149), or to Control (no spacer, n=73). At 1 week patients underwent CT and MR imaging for IG-IMRT dose planning (79.2Gy in 44 fractions) to the prostate +/- seminal vesicles. Following completion of radiotherapy, all patients were followed at 3, 6, 12, 15 and 37 months; toxicity and QOL (Expanded Prostate Cancer Index Composite) data were collected.
The implant procedure and quality
Spacer application resulted in an average of 12.6+3.9 mm of space between the prostate and rectum in the Spacer group. Spacer patients experienced little or no spacer sensation immediately following placement, although 10% reported transient application-related adverse events (perineal discomfort, etc) lasting only a few days. Prostate-rectum hydrogel was present in almost all cases at 1-week of imaging, thus resulting in a 99% technical success rate. There were no adverse events attributed to the hydrogel spacer itself.
Spacer reduction in rectum and penile bulb radiation dose
Spacer application resulted in a significant reduction of median rectal V70 radiation dose (percent volume of rectum receiving 70 Gy radiation) compared to Control (2.3% vs 10.5%, p=<0.0001). Additionally, the median penile bulb dose was also significantly reduced in the Spacer group (10.8Gy vs. 21.1Gy, p=0.036)
Acute and late GU and GI toxicity
During the acute phase (0-3 months) there was no difference in the rates of rectal or urinary toxicity in the Spacer and Control groups, however, rectal pain adverse events during the acute phase favored the Spacer group (2.7% vs 11.1%, p=0.022).
Late G1+ rectal toxicity through 37-months favored the Spacer arm (2% vs 9%, p<0.03), with no Spacer men experiencing rectal toxicity greater than G1. There was no difference in late G1+ urinary toxicity between groups, although fewer Spacer men experienced G1+ urinary incontinence (4% vs 15%, p=0.046).
Patient Reported Outcomes
Both groups experienced QOL declines during radiotherapy, however, the Spacer group bowel and urinary QOL was at or near baseline from 6 to 37 months. At 37-months the mean Control bowel and urinary QOL scores were 5.8 points (p=0.0009) and 3.9 points (p=0.013) lower than SpaceOAR QOL scores, respectively.
Alternatively, one can look at the percent of men in the two groups experiencing clinically significant declines in QOL surpassing the pre-established Minimally Important Difference (MID) threshold (Bowel: 5 points, Urinary: 6 points, Sexual: 11 points). At 37 months 41% of Control and 14% of Spacer men were experiencing bowel MID QOL declines (p=0.002), while 30% of Control and 17% of Spacer men were experiencing urinary MID QOL declines QOL (p=0.04).
Overall well-being was assessed by reviewing the proportion of patients experiencing MID declines in all three QOL domains (bowel, urinary and sexual). At 37-months 2.5% of men in the Spacer arm (1 in 40) experienced MID declines in all 3 domains compared to 20% (1 in 5) of men in the Control arm (p=0.002).
Spacer-related benefits in baseline potent men were also observed, with 37.5% of Control and 66.7% of Spacer patients retaining “erections sufficient for intercourse” at 37 months (p=0.046).
Number Needed to Treat (NNT)
The spacer proved to be very effective inpreventing complications and declines in QOL, as measured by NNT calculations. For example, the number of men needed to treat with SpaceOAR hydrogel to prevent one patient from experiencing (at 37 months) a MID decline in bowel QOL is 3.7, to prevent erectile dysfunction in baseline potent men is 3.4, and to prevent a MID decline in all three domains is 5.7.
To put this effectiveness into perspective, in the ProtecT trial the number of men needed to treat to prevent one man from developing metastasis from prostate cancer was 27 for radical prostatectomy and 33 for radiation therapy. [8]
Conclusions
These clinical trial results demonstrate that the prostate-rectum spacer application technique is safe and highly effective in reducing post radiotherapy GI toxicity and declines in QOL. Urologists treating newly diagnosed prostate cancer patients appropriate for radiation therapy are well suited to perform this spacing procedure. Of note, the AMA has established a new CPT code (55874) which goes into effect January 1, 2018 for periprostatic implantation of biodegradable material, under which SpaceOAR placement may be billed. With coverage becoming established in 2018, urologists can offer this new technology to their patients considering prostate radiation therapy.
Written by: Neal Shore, MD, FACS
References
[1] D. Dearnaley et al., “Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial,” Lancet Oncol., vol. 17, no. 8, pp. 1047–1060, 2016.
[2] S. Aluwini et al., “Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial,” Lancet Oncol., vol. 17, no. 4, pp. 464–474, 2016.
[3] R. C. Wortel et al., “Late Side Effects After Image Guided Intensity Modulated Radiation Therapy Compared to 3D-Conformal Radiation Therapy for Prostate Cancer: Results From 2 Prospective Cohorts,” Int. J. Radiat. Oncol., vol. 95, no. 2, pp. 680–689, 2016.
[4] C. N. Catton et al., “Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer,” J. Clin. Oncol., vol. 35, no. 17, pp. 1884–1890, 2017.
[5] N. Mariados 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., vol. 92, no. 5, pp. 971–977, 2015.
[6] D. A. Hamstra et al., “Continued Benefit to Rectal Separation for Prostate RT: Final Results of a Phase III Trial,” Int. J. Radiat. Oncol. • Biol. • Phys., vol. 97, no. 5, pp. 976–985, 2017.
[7] D. A. Hamstra et al., “Sexual Quality of Life Following Prostate Intensity Modulated Radiotherapy (IMRT) with a Rectal/Prostate Spacer: Secondary Analysis of a Phase III Trial,” Pract. Radiat. Oncol., vol. In Press, 2017.
[8] F. C. Hamdy et al., “10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer,” N. Engl. J. Med., vol. 375, no. 15, pp. 1415–1424, 2016.
Urology. 2017 Nov 23. pii: S0090-4295(17)31213-X. doi: 10.1016/j.urology.2017.11.016. [Epub ahead of print]
Watch: SpaceOAR® Hydrogel Application Video performed by: Marcio Fagundes