Long-Term Study on the use of Rectal Spacers with the Treatment

of Prostate Cancer
Katelyn Larger
7/30/17
Introduction:
Prostate cancer is one of the most common types of cancer among the male population.1
Because of this, it is important to provide the best treatment possible for each patient that will
ultimately give them the best quality of life.2 External beam radiation therapy is one of several
ways that prostate cancer can be treated and is an effective method of treatment that helps many
patients achieve remission.1,6 Though this is true, many patients experience acute and late side
effects associated with this form of treatment, specifically when it comes to the rectum.3
Receiving too much dose to the rectum can lead to adverse side effects that can last the duration
of the treatment and, possibly, continue after treatment and reduce the patients’ quality of life.2
Such side effects can include rectal bleeding, fecal frequency, and urgency.3,4 Different treatment
methods have been developed to reduce the dose to the rectum, one of those methods being the
use of a rectal spacer.1 Rectal spacers are designed to be placed between the prostate and the
rectum in order to push the rectum farther away from the prostate.4 Studies have shown that
using a rectal spacer for the duration of a prostate treatment can significantly lower the dose to
the rectum.4,5,7 It is then inferred that this would cause a reduction in late side effects that patients
may experience, but long-term studies are yet to be conducted to confirm this.1,4,5 Long-term
follow up is important when evaluating whether or not rectal spacers reduce the dose to the
rectum enough to limit late side effects.

Research Question/Hypothesis:
If long term follow-up is included when tracking patients who have undergone radiation
therapy to the prostate with the use of a rectal spacer, then we will find that late side effects
caused by radiation will be reduced and overall quality of life will be increased. This hypothesis
should be correct due to the evidence that rectal spacers reduce the amount of dose that the
rectum is receiving. Studies have also shown, with the use of short-term follow up, that late
grade 1 side effects have been significantly reduced in groups where rectal spacers were used.
Literature Review:
Men who have been treated for early stage prostate cancer can achieve remission and live
for several years after.2 Radiation therapy is one modality that is used as a curative treatment for
prostate patients.6 Because of the high ability for radiation therapy to cure early stage prostate
cancer, it is important to reduce the amount of side effects caused by RT treatment so that the
patient can continue to have a high quality of life. Thor has reported that as of 2015, 50% of
long-term survivors of prostate cancer will suffer from side effects associated with radiation
treatment.3 Of these side effects, bowel dysfunction is most likely to occur.2 Side effects
associated with bowel dysfunction can include things such as rectal bleeding, fecal frequency,
and urgency, which can diminish a patients’ quality of life after treatment.2,3,4 Reducing the dose
to the rectum is critical to reducing the occurrence of these side effects. One way that has been
proven to significantly reduce the dose to the rectum is the use of rectal spacers during the
treatment of prostate cancer.4,5, 7 Mariados
reported that with the use of rectal spacers, there
was a “significant decrease in rectal
irradiation.”5 Whalley also concurred that “rectal
doses were significantly lower (see Figure 1) in
the post-hydrogel plans for all dose-volume end
points.”4
Along with a reduced dose to the rectum,
studies have shown that the use of rectal spacers
significantly reduces late grade 1 rectal toxicity.4,5 Mariados’ study showed that there was a
significant reduction of late grade 1 side effects in the rectal spacer group.5 This has been proven
with the use of short-term follow ups (3-15 months) of patients treated with and without the
rectal spacers.5 According to Vanneste, “the long-term outcomes are not yet clear” in regards to
rectal spacers.1 In order to truly see if late side effects (late grade 2 toxicity or greater) are
reduced with the use of rectal spacers, longer follow-ups are needed. Whalley’s study
acknowledges that “late grade >2 gastrointestinal toxicity occurs at a median of 17 months after
treatment, with peaks at 1.5 and 4.5 years.”4 This shows that using short-term follow up to try to
evaluate late side effects is not effective. Whalley’s study has also stated that “it is possible that
with more time, we may see a significant difference in the rates of more severe gastrointestinal
toxicity.”4 This evidence proves that long-term follow up on patients who have been treated with
the use of rectal spacers is needed in order to evaluate late side effects. If late side effects are
reduced, as has been predicted, then it would prove that rectal spacers are an even more valuable
asset to use in the treatment of prostate cancer.

Methods:
The methods section of this study is drawing from the methods of Mariados et al.5 222
patients were recruited for this study who had been diagnosed with clinical stage T1 or T2
prostate cancer. The criteria for selection included being a male with stage T1 or T2 prostate
cancer, having a Gleason score of less than or equal to 7, a prostate-specific antigen (PSA)
concentration of less than or equal to 20ng/mL, and a Zubrod performance status of 0 to 1 that
were going to be undergoing IG-IMRT for their treatment. Exclusion criteria for this study
included having a prostate volume of greater than 80cm3, extracapsular extension of disease or
greater than 50% positive biopsy cores, metastatic disease, indicated or recent androgen
deprivation therapy, and prior prostate surgery or radiation therapy.
For this study, two primary endpoints were defined. The first endpoint was the primary
effectiveness endpoint. This endpoint was defined as “the proportion of patients achieving >25%
reduction in rectal volume receiving at least 70Gy (rV70) due to spacer placement.”5 These
parameters were chosen because a 25% reduction in rectal volume was deemed to be clinically
relevant because it “approximates the reduction achieved when progressing from 3-dimensional
conformal RT to IMRT.”5 rV70 was chosen because studies have shown that there is a
correlation between this and the risk that the patient will develop late side effects. The second
endpoint was the primary safety endpoint, which was the “portion of spacer and control patients
experiencing grade 1 or greater rectal or procedural adverse events (AEs) in the first 6 months.”5
Each patient had to provide written, informed consent as well as undergo a physical
examination. The physical examination included collecting “medical/surgical history, baseline
concomitant medications, and a computed tomography (CT) scan and magnetic resonance
imaging (MRI) for baseline IG-IMRT treatment planning.”5 Three gold intra-prostate fiducial
markers were placed inside patients using an aseptic transperineal technique. Immediately after
this, patients were randomized with the use of sealed envelopes to receive transperineal injection
of a spacer or no injection of a spacer. Patients were blinded to this randomization.
Approximately five to ten days after the procedure, patients had a second CT and MRI scan for
postprocedural IG-IMRT treatment planning.
Clinical target volumes (CTVs) were to include the prostate and possible inclusion of the
proximal seminal vesicles, which was determined by the physician. “The planning methodology
for baseline and postprocedural plans was the same. The prescription dose was 79.2Gy at 1.8Gy
per fraction, delivered to ≥98% of the planning target volume (PTV) and 100% of the CTV, with
the CTV maximum of ≤110% of the prescription dose. PTV margins were institutionally
determined within protocol-defined limits of 5 to 10mm, and normal rectal dose constraint
objectives for 15%, 20%, 25%, 35%, and 50% of the rectal volume were <75Gy, <70Gy, <65Gy,
<60Gy, and <50Gy, respectively, per quantitative analysis of normal tissue effects in the clinic
(QUANTEC) guidelines.”5 All of the IG-IMRT planning documentation and CT/MRI scans were
sent out to a blinded, independent core laboratory. The laboratory verified the GTV, CTV, PTV,
and critical normal structures such as the rectum, bladder, and penile bulb contours, as well as
dose volume histograms. The laboratory also verified all of the Dosimetric study data, measured
the distance between the posterior prostatic capsule and anterior rectal wall (on axial mid-gland
T2 weighted MRIs) at the baseline as well as at 3 months, evaluated the patients for the
successful placement of the hydrogel spacers, and assessed the amount of absorption of the
spacers using the 12 month MRI.
Patient evaluations took place at baseline, once a week throughout the course of
treatment, and then at 3, 6, 12, and 15 month follow up appointments. Additionally, follow up
was elongated in this study in order to get a better understanding of the degree to which rectal
spacers reduce side effects to the rectum. This included the addition of follow up appointments at
18, 21, and 24 months, and then every 6 months for two and a half years. These patient
evaluations were used to assess changes in bowel function as well as other side effects that could
be occurring. All side effects were recorded, making sure to include the event type, severity, and
progression. Also, side effects were evaluated to show the relatedness to the device, procedure,
radiation, or other in order to understand why these events were occurring. This was done by an
independent Clinical Events Committee (CEC), which was blinded to treatment randomization.
All rectal side effects that occurred due to radiation were included for toxicity analysis according
to National Cancer Institute’s Common Terminology Criteria for Adverse Events (CCTCAE)
version 4.0.
 At baseline, 3, 6, 12, 15, 18, 21, 24, 30, 36, 42, 48, and 54 months, patients had to
complete an Expanded Prostate Cancer Index Composite health-related quality of life (QOL)
questionnaire. Data from the questionnaires was analyzed in order to determine the mean change
in QOL score from the baseline visit up to the 54th month follow up. Along with this, patients
that were experiencing rectal side effects when compared to baseline were “evaluated using a
previously determined 5 and 10 point thresholds for minimal clinically detectable QOL
changes.”5

Possible Results:
Looking at results from previous studies, it is clear that rectal spacers can reduce the dose
that the rectum receives during radiation treatment to the prostate. Several studies have shown
that the placement of a rectal spacer between the prostate and the rectum can significantly lower
the dose to the rectum, as shown in figure 2.4,5,7
Achieving a lower dose to the rectum is
important in the treatment of prostate cancer
since late side effects caused by irradiation of the
rectum can diminish a patients’ quality of life
after treatment. Rectal spacers have not only been
Figure 2
shown to reduce the dose to the rectum, but to also reduce the
appearance of late grade 1 rectal toxicity.4,5 This reduction of late grade 1 rectal toxicity was
done with the use of short term follow ups that were anywhere from 3-15 months. This
hypothesis, if true, is to show that with long term follow up, there will still be a reduction in late
toxicities ( grade 2 rectal toxicity). As stated in a study done by Whalley et al, late grade 2
rectal toxicity can peak at 1.5 and 4.5 years.4 With this information, a study that includes long
term follow up of at least 4.5 years should be able to prove whether or not there is a continued
decrease in late toxicity with the use of rectal spacers. If the hypothesis were to fail, then there
would most likely be no change in the amount of late rectal toxicity that patients were to
experience when comparing a rectal spacer vs non rectal spacer patient.
References Cited:
1. Vanneste BGL, Limbergen EJV, Lin ENV, Roermund JGHV, Lambin P. Prostate Cancer
Radiation Therapy: What do Clinicians Have to Know? BioMed Research International.
2016; 2016: 1-14. doi:10.1155/2016/6829875.
2. Davis KM, Kelly SP, Luta G, Tomko C, Miller AB, Taylor KL. The Association of Long-
Term Treatment-Related Side Effects with Cancer-Specific and General Quality of
Life Among Prostate Cancer Survivors. Urology. 2014; 84(2): 300-306.
doi:10.1016/j.urology.2014.04.036
3. Thor M, Olsson CE, Oh JH, et al. Relationships Between Dose to the Gastro-Intestinal
Tract and Patient-Reported Symptom Domains After Radiotherapy for Localized Prostate
Cancer. Acta Oncologica. 2015; 54(9): 1326-1334. doi:10.3109/0284186x.2015.1063779.
4. Whalley D, Hruby G, Alfieri F, Kneebone A, Eade T. Spaceoar Hydrogel in Dose-Escalated
Prostate Cancer Radiotherapy: Rectal Dosimetry and Late Toxicity. Clinical Oncology.
2016; 28(10): 148-154. doi:10.1016/j.clon.2016.05.005.
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. International Journal of Radiation Oncology*Biology*Physics. 2015; 92(5): 971-
977. doi:10.1016/j.ijrobp.2015.04.030.
6. Wortel RC, Incrocci L, Pos FJ, 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. International Journal of Radiation
Oncology*Biology*Physics. 2016; 95(2): 680-689. doi:10.1016/j.ijrobp.2016.01.031.
7. Hamstra D, Mariados N, Shah D, et al. Continued Benefits of Rectal Separation for Prostate
RT: Final Results of a Phase III Trial. International Journal of Radiation
Oncology*Biology*Physics. 2016; 97(5): 976-985. doi:10.1016/j.ijrobp.2016.09.050.