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Validation of rectal sparing throughout the course of proton therapy treatment in prostate cancer patients treated with SpaceOAR®

Abstract The purpose of this study was to investigate the consistency of rectal sparing using multiple periodic quality assurance computerized tomography imaging scans (QACT) obtained during the course of proton therapy for patients with prostate cancer treated with a hydrogel spacer. Forty‐one low‐ and intermediate‐risk prostate cancer patients treated with image‐guided proton therapy with rectal spacer hydrogel were analyzed. To assess the reproducibility of rectal sparing with the hydrogel spacer, three to four QACTs were performed for each patient on day 1 and during weeks 1, 3, and 5 of treatment. The treatment plan was calculated on the QACT and the rectum V90%, V75%, V65%, V50%, and V40% were evaluated. For the retrospective analysis, we evaluated each QACT and compared it to the corresponding treatment planning CT (TPCT), to determine the average change in rectum DVH points. We were also interested in how many patients exceeded an upper rectum V90% threshold on a QACT. Finally, we were interested in a correlation between rectum volume and V90%. On each QACT, if the rectum V90% exceeded the upper threshold of 6%, the attending physician was notified and the patient was typically prescribed additional stool softeners or laxatives and reminded of dietary compliance. In all cases of the rectum V90% exceeding the threshold, the patient had increased gas and/or stool, compared to the TPCT. On average, the rectum V90% calculated on the QACT was 0.81% higher than that calculated on the TPCT. The average increase in V75%, V65%, V50%, and V40% on the QACT was 1.38%, 1.59%, 1.87%, and 2.17%, respectively. The rectum V90% was within ± 1% of the treatment planning dose in 71.2% of the QACTs, and within ± 5% in 93.2% of the QACTs. The 6% threshold for rectum V90% was exceeded in 7 out of 144 QACTs (4.8%), identified in 5 of the 41 patients. We evaluated the average rectum V90% across all QACTs for each of these patients, and it was found that the rectum V90% never exceeded 6%. 53% of the QACTs had a rectum volume within 5 cm3 of the TPCT volume, 68% were within 10 cm3. We found that patients who exceeded the threshold on one or more QACTs had a lower TPCT rectal volume than the overall average. By extrapolating patient anatomy from three to four QACT scans, we have shown that the use of hydrogel in conjunction with our patient diet program and use of stool softeners is effective in achieving consistent rectal sparing in patients undergoing proton therapy.

rectum V90%, V75%, V65%, V50%, and V40% were evaluated. For the retrospective analysis, we evaluated each QACT and compared it to the corresponding treatment planning CT (TPCT), to determine the average change in rectum DVH points.
We were also interested in how many patients exceeded an upper rectum V90% threshold on a QACT. Finally, we were interested in a correlation between rectum volume and V90%. On each QACT, if the rectum V90% exceeded the upper threshold of 6%, the attending physician was notified and the patient was typically prescribed additional stool softeners or laxatives and reminded of dietary compliance.
In all cases of the rectum V90% exceeding the threshold, the patient had increased gas and/or stool, compared to the TPCT. On average, the rectum V90% calculated on the QACT was 0.81% higher than that calculated on the TPCT. The average increase in V75%, V65%, V50%, and V40% on the QACT was 1.38%, 1.59%, 1.87%, and 2.17%, respectively. The rectum V90% was within AE 1% of the treatment planning dose in 71.2% of the QACTs, and within AE 5% in 93.2% of the QACTs. The 6% threshold for rectum V90% was exceeded in 7 out of 144 QACTs (4.8%), identified in 5 of the 41 patients. We evaluated the average rectum V90% across all QACTs for each of these patients, and it was found that the rectum V90% never exceeded 6%. 53% of the QACTs had a rectum volume within 5 cm 3 of the TPCT volume, 68% were within 10 cm 3 . We found that patients who exceeded the threshold on one or more QACTs had a lower TPCT rectal volume than the overall average. By extrapolating patient anatomy from three to four QACT scans, we have shown that the use of hydrogel in conjunction with our patient diet program and use of stool softeners is effective in achieving consistent rectal sparing in patients undergoing proton therapy.

| INTRODUCTION
In the management of localized prostate cancer, multiple treatment options have been employed, including radical prostatectomy, external beam radiation therapy using intensity-modulated photon beam (IMRT), brachytherapy, cryotherapy, and proton therapy. [1][2][3] Proton therapy provides an advantage over IMRT by reducing the radiation dose delivered to normal tissues outside of the target volume. 4,5 Image-guided treatment delivery, as well as use of endorectal balloons (ERB), have been historically employed to allow for tighter planning target margins thus decreasing the volume of rectum exposed to high radiation doses. [6][7][8][9] However, due to the proximity of the anterior rectal wall to the prostate, high radiation doses to the rectum are still delivered by the various radiotherapy techniques, including protons.
Endorectal balloons will naturally distend the rectum and result in the displacement of the anterior rectal wall into the prostate, thus into the high dose region. A novel concept consisting of the use of a tissue spacer to displace the anterior rectal wall away from the prostate has been shown to be feasible and to remain stable during the course of treatment, with the advantage of significantly decreasing rectal irradiation. [10][11][12][13][14][15] In a multicenter trial, high dose rectal sparing with hydrogel spacer for patients undergoing IMRT was associated with reduced rectal toxicity severity and improved bowel quality of life scores. 16 The commercial availability of a polyethylene-glycol hydrogel absorbable water spacer (SpaceOAR, Augmenix, Inc., Waltham, MA, USA) has led to increased interest in adopting this method to minimize radiation-induced rectal toxicity. 17 Our clinic has been utilizing SpaceOAR since its FDA approval in April 2015, and we have treated over 250 patients with the gel spacer and proton therapy, as of June 2016. We have treated with both uniform scanning (US) and pencil beam scanning (PBS), with either ERB or hydrogel spacer, and our results comparing the two treatment modalities are presented elsewhere. 18,19 The purpose of this study was to investigate the consistency of rectal sparing using multiple periodic quality assurance computerized tomography imaging (QACT) obtained during the course of proton therapy treatment. To our knowledge, this is the first study to analyze rectal dose sparing reproducibility in patients treated with proton therapy and rectal spacer.   were performed sequentially on the same day with an empty rectum, to provide the best-case scenario. Patients were also instructed to have a nearly full bladder for treatment, and the drinking water volume and time-prior-to-treatment was recorded by therapists to replicate for each treatment. Patients were instructed to maintain a low residue diet and use a daily gas prevention medicine.

2.A | Hydrogel implant
The MRIs were fused to the TPCT based on three implanted gold fiducials in the prostate. Figure  Treatment was planned using the RayStation planning system with the following objectives and dose constraints: For target coverage, 95% of the PTV was to receive 100% of the prescribed dose and 100% of the PTV was planned to receive a minimum of 95% of the prescription dose. We have previously documented the ability to reach a rectum V90% of ≤ 1% using pencil beam scanning proton therapy and SpaceOAR with the margins and expansions described above, so our rectum OAR constraint was routinely set at V90% ≤ 1% while maintaining target coverage priority. 18,19 Each patient in this study was treated with two opposing lateral fields.
For each plan, the rectum V90%, V75%, V65%, V50%, and V40% were evaluated. Each patient underwent a robust evaluation by a medical physicist, analyzing the effects of 5 mm of motion in all directions, 3 degrees of roll, 3 degrees of yaw, and 2.5% + 1 mm range uncertainty. Under all perturbations, the prostate CTV must maintain V100% ≥ 95%.
In the treatment room, patients were imaged with orthogonal xrays and aligned based on fiducials. Each fiducial contour on the DRR had a 2-mm uniform expansion. Patients were imaged before each field and the table was translated, as necessary, to align the fiducials within the expanded contours.

2.C | QACT analysis
To assess the reproducibility of rectal sparing with the hydrogel spacer, three to four quality assurance CTs (QACT) were performed for each patient on day 1 and during weeks 1, 3, and 5 of treatment.
Each patient was set up in the treatment position and scanned.
These QACTs were performed either immediately before or after the patient's treatment, so bladder filling was not necessarily at the ideal volume for treatment. A physicist would then fuse the QACT F I G . 1. Left: treatment planning CT (TPCT), indicating the prostate (red), hydrogel (blue), and rectum (brown). Right: MRI acquired on the same day to visualize the hydrogel.
to the TPCT, based on fiducials, and deform the contours to the QACT. A physicist would analyze the deformed contours and make changes, as necessary. The treatment plan was then calculated on the QACT and the rectum V90%, V75%, V65%, V50%, and V40% were evaluated. Because the use of hydrogel spacers has been shown to significantly improve rectum V90%, we chose to use V90% as our prospective action point. 16 In a previous study, we evaluated the improvement in rectal sparing with gel compared to an ERB. 19 Based on our previous data, our ERB average rectum V90% is 6%. In this study, the gel was considered to have reproducibly spared the rectum on a QACT when it improved upon the ERB values. Figure 2 illustrates the average rectum DVH values for our ERB and gel patients. We used this 6% value as an upper threshold limit when analyzing QACTs.
The analysis of each QACT was performed within 1 day of CT acquisition, and the results of each analysis were reported to the attending physician. If the rectum V90% on a QACT exceeded our threshold, actions were taken, as discussed in the results section.
Retrospective analysis was also performed on each QACT, evaluating the rectum DVH points. For the retrospective analysis, we evaluated each QACT and compared it to the corresponding TPCT to determine the average change in rectum DVH points. We were also interested in how many patients exceeded the upper rectum V90% threshold on a QACT. Finally, we were interested in a correlation between rectum volume and V90%. PTV coverage and bladder sparing were also evaluated for consistency, but were not part of this study.
For this study, we did not analyze the hydrogel separation on each QACT. A detailed analysis of hydrogel separation throughout treatment would require sequential MRI scans, which is not typically feasible due to insurance coverage and limitations. Song et al. found that the hydrogel volume is stable throughout the course of treatment. 13 Therefore, we would not expect to identify a change in gel separation over time, up to 3 months.

| RESULTS
All patients tolerated fiducial and gel implants well and successfully completed treatment. A total of 144 QACT scans were analyzed, with each patient receiving three to four QACTs. Data of the analyzed patient population are in (Table 1). Data include the time between the gel implant and the TPCT, time between the gel implant and the first fraction, prostate volume, as measured on MRI, and gel separation distance between the prostate and rectum, measured at the centroid of the prostate. The data are included for the average of all 41 patients and separated into the patients who had at least one QACT that exceeded the rectum V90% upper threshold and those who were consistently below the threshold.

3.A | QACT analysis during treatment
On each QACT, if the rectum V90% exceeded the upper threshold of 6%, the attending physician was notified and the patient was F I G . 2. DVH comparison of our average ERB data (dashed) versus our average gel data (solid).  Patient population data are included for the average of all 41 patients and separated in to those patients who had at least one QACT that exceeded the rectum V90% threshold of 6% ("Patients above threshold") and those that did not ("Patients below threshold"). Average values are reported with one standard deviation.
HEDRICK ET AL.   Fig. 4, where a positive change on the histogram represents a higher QACT V90%, compared to the TPCT. We were also interested in the difference when analyzing change in absolute volume of the rectum receiving 90% and relative volume receiving 90%. The relative change is the data reported above, that is, the change in percent volume receiving 90% of the prescription dose. These data are shown in the grey bars in the histogram. We also analyzed the change in rectum V90% absolute volume, that is, the change in cubic centimeters, rather than percent of rectum volume. This is shown in the black  We also evaluated the change in rectal volume and found that 53% of the QACTs had a rectum absolute volume within 5 cm 3 of the TPCT volume, 68% were within 10 cm 3 .

3.B | Retrospective QACT analysis
The 6% threshold for rectum V90% was exceeded in 7 out of 144 QACT's (4.8%), identified in 5 of the 41 patients. These five patients were further investigated, specifically looking at all of the QACTs for each patient. The TPCT and each QACT rectum V90% for these five patients are presented in (Table 3). The QACTs with rectum V90% that exceeded the 6% threshold are highlighted. Four of the five patients had only one QACT that exceeded the threshold, while the 5th patient had three of the four QACTs exceed the threshold. We evaluated the average rectum V90% for each of these five patients and found that the average rectum V90% never exceeded 6%. The QACTs that exceeded the 6% threshold could rather be seen as outliers or could be correlated with a situation where rectum filling was not necessarily representative of the entire treatment.
It is interesting to note that the average rectum volume on the verification, no changes in gel thickness were identified as a confounding factor. We therefore chose a rectum V90% > 6% to prompt further intensification of stool softeners, use of laxatives, and addition of antigas medication to improve rectal emptying.
The choice of the rectum V90% > 6% threshold was based on our previous experience with ERB, where the mean rectum volume receiving 90% of prescribed dose was above 6%. It should be noted that the typical total rectum volume in patients treated with ERB at our center is 145 cm 3 . In such a case, for example, the absolute rectum volume exposed to 90% of the prescribed dose would be 8.7 cm 3 . By comparison, the mean total rectal volume in this population was 60 cm 3 , in which case 6% would only represent 3.6 cm 3 of the rectum exposed to the same nominal dose. Therefore, we felt comfortable accepting such a threshold, prior to prompting additional repeat QACTs for confirmation of improved rectum emptying and thus dose sparing.
Even when we evaluated the absolute QACT rectum volume, which was increased, the mean was 64 cm 3 , in which case 6% would only represent 3.8 cm 3 . Based on our results of the absolute change in rectum V90%, we found that the absolute change was, on average, less than the relative change. This negated the effect of rectal filling on the DVH and only looked at the effect of rectal filling on change in absolute volume receiving 90% of the prescription.
When evaluating the seven QACTs that exceeded the rectum V90% threshold, the maximum absolute rectum volume receiving 90% of the dose was 9.4 cm 3 , identified for patient 1. This one event is the only QACT to exceed the ERB average absolute rectum volume of 8.7 cm 3 . The average absolute rectum volume on these seven QACTs is 6.2 cm 3 . Even though the relative rectum volume receiving 90% of the dose for these seven QACTs exceeds the ERB average, the absolute rectal volume does not.
It is also worth noting that daily kV/kV orthogonal imaging for fiducial alignment did allow the ability to visualize the presence of gas and even increased presence of stools, in many cases, prompting the therapist to either evacuate the gas with a thin rectal tube or to have the patient visit the toilet for a bowel movement before treatment delivery. Because a combination of all these measures were taken, it is unlikely that a patient would have received multiple fractions with unusually large rectal filling.
The use of QACTs to evaluate the stability of the rectum geometry/filling has been instrumental in fine-tuning our prostate gel workflow. Since the beginning of the gel program, we have introduced a daily gas prevention medicine and it has decreased the QACT failure rate. Additionally, we have identified patients who are likely not good candidates for the hydrogel implant, such as those with hip prostheses or chronic constipation. Hip prostheses, for proton therapy, often require a beam passing through the rectum, which is sensitive to changes in filling. For these patients, a balloon provides more consistent filling.

| CONCLUSION
The efficacy of a SpaceOAR hydrogel in rectal sparing has been demonstrated in several dosimetric and clinical studies. Multiple authors had previously documented significant rectal sparing on a single planning CT, however, information was lacking regarding the stability of rectal sparing throughout treatment. The purpose of our study was to obtain this valuable information to evaluate and confirm the efficacy of this method across the duration of a treatment course. By extrapolating patient anatomy from three to four QACT scans, we have shown that the use of hydrogel in conjunction with our patient diet program and use of stool softeners is effective in achieving consistent rectal sparing in patients undergoing proton therapy.

CONFLI CT OF INTEREST
The authors have no conflicts of interest to disclose.