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1 Acta Oncologica ISSN: X (Print) X (Online) Journal homepage: Bag and loop small bowel contouring strategies differentially estimate small bowel dose for posthysterectomy women receiving pencil beam scanning proton therapy Melody J. Xu, Maura Kirk, Huifang Zhai & Lilie L. Lin To cite this article: Melody J. Xu, Maura Kirk, Huifang Zhai & Lilie L. Lin (2016) Bag and loop small bowel contouring strategies differentially estimate small bowel dose for post-hysterectomy women receiving pencil beam scanning proton therapy, Acta Oncologica, 55:7, , DOI: / X To link to this article: View supplementary material Published online: 29 Feb Submit your article to this journal Article views: 939 View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at

2 ACTA ONCOLOGICA, 2016 VOL. 55, NO. 7, ORIGINAL ARTICLE Bag and loop small bowel contouring strategies differentially estimate small bowel dose for post-hysterectomy women receiving pencil beam scanning proton therapy Melody J. Xu, Maura Kirk, Huifang Zhai and Lilie L. Lin Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA ABSTRACT Background Small bowel (SB) dose-volume relationships established during initial computed tomography (CT) simulations may change throughout therapy due to organ displacement and motion. We investigated the impact of organ motion on SB dose-volume histograms (DVHs) in women with gynecologic malignancies treated with pencil beam scanning (PBS) proton therapy and compared PBS SB DVHs to intensity-modulated radiation therapy (IMRT). Material and methods Post-hysterectomy patients (n ¼ 11) treated for gynecologic cancers were enrolled on an image-guided proton therapy protocol involving CT simulation with full (CT F ) and empty (CT E ) bladders and weekly/biweekly on-treatment scans. IMRT plans were generated for comparative analysis. SB was contoured as bowel loops or bowel bag. Wilcoxon signed-rank tests were used for matched-pair comparisons of SB, bladder, and rectum dose-volumes between CT scans and between PBS and IMRT plans. Results In PBS loops analysis, on-treatment DVH was significantly higher than CT F for doses <45 Gy (p < 0.05), and not significantly different than CT E. Specifically, V15 for loops was higher on-treatment (median 240 cm 3 ) compared to CT F (median 169 cm 3, p ¼ 0.03). In PBS bag analysis, on-treatment DVH was not significantly different from CT F across all dose ranges. Bowel bag V45 was not significantly different between on-treatment (median 540 cm 3 ) and CT F (median 499 cm 3, p ¼ 0.53). Decreasing bladder volume was associated with increasing V15 for loops and V45 for bowel bag (p < 0.005, both). Comparing PBS and IMRT, PBS resulted in significantly lower DVHs at low dose regions (<38 Gy) and higher DVHs at high dose regions ( Gy) in both loops and bag analysis. IMRT plans demonstrated higher on-treatment SB loop DVHs and only minimal differences in bowel bag DVHs compared to CT F. Conclusions SB DVHs were well estimated by CT F bowel bag and underestimated by CT F loops in the setting of inconsistent bladder filling. Verifying bladder filling prior to treatment or using CT E for planning may more conservatively estimate SB dose-volume relationships. ARTICLE HISTORY Received 22 October 2015 Revised 6 January 2016 Accepted 10 January 2016 Published online 26 February 2016 Radiation dose to the small bowel (SB) is considered a dose limiting constraint in pelvic irradiation as acute and chronic SB toxicity is associated with considerable morbidity [1]. Several studies have sought to correlate radiation dose and SB toxicity to better define dose-volume constraints. A recent Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) analysis, which reviewed six quantitative studies, recommended dose-volume constraints of V cm 3 when SB is contoured as bowel loops and V cm 3 when SB is contoured as a bowel bag [2]. Many questions regarding the application of these guidelines remain. As these recommendations are based on studies of a heterogeneous population of patients receiving pelvic irradiation for rectal, cervical, or endometrial cancers, it is unclear whether contouring methodologies should differ for different clinical scenarios. Whether loops or bowel bag contouring is better for gynecologic malignancies was recently addressed by Poorvu et al. [3]. The preliminary study findings did not find clinically meaningful differences between the two methods. QUANTEC guidelines also do not make specific recommendations for patients with prior abdominal surgery despite studies demonstrating that prior abdominal surgery predisposes to fixed SB loops and increased SB volume within the pelvic irradiation field [1,4]. Therefore, a comparison of bowel loops and bowel bag analysis for post-hysterectomy gynecologic cancer patients may provide useful additional information to the existing literature. Another open question is whether initial computed tomography (CT) scans accurately model SB dose-volume relationships throughout treatment. Important decisions regarding toxicity and treatment strategy rely on the DVHs generated from the initial CT scan [4 9], however, these scans may not account for organ displacement and inter-fraction motion. In particular, bladder volume has been shown to be widely variable throughout treatment despite detailed patient instruction [10 12]. This is especially concerning as the full bladder technique is commonly employed to reduce the volume of SB in the pelvic irradiation field. Therefore, this study sought CONTACT L. L. Lin Lilie.Lin2@uphs.upenn.edu Department of Radiation Oncology, Hospital of the University of Pennsylvania, 3400 Civic Center Blvd. PCAM/ TRC 4West, Philadelphia, Pennsylvania 19104, USA Supplemental data for this article can be accessed here. ß 2016 Informa UK Limited, trading as Taylor & Francis Group

3 ACTA ONCOLOGICA 901 to capture additional on-treatment CT scans to compare subsequent SB, bladder, and rectum DVHs against estimated DVHs from initial CT simulations. Lastly, of the available quantitative dose-volume studies for SB toxicity, only one was done with IMRT and none involved proton beam therapy. While little is known regarding the best parameters and models for SB toxicity in IMRT, even less is known in proton therapy. We herein investigate the impact of bowel and bladder motion on SB DVHs over time in a cohort of patients treated for gynecologic cancers with pencil beam scanning (PBS) proton therapy utilizing two common contouring techniques (loops of bowel vs. bag of bowel). We additionally model IMRT plans to compare DVH consistency between PBS and IMRT. We examined all dose ranges, focusing particularly on V15 in loops analysis and V45 in bag analysis to compare dose-volume relationships to previously described toxicity parameters. Material and methods Patient characteristics This analysis included 11 patients treated with radiotherapy (RT) for gynecologic cancers post-hysterectomy who were enrolled on an institutional review board-approved prospective image-guided proton therapy protocol (Supplementary Table 1, available online at com). Patients with cervical (n ¼ 7, one with recurrence), endometrial (n ¼ 3, one with recurrence), and vaginal cancer (n ¼ 1) underwent hysterectomy and bilateral salphingooophorectomy with or without lymph node dissection. One patient with vaginal cancer had prior hysterectomy for benign reasons. The median age was 54 years (range 23 76). The median body mass index (BMI) was 31.8 (range ). RT dose was Gy with five patients receiving brachytherapy. Chemotherapy regimens included concurrent cisplatin (n ¼ 5), sandwich chemotherapy (carboplatin and paclitaxel) and concurrent cisplatin (n ¼ 3), sandwich chemotherapy of carboplatin and paclitaxel alone (n ¼ 1), and concurrent cisplatin with adjuvant carboplatin and paclitaxel (n ¼ 1). One patient declined chemotherapy. Concurrent cisplatin was given to patients with cervical or vaginal cancers and sandwich or sequential carboplatin-paclitaxel chemotherapy with concurrent cisplatin with RT was given to patients with endometrial and high stage cervical cancers. CT simulation Patients were instructed to initiate simethicone before meals starting the week prior to simulation, then keep a clear liquid diet after noon the day prior to simulation. They prepared for simulation with at least one enema two hours prior and drank two cups of fluid (473 cm 3 ) 30 minutes prior. Patients underwent CT simulation in the supine position using an indexed knee-foot lock for immobilization and scanned initially with a full bladder (CT F ) and inflated rectal balloon (Radiadyne, Houston, TX, USA). This was followed by bladder voiding and a second CT scan with an empty bladder (CT E ) and inflated rectal balloon. For subsequent treatments, patients continued simethicone with every meal and drank two cups of fluid (473 cm 3 ) 30 minutes prior to daily treatment. Treatment planning and analysis Proton therapy and IMRT plans were generated using the Eclipse (Varian Medical Systems, Palo Alto, CA, USA) planning software. The planned dose was Gy in 1.8 Gy daily fractions. Target vaginal volume was calculated as an internal target volume (ITV) using the range of vaginal motion between CT F and CT E. The clinical target volume (CTV) included the pelvic lymph nodes (external iliac, internal iliac, common iliac and obturator lymph nodes), which were contoured according to Radiation Therapy Oncology Group (RTOG) guidelines [13]. The nodal planning target volume (PTV) was generated by adding a margin of 7 8 mm to the nodal CTV and the vaginal PTV was created by adding a margin of mm to the vaginal ITV. The CT F dataset was used for treatment planning. IMRT simulation plans using seven beams of 6 and 15 MV photons were generated for research purposes for comparison against proton plans using the same target volumes and dose parameters. The bladder, rectum, and SB (as loops of bowel or as a bowel bag) were contoured according to the RTOG Female Pelvis Normal Tissue Guidelines. For bladder and rectum, the dose-volume constraints were as low as reasonably achievable. SB goal constraints were to limit the bowel bag V45 to less than 195 cm 3. PBS plans were optimized with single field uniform dose utilizing two PBS beams oblique from the posterior. After patients initiated treatment, weekly or biweekly scans were obtained and bladder, rectum, and SB (as loops of bowel and bowel bag) were contoured according to the RTOG Female Pelvis Normal Tissue Guidelines. The range of worst case scenarios for PBS plan robustness with respect to SB dose was analyzed by generating plans with a 0.5 cm isocenter shift in six directions (6x, y, z) and 63.5% shift in Hounsfield units to simulate proton range uncertainty. The maximum V15 in SB loops and V45 in SB bag from the shifted plans for each patient were analyzed to find the average worst case difference in dose to SB from the nominal plan due to simulated isocenter misalignment and proton range uncertainty. Statistical analysis Statistical analysis was done using the STATA program (version 13, StataCorp, College Station, TX, USA). DVH data were compared and analyzed using the RadOnc package for R statistical software as described by Thompson [14]. To account for intrapatient anatomical differences in bladder volume, changes in bladder volume were expressed as percentages of the CT F bladder volume. Changes in SB dose-volume metrics were calculated as median on-treatment SB volume at V15 for loops and V45 for bowel bag as a percentage of the matching CT F SB volumes. t-tests were used to identify intrapatient variability in bladder volume. Wilcoxon signed-rank

4 902 M. J. XU ET AL. tests were used for matched-pair mean comparisons of bladder, rectum, and SB volumes and for comparisons between PBS and IMRT plans. All p-values were generated from two-sided t-tests. Linear regression models were used to determine associations between change in bladder volume and change in SB dose from CT F to subsequent ontreatment scans. Results We compared DVHs between initial CT simulation scans (CT E and CT F ) for PBS and IMRT. The volume of SB receiving any particular dose was lower in CT F compared to CT E (p < 0.05), except in IMRT for SB bag, where CT F and CT E DVHs were similar in the <30 Gy region (Figure 1). In bowel loop V15 analysis, CT F was lower than CT E in both PBS and IMRT (both p < 0.02, median and range values in Table 1). In bowel bag V45 analysis, CT F was also lower than CT E in both PBS (p ¼ 0.02) and IMRT (p ¼ 0.03, median and range values in Table 1). Comparing PBS and IMRT CT F DVHs, PBS plans resulted in lower volumes of SB receiving dose at low dose regions (<38 Gy, p < 0.05) in both loop and bag analysis (Figure 2A B). At higher dose ranges (e.g Gy), PBS resulted in significantly higher SB bag dose compared to IMRT (p < 0.05, Figure 2B). Comparing bowel loop dose-volume constraints (V cm 3 ), PBS resulted in lower V15 than IMRT in CT F (p < 0.01, Table 1). Both PBS and IMRT plans exceeded bowel loop dose constraints in CT F with PBS Figure 1. Dose-volume histogram comparison between CT E and CT F for SB loops in (A) PBS and (B) IMRT, and SB bag in (C) PBS and (D) IMRT. Top: continuous corresponding p-values calculated using Wilcoxon signed-rank test. The shading under p ¼ 0.05 represents doses for which there is statistically significant difference between CT E and CT F. Gray bands represent SD. CT E, empty bladder initial CT scan; CT F, full bladder initial CT scan.

5 ACTA ONCOLOGICA 903 Table 1. Comparison of proton beam scanning (PBS) proton therapy and IMRT dose-volume relationships with initial CT simulation scans (CT E and CT F ). Specific dose-volume relationships investigated were median and range of SB V15 in loops analysis and V45 in bowel bag analysis. p-values obtained using Wilcoxon signed-rank tests. CT E, empty bladder initial CT scan; CT F, full bladder initial CT scan; On-Tx, on-treatment. Scan Contour strategy-specific constraint PBS IMRT p Value CT F Loops V15 (range) in cm (87 448) 347 (94 780) p < 0.01 Bag V45 (range) in cm ( ) 471 ( ) p ¼ 0.02 CT E Loops V15 (range) in cm ( ) 475 ( ) p < 0.01 Bag V45 (range) in cm ( ) 519 ( ) p ¼ 0.09 On-Tx Loops V15 (range) in cm (61 511) 416 ( ) p < 0.01 Bag V45 (range) in cm ( ) 489 ( ) p < 0.01 median V15 of 169 cm 3 and IMRT median V15 of 347 cm 3. However, 45% of PBS plans met the SB loop V15 constraint, compared to only 9% of IMRT plans. When investigating the dose-volume constraints applied to bowel bag on CT F (V cm 3 ), PBS resulted in higher V45 than IMRT (p ¼ 0.02). However, both PBS and IMRT plans exceeded bowel bag dose constraints in CT F with PBS median V45 of 499 cm 3 and IMRT median V45 of 471 cm 3, with 0% of PBS and 0% of IMRT plans meeting SB bag V45 volume constraints. We also compared other organs at risk (OAR) DVHs between initial CT simulation scans for PBS and IMRT. Median bladder volume was 306 cm 3 (range cm 3 ) for CT F and 121 cm 3 (range cm 3 ) for CT E (p < 0.01). Comparing PBS and IMRT bladder DVHs in CT F, PBS resulted in Figure 2. Dose-volume histogram comparison between PBS and IMRT for CT F in (A) SB loop and (B) SB bag analysis and on-treatment (On-Tx) scans in (C) SB loop and (D) SB bag analysis. Top: continuous corresponding p values calculated using Wilcoxon signed-rank test. The shading under p ¼ 0.05 represents doses for which there is statistically significant difference between PBS and IMRT plans. Gray bands represent SD. CT F, full bladder initial CT scan; Median, median On-Tx SB volume.

6 904 M. J. XU ET AL. Figure 3. Dose-volume histogram comparison between CT F and on-treatment (On-Tx) SB loops in (A) PBS and (B) IMRT and for SB bag in (C) PBS and (D) IMRT. Top: continuous corresponding p-values calculated using Wilcoxon signed-rank test. The shading under p ¼ 0.05 represents doses for which there is statistically significant difference between CT F and On-Tx. Gray bands represent SD. CT F, full bladder initial CT scan; Median, median On-Tx SB volume. significantly lower volumes of bladder receiving 0 39 Gy and significantly higher volume of bladder receiving Gy (Supplementary Figure 1A, available online at informahealthcare.com). Median rectal volume was 146 cm 3 (range cm 3 ) for CT F and 131 cm 3 (range cm 3 ) for CT E (p ¼ 0.03). Comparing PBS and IMRT rectal DVHs in CT F, PBS resulted in significantly lower volume of rectum receiving low dose radiation (1 5 Gy, p < 0.05) and significantly larger volume of rectum receiving higher dose radiation (24 45 Gy, p < 0.05) (Supplementary Figure 1B). Next, we characterized concordance between on-treatment and initial simulation DVHs (Figure 3, Supplementary Figure 2, available online at The median number of on-treatment scans per patient was four (range 2 5) for a total of 69 scans including CT E and CT F. For both PBS and IMRT, the on-treatment SB loop DVH was significantly higher than the initial CT F DVH (Figure 3A B), especially at low dose regions (<30 Gy), and not significantly different from the CT E DVH (Supplementary Figure 2A B). Findings in dose-volume constraint parameters were similar. In PBS and IMRT loops analysis, on-treatment median SB V15 was significantly higher than CT F (p ¼ 0.03 for both) and not significantly different from CT E (p ¼ 0.29 in PBS, p ¼ 0.93 in IMRT) (Table 2). Comparing PBS and IMRT SB loop DVHs (Figure 2C), PBS resulted in significantly lower SB volume receiving low dose radiation (1 27 Gy, p < 0.05) and significantly higher SB volume receiving higher dose radiation ( Gy and Gy, p < 0.05) compared to IMRT. On-treatment bowel bag DVHs were similar to initial DVHs (Figure 3C D, Supplementary Figure 2C D). PBS had no significant bowel bag DVH differences between CT F and ontreatment scans from 0 to 52 Gy. For IMRT, on-treatment

7 ACTA ONCOLOGICA 905 bowel bag DVHs were higher than both initial CT scans at low dose regions ( Gy, p < 0.05 for CT F and <6.5 Gy, p < 0.05 for CT E ) and lower than CT E at high dose regions (28 54 Gy, p < 0.05). These relationships were maintained for bowel bag V45 analysis (Table 3). On-treatment PBS V45 was Table 2. Summary of SB loop V15 for PBS and IMRT plans for initial CT simulation (CT E and CT F ) compared to on-treatment (On-Tx) scans. p Values obtained using Wilcoxon signed-rank tests. CT E, empty bladder initial CT scan; CT F, full bladder initial CT scan. PBS IMRT Median Range On-Tx vs. initial CT Median Range On-Tx vs. initial CT CT F p ¼ p ¼ 0.03 CT E p ¼ p ¼ 0.93 On-Tx Table 3. Summary of SB bag V45 for PBS and IMRT plans for initial CT simulation (CT E and CT F ) compared to on-treatment (On-Tx) scans. p Values obtained using Wilcoxon signed-rank tests. CT E, empty bladder initial CT scan; CT F, full bladder initial CT scan. PBS IMRT Median Range On-Tx vs. initial CT Median Range On-Tx vs. initial CT CT F p ¼ p ¼ 0.72 CT E p ¼ p ¼ 0.02 On-Tx not significantly different from CT E and CT F (p ¼ 0.25 and p ¼ 0.53, respectively). On-treatment IMRT V45 was significantly lower than CT E (p ¼ 0.02) and not significantly different from CT F (p ¼ 0.72). When comparing PBS and IMRT bowel bag DVHs (Figure 2D), PBS resulted in significantly lower bowel bag volume receiving low dose radiation (1 28 Gy, p < 0.05) and significantly higher SB volume receiving higher dose radiation ( Gy and Gy, p < 0.05). Bladder volume calculated during treatment was highly variable. Three patients had significantly higher bladder volumes (all p < 0.02), six patients had non-significant changes, and two patients had lower bladder volumes (p ¼ 0.03 and p ¼ 0.02) on-treatment compared with their original full bladder scan. Four patients (36% of patients) were found to have at least one on-treatment bladder volume lower than the CT E volume during the course of treatment. In a linear regression model comparing change in bladder volume on-treatment with change in median PBS SB V15 or V45 on-treatment, decreasing bladder volume was significantly associated with increased SB dose regardless of loop or bowel bag modeling (p < for both). Representative examples of changing bladder volumes impacting SB dose with PBS are illustrated in Figure 4. Of note, change in bladder volume was not significantly associated with changes in SB dose on IMRT analysis (p ¼ 0.23 for V15 in loops analysis and p ¼ 0.11 for V45 in Figure 4. SB dose varies as bladder volume changes during the course of treatment. (A) Decreased bladder volume (bladder, black) associated with increased SB V15 for bowel loops (magenta) and SB V45 for bowel bag (blue). Left: CT F with full bladder (arrow). Middle: At week 2, bladder volume is decreased with SB descending inferiorly into space previously occupied by full bladder (area under white dotted line). Right: Line graph of bladder volume, SB V15 volume in loops analysis, and SB V45 volume in bag analysis during treatment. (B) Increased bladder volume (bladder, black) associated with decreased SB V15 for bowel loops (magenta) and SB V45 for bowel bag (blue). Left: CT F with full bladder (arrow). Middle: At week 2, bladder volume is increased with bladder displacing SB even further superiorly (area superior to white dotted line). Right: Line graph of bladder volume, SB V15 volume in loops analysis, and SB V45 volume in bag analysis during treatment. CT F, full bladder initial CT scan.

8 906 M. J. XU ET AL. bag analysis). Comparing on-treatment PBS and IMRT bladder DVHs, PBS resulted in significantly lower bladder volumes receiving radiation from 0.5 to 38 Gy (p < 0.05, Supplementary Figure 1C). Comparing on-treatment PBS and IMRT rectum DVHs, PBS resulted in significantly lower rectal volumes receiving radiation from 0 to 5.5 Gy (p < 0.05) and significantly higher rectal volumes receiving radiation from 24 to 45 Gy (p < 0.05) (Supplementary Figure 1D). Rectum V50 was consistently <50% in all CT F and on-treatment scans between PBS and IMRT. We investigated the range of SB doses that could be expected due to patient setup and proton range uncertainty (Supplementary Figure 3, available online at The mean difference between the worst case scenario and nominal plan PBS dose to SB loops for V15 was 46 cm 3 (range 6 91 cm 3 ). The worst case V15 for SB loops from the shifted plans underestimated the actual V15 for 63% of the on-treatment scans. The mean difference between the worst case scenario and the nominal plan PBS dose to SB bag for V45 was 84 cm 3 (range cm 3 ). The worst case V45 for SB bag from the shifted plans underestimated the V45 for 26% of the on-treatment scans. Discussion Our study uses SB loops and bowel bag techniques to investigate SB DVH changes for PBS and IMRT plans as a function of organ displacement and motion in a cohort of post-hysterectomy patients receiving PBS for gynecologic malignancies. Our results demonstrate that the choice of SB modeling technique has differing implications for dose estimation during treatment. Additionally, variability in intra- and interpatient bladder filling affects posterior oblique PBS approaches more significantly than IMRT. PBS plans may thus be more conservatively modeled using CT E and additional measures may need to be considered to account for organ displacement and motion during treatment. The primary objective was to examine the degree of concordance between SB DVHs on CT F compared to on-treatment scans. In loops analysis, SB DVH estimations from CT F tended to underestimate the actual dose-volume relationships during treatment, with more differences observed for PBS versus IMRT plans. In contrast, no significant differences in SB DVHs were noted between on-treatment and CT E for both PBS and IMRT. Worst case scenario robustness evaluations also tended to underestimate SB V15 during treatment. We hypothesized that the difference in SB DVHs during treatment was related to variability in bladder volume, consistent with previously described observations in RT for bladder carcinoma [15]. Linear regression models confirmed that decreasing bladder volume was statistically significantly associated with increasing SB V15 volumes for PBS (p < 0.001), but not IMRT (p ¼ 0.23). These findings suggest that the loop contouring technique is highly sensitive to variability in bladder volume, particularly in the context of two-beam posterior oblique PBS approach, and SB DVHs may be more conservatively estimated using the CT E scan. One strategy to account for SB motion is creating a planning OAR volume (PRV) on CT F with up to 30 mm isotropic expansions of SB loop margins [15 17]. Another strategy is employing frequent ultrasound bladder scans to ensure consistent bladder filling. Bladder scans have high correlation with CT bladder volumes in rectum and prostate RT literature [11,12,18] and further investigation into bladder scan and/or PRV to minimize and account for SB motion may help inform clinical practice. For bowel bag analysis, only minimal low dose SB DVH differences were found between on-treatment and CT F scans regardless of PBS or IMRT plan. The bowel bag may represent a more consistent approach to estimating bowel dose over the course of treatment as it may be less sensitive to changes in bladder volume. This is expected, as the bowel bag is designed to capture the entirety of the peritoneal space within which bowel may be expected to move and includes both large and SB. Worst case scenario robustness evaluations for bowel bag contouring underestimated PBS V45, but this was less than what was observed in loops analysis (26% vs. 63% for bag and loop analysis, respectively). However appealing, the bowel bag may be as a more robust approach for estimating dose-volume relationships, we found that neither PBS nor IMRT plans met QUANTEC SB bag guidelines. Although IMRT resulted in significantly lower V45 than PBS, the significance of this finding is unclear as the dose range of significance is quite narrow (e.g Gy in CT F and Gy in on-treatment scans). Additionally, the dosimetric association between bowel bag guidelines and SB toxicity has not been well replicated. The QUANTEC guidelines for bowel bag are based on a single study by Roeske et al. in 2003 [6]. Later studies by Gunnlaugsson et al. [9], Poorvu et al. [3], and Isohashi et al. [19] did not find significant associations between SB bag doses and enteritis. Furthermore, the Roeske study included a heterogeneous group of patients with and without hysterectomies and the dose constraints established in this study may not apply to post-hysterectomy patients. Therefore, more investigation into the association between bowel bag dose, particularly V45, and SB toxicity is needed to balance its benefit of consistent dose-volume estimations to its risk of non-clinical correlation to toxicity. Acknowledging that most patients receive post-hysterectomy IMRT instead of PBS in clinical practice, we sought to compare OAR dose-sparing between the two techniques. In both initial CT and on-treatment scans, PBS resulted in a significantly lower SB DVH at low dose regions (in general, 0 30 Gy) and significantly higher SB DVH at narrow high dose regions (45 50 Gy) compared to IMRT (Figure 2). This is consistent with prior data demonstrating PBS results in more favorable DVHs at low dose regions compared to IMRT [20,21]. Other than these differences, PBS and IMRT had similar patterns of concordance between initial CT and on-treatment scans. In loops analysis, both PBS and IMRT ontreatment DVHs were significantly higher than CT F. In bowel bag analysis, both PBS and IMRT on-treatment DVHs were not significantly different from CT F, with the exception of a higher on-treatment DVH at low dose regions for IMRT. Therefore, although PBS and IMRT are different treatment modalities, the choice of SB contouring technique and employment of

9 ACTA ONCOLOGICA 907 strategies to minimize inter-treatment bladder volume variability and account for SB motion is a unifying challenge. For PBS and IMRT treatment plans, large volumes of rectum received nearly therapeutic doses of radiation (Supplementary Figure 1B and D). Compared to IMRT, PBS resulted in larger volumes of rectum receiving higher radiation doses in CT F and on-treatment scans. This is likely due to the use of single field uniform dose for PBS instead of intensity-modulated proton therapy. However, the two posterior oblique beams were preferred due to concerns with lack of robustness with anterior fields and lack of cone beam CT on our gantries. Despite PBS requiring a posterior approach with increased rectal dose, V50 was consistently <50% in all CT F and on-treatment scans, thereby meeting QUANTEC rectal dose constraint guidelines. Yet, QUANTEC rectum dose guidelines are based on three-dimensional conformal radiotherapy (3D-CRT) studies and their application in IMRT and PBS settings are not clearly defined [22]. As this study did not seek to characterize patient toxicity, further studies are needed to specify rectal dose guidelines for PBS at intermediate dose ranges of <50 Gy. This study is limited by small sample size of 11 patients. To our knowledge, it is the first study evaluating the effectiveness of CT F in estimating SB dose volumes during proton beam therapy. Our proton therapy approach utilizes PBS in two posterior oblique beams, which may not be generalizable to other proton therapy modalities. Differences in bladder and SB anatomy results in difficulty comparing absolute SB and bladder volumes across patients, although we have attempted to correct for this by utilizing matched-pair statistical tests and normalizing SB V15 or V45 volume differences whenever possible. This study is hypothesis generating and study of a larger cohort of patients with more homogenous treatment planning and with or without intervention to maintain stable bladder volumes are needed. Further studies are also needed to examine the optimal dose-volume constraints, sensitivity, and ability to predict acute and late SB toxicity for both contouring techniques. In conclusion, our results demonstrate that SB modeling as loops versus bowel bag have differing implications for dosevolume estimations. For both PBS and IMRT, bowel bag analysis provides a good estimate of SB DVH during treatment, but the clinical correlation between bowel bag dose-volume constraints and SB toxicity is not well established. Loops analysis tends to underestimate SB DVH during treatment for both PBS and IMRT, suggesting a role for more conservative modeling using empty bladder scans, PRV expansions, and frequent use of ultrasound bladder scans to verify bladder volume. Disclosures and Financial information MJX received biostatistics support through the Clinical Translational Research Center, which was funded by a Clinical and Translational Science Award (Grant Number UL1TR000003) from the National Center for Advancing Translational Sciences of the National Institutes of Health. LLL received a research grant through Varian Medical Systems for health-related quality of life research unrelated to this study. References 1 Minsky BD, Conti JA, Huang Y, Knopf K. Relationship of acute gastrointestinal toxicity and the volume of irradiated small bowel in patients receiving combined modality therapy for rectal cancer. J Clin Oncol 1995;13: Kavanagh BD, Pan CC, Dawson LA, Das SK, Li XA, Ten Haken RK, et al. Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys 2010;76:S Poorvu PD, Sadow CA, Townamchai K, Damato AL, Lee LJ, Viswanathan AN. 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