Evaluation of small bowel motion and feasibility of using the peritoneal space to replace bowel loops for dose constraints during intensity-modulated radiotherapy for rectal cancer

Background The goal of this study was to assess small bowel motion and explore the feasibility of using peritoneal space (PS) to replace bowel loops (BL) via the dose constraint method to spare the small bowel during intensity-modulated radiotherapy (IMRT) for rectal cancer. Methods A total of 24 patients with rectal cancer who underwent adjuvant or neoadjuvant radiotherapy were selected. Weekly repeat CT scans from pre-treatment to the fourth week of treatment were acquired and defined as Plan, 1 W, 2 W, 3 W, and 4 W. The 4 weekly CT scans were co-registered to the Plan CT, BL and PS contours were delineated in all of the scans, an IMRT plan was designed on Plan CT using PS constraint method, and then copied to the 4 weekly CT scans. The dose-volume, normal tissue complication probability (NTCP) of the small bowel and their variations during treatment were evaluated. Results Overall, 109 sets of CT scans from 24 patients were acquired, and 109 plans were designed and copied. The BL and PS volumes were 250.3 cc and 1339.3 cc. The V15 of BL and PS based plan of pre-treatment were 182.6 cc and 919.0 cc, the shift% of them were 28.9 and 11.3% during treatment (p = 0.000), which was less in the prone position than in the supine position (25.2% vs 32.1%, p = 0.000; 9.9% vs 14.9%, p = 0.000). The NTCPC and NTCPA based plan of pre-treatment were 2.0 and 59.2%, the shift% during treatment were 46.1 and 14.0% respectively. Majority of BL’s Dmax and V15 were meet the safety standard during treatment using PS dose limit method except 3 times (3/109) of V15 and 5 times of Dmax (5/109). Conclusions This study indicated that small bowel motion may lead to uncertainties in its dose volume and NTCP evaluation during IMRT for rectal cancer. The BL movements were significantly greater than PS, and the prone position was significantly less than the supine position. It is feasibility of using PS to replace BL to spare the small bowel, V15 < 830 cc is the dose constraint standard.


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Conclusions: This study indicated that small bowel motion may lead to uncertainties in its dose volume and NTCP evaluation during IMRT for rectal cancer. The BL movements were significantly greater than PS, and the prone position was significantly less than the supine position. It is feasibility of using PS to replace BL to spare the small bowel, V 15 < 830 cc is the dose constraint standard.

Background
Radiochemotherapy is a widely accepted treatment mode in patients with locally advanced rectal cancer. It can result in a significant reduction in the local recurrence rate by up to 30% and improve the 5-year disease-free survival rate [1][2][3][4][5][6].
Although radiochemotherapy can help cure many rectal cancer survivors, acute and chronic intestinal side effects (12-50%) such as diarrhoea, faecal incontinence, and late small bowel obstructions have attracted increasing attention because they may affect patients' quality of life and even interrupt treatment [7][8][9][10]. Studies have shown that the irradiated small bowel volume is closely related to toxicity caused by radiotherapy, so reducing its irradiated volume is the key approach to effectively prevent and reduce toxicity [11,12]. Although intensitymodulated radiation therapy (IMRT) reduces the risk of radiation-induced toxicity, toxicity remains a significant concern.
In 2010, the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) review provided the available dose volume data for small bowel toxicity. Acute small bowel injury has been described with a threshold dose of grade 3 or greater toxicity when 120 cc volume of individually contoured bowel loops (BLs) receive ≥15 Gy or when 195 cc of the contoured peritoneal space (PS) receives ≥45 Gy [13,14]. These are commonly incorporated into radiotherapy protocols in clinical practise.
Contouring the PS and BL are two primary ways to evaluate the small bowel dose volume [15,16]. However, the small bowel is always in motion and there may be uncertainties in dose volume evaluations. The characteristics of narrow high dose distribution in IMRT technology will further increase this uncertainty.
PS contouring has the advantages of accuracy, convenience, and repeatability compared with BL contouring. This volume can allow the small bowel to lie at any point during treatment and can mitigate the impact of small bowel movements. The scope of this study was to quantify the impact of small bowel movements on the dose volume and normal tissue complication probability (NTCP) estimates and feasibility of using PS replace BL for dose constraints to provide an optimised method of sparing the small bowel during IMRT for rectal cancer.

Patients
The ethics board of the hospital approved the present study, and all of the investigations were conducted in accordance with the relevant guidelines and regulations. From March 2014 to March 2016, 24 patients with rectal cancer who underwent adjuvant or neoadjuvant radiotherapy were selected. The patient characteristics are summarised in Table 1.

Planning CT
CT scans (3 mm thick slices) of the patients' whole abdomen and pelvis were obtained with the treatment position on a Siemens Emotion-Duo CT simulator. Standard commercial immobilisation devices were applied. A carbon fibre frame and thermoplastic mask fixation (Pelvicast system, Orfit, Wijnegem, Belgium) was used. The patients were in the supine position with a pillow under their heads. Their knees and ankles were supported with vacuum cushions, and their arms resting on their chests. In the prone position, a belly board (Civco Medical Solutions, Coralville, IA, USA) was applied to allow the abdomen to extend into its aperture. The patients were instructed to empty the bladder an hour before CT simulation. Gastrografin solution (600 mL) was administered orally an hour before scanning to better visualise the small bowel for delineation. CT scans were subsequently imported into the treatment planning system (Pinnacle 9.0, Philips Radiation Oncology, Fitchburg, MA. USA) for target delineation and treatment planning design. After the plan was confirmed, the patients were treated at the Medical Synergy Accelerator (Elekta Synergy, Elekta Oncology Systems, Crawley, UK), and when treatment they were required to keep their bladder moderately filled similar to simulation. CT images were obtained and defined as 1 W, 2 W, 3 W, and 4 W, respectively, on the Friday of weeks 1-4 during treatment under the same scanning conditions. Subsequently, the 4 weekly CT scans were automatically co-registered to the Plan CT respectively based on pelvic bone anatomy, algorithm of Normalized Mutual Information in treatment planning system was used.

Delineation of PS and BL
Per the delineation methods of small bowel from RTOG [17] and Robyn B [16], BL and PS were delineated for each patient's group of CT images. BL was delineated along the bowel loop's outer surface based on the contrast effect of Gastrografin solution and excluding the colon. The upper boundary was 1 cm above the superior level of the planning target volume (PTV), and the lower boundary was delineation of the small bowel until it ended. For the PS, the anterior and bilateral boundaries were the inner surface of the abdominal muscles, the posterior boundary was the vertebral body, sacrum, or sigmoid colon. The upper boundary was 1 cm above the superior PTV level. The lower boundary was parallel to the inferior sigmoid colon level. The PS included the small bowel and colon, but did not include the bladder, ovary, and uterus. A window width of 600 and window level of 40 were selected for delineation of the BL and PS and were completed by the same senior attending physician.

Target volume definition and treatment planning design
The target volume was delineated per the RTOG and NCCN guidelines [18,19]. The clinical target volume (CTV) included the lymphatic drainage area of the perirectal lymph nodes, presacral lymph nodes, and internal iliac lymph nodes, and some patients' external iliac lymph nodes were included. A margin of 1 cm in the cranial-caudal direction and 0.5 cm in the anteriorposterior and lateral directions was given to the CTV to form the PTV. The prescription was 50 Gy in 25 fractions to the PTV. In the Pinnacle 9.0 treatment planning system, 7 field IMRT plans used the PS (V 15 < 830 cc) dose constraints were designed [16]. The plans used a 6 MV X-ray CC convolution algorithm and a 0.3 cm computational grid. An Elekta Synergy accelerator and 40 pairs of MLCs were selected. Dose constraints of V 40 < 50% and V 50 < 5% were used for the bladder and bilateral femoral head respectively. The target dose coverage required more than 95% of the PTV covered by 100% of the prescription dose and a maximum dose (D max ) < 54 Gy inside and outside the PTV. Subsequently, the IMRT plans from the Plan CT were copied to the 1-4 W CT images which had co-registered to the Plan CT.

Evaluation of small bowel dose volume
The absolute irradiated volume (cc) of the small bowel was described by its volume exposed to 5-50 Gy with 5 Gy intervals. Each patient's small bowel volume (or irradiated volume) was expressed by the mean value over their CT images. All of the patients' small bowel volumes (or irradiated volumes) during treatment were expressed as their median volume values.

Evaluation of small bowel motion
The shift% was used to describe the small bowel movements, and shift% = SD/mean [20]. The SD and mean were the standard deviation and mean of the small bowel volume (or irradiated volume) from all of the CT images. The variations among the patients were expressed by their median values. A larger shift% signified greater motion of the small bowel during treatment.

NTCP prediction of small bowels
The Lyman-Kutcher-Burman (LKB) calculation module in Pinnacle 9.0 was used to predict chronic complications of the small bowel (called NTCP C ) [21][22][23]. The n (volume factor), m (slope of dose response curve), and TD 50 (mean dose of 50% complication probability) parameters were set to 0.15, 0.16, and 55 Gy, respectively [24]. The complications were defined as small bowel obstructions, perforations, or fistulas. Logistic formula NTCP = (1 + (V 50 /V) k ) − 1 was used to calculate the acute toxicity of the small bowel based on its V 15 (called NTCP A ), where V 50 and k were 130 cc and 1.1, respectively [25]. Each patient's NTCP was expressed by the mean value over their all of the CT images. The NTCP of all of the patients during treatment was expressed by their median values. The shift% here was used to describe the NTCP variations during treatment, and shift% = SD/mean.
Safety assessment of small bowel during treatment V 15 < 275 cc from Robyn B et al. [16] and D max ≦54Gy were used as the criteria for safety evaluation of the small bowel during treatment. The small bowel was at risk when the value exceeded these criteria.
Statistical analysis SPSS 19.0 software was used for the data analysis. Sigma Plot 10.0 and Microsoft Excel 2007 were used for figure plotting. A paired sample t-test was used to compare the differences between the two groups' data, and their correlation was analysed via Pearson's correlation coefficient. A two-tailed value of p < 0.05 was considered statistically significant.

NTCP of small bowels
As shown in Table 2 (BL), the NTCP C and NTCP A based plan of pre-treatment were 2.0 and 59.2%, the shift% during treatment were 46.1 and 14.0% respectively. The difference of NTCP A in 2 W and 4 W, and difference of NTCP C in 2-3 W were significant compared with the plan pre-treatment (p < 0.05). As shown in Table 4, NTCP in supine patients were mildly larger than in prone patients, NTCP C 4.9% vs 2.3% (p = 0.055) and NTCP A 58.3% vs 55.7% (p = 0.109).

Safety assessment of small bowels during treatment
As shown in Fig. 4, V 15 of the small bowel exceeded 275 cc 3 times (3/109) during treatment, with a maximum of 311.3 cc (over 13.18%). D max of the small bowel > 54 Gy 5 times, and the maximum value was 54.3 Gy.

Discussion
Because the small bowel is a radiosensitive organ, acute and chronic side effects may occur during rectal cancer radiotherapy. The side effects can be reduced by limiting the dose volume. However, evaluating the small bowel dose volume can be challenging. Characteristics of small bowel movement may weaken the dose-limiting function. The small bowel loops do not remain in the same positions at all times. They experience both oscillating displacements of the wall due to peristalsis and large amplitude shifts due to changes in content. The frequency of peristalsis can reach 8-11 times per minute, and it can combine into complex forms of motion at different times and spaces [26]. Small bowel movements have to be taken into account when evaluating the dose volume by contouring the BL, while the peritoneal space can account for any potential region that may be occupied by the small bowel and covering its movements, so it  The P 1 , P 2 , P 3 , and P 4 represent the comparison between the 1-4 W and Plan respectively replaces the BL for dose constraints with clinical significance.
In this study, we first evaluated small bowel movement during treatment. Our results showed that variations of all BL's dose-volume were larger than 28%, while most of PS were below 20% (V 5-40 ), and variations in prone position was significantly lower than in the supine position (Fig. 2). Kvinnsland et al. studied the dose volume changes in the small bowel through 6 to 8 repeated CT scans in 10 patients with bladder cancer. Their results showed that the relative standard deviations of V 30.8 , V 49.5 , and V 53.5 were 20, 24, and 26% respectively. The authors believed that small bowel dose limitations should be carefully considered when variations in the irradiation volume exceeded 20% [27]. Sanguineti et al. confirmed small bowel movement during prostate cancer radiotherapy by continuous CT scanning. The results showed that 280 cc of the small bowel completely changed position on planned CT, while only 20% remained in its original position [28].
The movement characteristics of the small bowel make it necessary to explore the reliability of the PS dose limit method for small bowel sparing in IMRT. We used V 15 < 275 cc and D max ≦ 54Gy as the safety standard for small bowel during treatment, our results showed that majority of D max and V 15 were meet the safety standard, and indicating that the PS limit method was feasible for small bowel sparing.
Although the recommended dose constraint from Robyn B was used in this study [16], there are slightly different research methods and irradiation techniques between the two. The PS dose and small bowel with PTV 45 Gy followed by tumour 5.4 Gy boost in the literature may be lower than the present study (50 Gy PTV dose), while the four-field conformal technique may lead to a higher dose than the IMRT technique used in this study. V 15 < 830 cc used as the dose constraint in this study was relatively strict, approximately half of the plans (13/24) exceeded this standard, and the median value exceeded 10.71%. But even so, our results showed that the small bowel dose-volume could be further reduced by strictly limiting the PS dose, so it is appropriate to use V 15 < 830 cc as the dose constraint.
Patients with prior abdominal surgery are tend to experience greater rates of radiation-induced enteritis   [29], it may also affect the movement of small bowel during treatment. Because neoadjuvant treatment was not fully popularized in our hospital in 2014 and 2015, only 8 patients with neoadjuvant radiotherapy were involved in our study. Among the 8 patients, 3 were supine and 5 were prone position, the mixing of position effects make it difficult to compare the difference of small bowel movement between neoadjuvant and adjuvant radiotherapy patients.
Regarding the upper boundary of the PS and BL, Robyn B defined 1.5 cm above the PTV [16] while our study used RTOG of 1.0 cm [17]. There was no substantial difference between 1.0 cm and 1.5 cm because coplanar IMRT technology and absolute volume (cc) evaluation were used in this study. An upper boundary larger than 1 cm above the PTV should be adopted when using non-coplanar irradiation, while 2-5 cm should be used for tomotherapy [17].
The supine and prone position with a belly board are common therapeutic positions in IMRT for rectal cancer. Our results showed that dose-volume, NTCP and their variations of small bowel were less in prone than supine position ( Fig.2 and Table 4), consistent with previous studies [30][31][32][33]. Nevertheless, the design reproducibility and target dose coverage were significantly superior in the supine position. Some studies reported that patient positioning in RT for rectal cancer patients may therefore be selected based on other factors such as the most comfortable position for the patients [33,34]. The PS defined in this study included the small bowel, colon, and space between the intestines. The PS used objectively in IMRT planning can reduce the overall PS dose volume, making it easier to reduce the small bowel dose. It reduces high dose irradiation caused by small intestinal movement during treatment, so it has an advantage over the BL limit. Which uses only the small bowel as the objective function. Further research showed that there was a significant correlation of V 15 between the PS and BL (Fig. 3, R = 0.455, p = 0.000), indicating that the PS can replace the BL as the objective function of the dose constraint in IMRT planning. However, when using the PS limit, attention should be paid to the occurrence of PS dose hotspots in the absence of BL evaluation, especially when the dose limits are more stringent, and dose hotspots in PS must be evaluated and avoided to prevent excessive small bowel irradiation.
Our study may be too broad in showing the amplitude of small bowel movement, because involving neoadjuvant and adjuvant therapy patients, which may be a limitation in our study. On the other hand, V 15 as the primary dose-volume evaluation methods in this study was from conformal radiotherapy era, whether it is suitable for IMRT needs further clinical verification. Recent research shows that the moderate to high dose (V 20-40 ) trends toward being significantly associated with acute toxity of small bowel in IMRT [35,36].

Conclusions
Our findings demonstrated that small bowel motion may lead to uncertainties in its dose volume and NTCP assessment during IMRT for rectal cancer. The BL movements were significantly greater than the PS and significantly less in the prone position than in the supine position. It is feasible to use the PS instead of the BL limit to spare the small bowel. V 15 < 830 cc can be used as the dose constraint standard.