To degas or not to degas? The effectiveness of pharmaceuticals in reducing the impact of bowel volume variations during liver SBRT treatment

Abstract

The indications for liver stereotactic body radiation therapy (SBRT) continue to expand in the management of liver cancer due to the improved rates of local control with acceptable normal tissue toxicity. Changes in internal anatomy, such as the bowel, may negatively impact the precision of treatment delivery of SBRT liver treatment by influencing daily image matching. Institutions have developed various approaches to promoting bowel volume consistency. One such strategy is the administration of pharmaceuticals. The administration of pharmaceuticals, such as Simethicone, has been adopted by the Princess Alexandra Hospital Radiation Oncology Department (ROPAIR) as a method to promote consistency in the amount of bowel gas observed in liver cancer patients. This case series examines a group of patients treated at ROPAIR with liver SBRT to determine whether current practices effectively reduce the impact of bowel volume variations for liver cancer patients. Initial observations from this hypothesis generating research suggest potential improved consistency of the small bowel's anatomical position for liver SBRT patients who were administered Simethicone (Bowel bag dice similarity coefficient – Simethicone group = 0.79–0.92, Standard group = 0.24–0.93). However, it appeared that this strategy alone may not be entirely effective achieving consistency in the amount of bowel gas present throughout the duration of treatment. Further investigation into the refinement of liver SBRT pre‐treatment preparation is therefore recommended.

Changes in internal anatomy, such as the bowel, may negatively impact the precision of treatment delivery of stereotactic body radiation therapy (SBRT) liver treatment by influencing daily image matching. This case series examines whether or not prescribing a pre‐treatment pharmaceutical (Simethicone) is effective in reducing bowel volume variation and improving image matching. Initial observations from this research suggest improved bowel volume consistency for patients administered Simethicone; however, this strategy alone may not be entirely effective therefore further refinement to the pre‐treatment liver SBRT preparation is recommended.

Introduction

Conventional external beam radiation therapy (EBRT) has traditionally played a limited role in the management of liver cancer. ¹ This is due to the liver's low tolerance to radiation and the previous inability to use steep dose gradients to spare healthy tissue. ¹ The indications for liver SBRT continue to expand the management of liver cancer due to the improved rates of local control with acceptable normal tissue toxicity. ² This is achieved through the creation of steep dose gradients that deliver ablative doses to the tumour volume whilst sparing normal tissues. ² Additionally, the increasing use of motion management techniques such as end‐expiration breath‐hold (EEBH) have allowed smaller margins to be used when delivering these high doses of radiation. While motion management has facilitated the use of reduced margins, variations in anatomy can still occur that are unrelated to respiratory motion, such as bowel volume variations. ¹ , ²

Liver SBRT is often used to treat secondary liver cancers and, in most cases, is considered a life lengthening rather than a curative treatment with the goal of achieving durable local control or a curative intent in oligometastatic settings. ³ , ⁴ Preservation of patient quality of life (QoL) is therefore an important consideration when designing treatment. The main organ at risk (OAR) to consider in liver SBRT is the liver itself, due to the associated risk of radiation induced liver disease (RILD) which can cause symptoms such as abdominal pain, fatigue, anicteric hepatomegaly and ascites. ⁵ , ⁶ Other important OARs to consider include luminal organs such as the stomach, small and large bowels because they are mobile organs, located in close proximity to the liver. Late bowel toxicities can have a severe impact on patient QoL and include pain, nausea, bloating, faecal urgency and diarrhoea. ⁵ , ⁶ , ⁷ Bowel strictures, perforation or bleeding are uncommon but potentially life‐threatening late bowel toxicities. ⁵ , ⁶ , ⁷

Anatomically, the liver is located in close proximity to the small bowel, therefore variations in internal anatomy, such as bowel gas, may negatively impact the accuracy of liver SBRT treatment delivery. ⁸ The potential daily inconsistencies in the size, shape and location of abdominal structures such as the stomach and small bowel can cause considerable deformation of the liver and influence image matching for daily cone‐beam computed tomography (CBCT) images taken throughout a course of liver SBRT. Clinicians will often bias an image match to avoid treating healthy bowel tissue to prevent the risk of late bowel toxicities which may negatively impact a patient's QoL. As a result, patients may miss a day of treatment if the bowel is demonstrating significant variation in its volume compared to the original planning scan. This decision is made at the discretion of the treating radiation oncologist. Consequently, there is a need for clinicians to investigate methods of both reducing bowel volume variation and ensuring any bowel gas present is consistent from planning to treatment. Reducing bowel volume variation by decreasing the amount of gas present may also increase the robustness of the liver SBRT plan to potential unwanted hot‐spots and variation in dose.

The administration of Simethicone has been adopted as a method to achieve consistency in the amount of bowel gas observed in liver cancer patients. Simethicone is an antifoaming agent that is taken orally and used to decrease the surface tension of gas bubbles. ⁹ Drug information suggests that this increases the rate at which gas exits the body. ⁹ Administering Simethicone to patients as part of their pre‐treatment preparation for liver SBRT may promote bowel volume consistency, potentially reducing challenges related to image‐matching caused by bowel volume variation that can be encountered for this cohort of patients. The purpose of this case series report was to conduct exploratory observations on whether Simethicone was effective in reducing bowel volume variation for a small cohort of liver SBRT patients to generate hypotheses for future investigation.

Patients

Institutional ethics approval was granted to retrospectively access the data of patients who had completed a course of liver SBRT at Princess Alexandra Hospital Radiation Oncology Department (ROPAIR). Nine patients >18 years of age who were treated between August 2019 and January 2020 had liver lesions located in areas that had the potential to be affected by gas were reviewed. One patient had two separate liver lesions resulting in ten separate lesions being reviewed. Five patients followed the standard clinical liver SBRT preparation, and four patients were also directed to take Simethicone for the entirety of their treatment course. Patient demographic information was collected from the MOSAIQ® Oncology Information System (Elekta AB, Stockholm, Sweden), including age, sex, prescription dose, diagnosis and tumour location.

Clinical treatment process

As per the standard clinical liver SBRT preparation, all patients were required to fast 2 hours prior to treatment and were prescribed a pre‐treatment antiemetic. Of the nine patients included in the study, four were also directed by their radiation oncologist to take Simethicone 30–60 min prior to their planning CT and each treatment fraction. This was in the form of a tablet that could be easily acquired from any supermarket or chemist. The remaining five patients did not take Simethicone.

Table 1 outlines the treatment details for the nine patients included in this case series. All SBRT liver patients were treated with volumetric modulated arc therapy (VMAT) using a 6 megavoltage (MV) flattening filter free (6FFF) beam. To minimise variations in anatomy caused by respiratory motion and allow reduced margins to be used, all patients were treated with motion management such as abdominal compression, deep inspiration breath‐hold (DIBH) and end expiration breath‐hold (EEBH).

Table 1.

Treatment details for liver SBRT patients.

Patient	Simethicone Y/N	Prescription	VMAT Arc Arrangement	Motion Management
1	Y	40Gy/5#	2 partial arcs	DIBH
2	Y	40Gy/5#	2 partial arcs	DIBH
3	Y	48Gy/5#	2 partial arcs	Abdominal compression
4	Y	50Gy/10#	3 partial arcs	DIBH
5	N	45Gy/5#	2 partial arcs	EEBH
6	N	35Gy/5#	2 partial arcs	EEBH
7	N	30Gy/5#	2 full arcs	DIBH
8	N	40Gy/5#	2 partial arcs	DIBH
9–2 lesions	N	SUP ABDO 38Gy/3# INF ABDO 30Gy/3#	2 partial arcs 2 partial arcs	DIBH

VMAT, Volumetric modulated arc therapy; DIBH, Deep inspiration breath hold; EEBH, End exhalation breath hold; Sup, superior; Inf, Inferior.

For each SBRT fraction, departmental protocol requires the treating radiation oncologist to attend and approve online CBCT image matches and setup corrections. A pre‐treatment CBCT was taken first to verify the position of the isocentre. After couch shifts were applied a confirmation CBCT was taken to ensure that the appropriate shifts were made and the patient had not moved prior to delivering the first arc. During treatment delivery, an intrafraction CBCT was acquired to ensure that the patient's internal anatomy had not shifted during treatment and any required shifts were performed prior to the delivery of the second arc. For the purpose of this case series, the planning CT (pCT), confirmation and intrafraction CBCTs were de‐identified and imported into the Pinnacle treatment planning system (V16.2, Koninklijke Philips N.V.) for contouring. CBCTs were registered with the pCT to replicate the online match.

Planning CT and CBCT Contouring

Using the contouring tools in Pinnacle, the liver, stomach and bowel bag were delineated on each patient's pCT as well as their daily confirmation and intrafraction CBCTs for each fraction. The liver, stomach and bowel bag contours were copied from the original clinical plan onto the pCT and CBCTs and were adjusted as per the visualised structure on the CBCT scans.

The small bowel was contoured as the entire bowel bag, following RTOG guidelines. ¹⁰ To ensure consistency across all patients, the bowel bag was contoured from its superior aspect to two centimetres inferior of the planning target volume (PTV). All other contours were delineated in their entirety. All study contours were delineated by one person. As part of the quality assurance process, the liver, stomach and bowel bag contours were checked by a second radiation therapist to ensure accurate delineation of these structures.

To ensure consistency in contouring across the pCT and CBCTs, new contours were generated. As the CBCT scans were acquired using a smaller field of view (FOV), this limited the anatomy able to be visualised on these images. Therefore, to identify the CBCT imaged region on the pCT, a circular contour was added and centred on the treatment isocentre for each patient's pCT and daily CBCTs. This circular contour had a diameter of 26.5 cm to reflect the size of the CBCT's small FOV (see Fig. 1).

Figure 1.

Example of a small FOV contour (white circle) used in the pCT (left) and mid‐treatment CBCT (right) to crop the liver (red) so that the structure was bound within the small FOV of the CBCT (yellow). Volume comparison.

Volume comparison

All bowel bag and stomach contours were exported from Pinnacle to the radiation therapy toolkit within 3D Slice.r ¹¹ The volume (in cubic centimetres) for each structure was recorded. The contours on the pre‐treatment confirmation CBCTs were compared to the pCT, to determine the interfraction variation between the stomach and bowel bag contours. The confirmation CBCTs were compared to the mid‐treatment CBCTs to assess intrafraction variation between the contours. Metrics calculated for contour comparison included the Dice Similarity Coefficient (DSC) and the average Hausdorff Distance (HD). DSC values indicate the overlap between contours, with a score of one indicating complete overlap and a score of zero suggesting no overlap between contours. ¹² Both interfraction and intrafraction DSC values were calculated for the stomach and bowel bag. The HD values describe the greatest perpendicular distance between the two closest points of a contour. ¹³ Lower HD values indicate greater agreement between contours. Descriptive statistics were used to summarise the data in this case study series.

Bowel volume comparison between patient groups

Table 2 presents the interfraction DSC and HD mean values for the bowel bag contours to determine the variation between treatment fractions. The DSC values for the patients who were not administered Simethicone had a larger range and the minimum DSC was smaller for the standard group. In general, the range of DSC values was smaller for the Simethicone patients and the values were also closer to one. This indicated greater overlap between the bowel bag contours for these patients, suggesting that Simethicone had some effect in reducing bowel volume variation between liver SBRT treatments. As seen in Table 2, the HD values for the patients who were not administered Simethicone demonstrated greater variation compared to the patients who were. Important to note is that Patient 6 is an outlier in these results. However, when removing this outlier, the results continue to demonstrate a larger range for the standard group. It should also be noted however, that the standard group demonstrated inconsistent HD values, suggesting these results are inconclusive based on this case series.

Table 2.

Interfraction mean DSC and HD for bowel bag contours.

	Bowel bag DSC (SD)	Bowel bag HD (SD)
Patient (Simethicone)
1	0.80 ± 0.04	2.67 ± 0.51
2	0.79 ± 0.06	3.48 ± 1.16
3	0.92 ± 0.04	1.80 ± 0.91
4	0.89 ± 0.05	1.62 ± 0.50
Range	0.79–0.92	1.62–3.48
Patient (Standard without Simethicone)
5	0.73 ± 0.06	3.48 ± 0.76
6	0.24 ± 0.06	10.22 ± 1.43
7	0.83 ± 0.02	2.19 ± 0.25
8	0.93 ± 0.04	1.20 ± 0.59
9	0.47 ± 0.29	5.57 ± 4.09
10	0.84 ± 0.05	2.66 ± 1.02
Range	0.24–0.93	1.20–10.22

DSC, Dice Similarity Coefficient; HD, Hausdorff Distance.

Figure 2 provides an example of the changes seen in the amount of bowel gas present at the planning CT (A) and pre‐treatment CBCT (B) for a liver cancer patient who was not administered Simethicone. The blue contour corresponds to the bowel bag in the planning CT. As seen in the pre‐treatment CBCT (B), a larger amount of gas is present in the bowel bag prior to the delivery of the second treatment fraction. In this case series, no patients missed a treatment day due to considerable bowel volume variation.

Figure 2.

Example of bowel volume variation occurring between planning CT and mid‐treatment CBCT. Blue outline = bowel bag, Pink outline = liver.

Considerations for Future Practice

Daily CBCT images taken during a course of liver SBRT can be influenced by bowel position. Clinicians will often decide on an image match that avoids treating healthy bowel tissue to prevent the risk of late bowel toxicities which may negatively impact a patient's QoL. As a result, the radiation oncologist may direct a patient to miss a day of treatment if the bowel is demonstrating significant variation in its volume compared to the original planning scan. An example of a treatment fraction where a patient, who was not prescribed Simethicone, was unable to be treated due to variation in bowel gas causing a large amount of variation in the image match can be seen in Figure 3. In this scenario, treatment was unable to be delivered because the image match that reduced healthy bowel being irradiated would have resulted in inadequate treatment of the liver lesion. Increased bowel gas also has the potential to negatively affect image quality, making it more difficult for clinicians to perform accurate image matching to ensure safe delivery of treatment.

Figure 3.

Example of a treatment fraction where a liver SBRT patient, who was not prescribed Simethicone, was unable to be treated due to variation in bowel gas causing a large amount of variation in the image match. Red outline = liver, Blue outline = bowel bag.

This case series suggests that Simethicone may have some effect in reducing the impact of bowel volume variation throughout a course of liver SBRT. This hypothesis needs to be thoroughly tested in a larger clinical study with an adequately powered sample size to more fully understand the impact of Simethicone in promoting bowel volume consistency and the role supplementary strategies may play. This would facilitate a more thorough statistical analysis to be conducted to determine any relationship between bowel variation and the metrics used to describe bowel overlap in this case series (DSC and HD values) as well as to determine threshold values that may be used to support clinical decision making.

Several authors have explored effective strategies to reduce the impact of bowel volume variation during radiation therapy treatment delivery in the prostate cancer setting. ¹⁴ , ¹⁵ Literature suggests that strategies such as routine dietary advice either alone or in conjunction with micro enemas has been effective in reducing interfraction bowel volume variation for prostate cancer patients. Further strategies such as treatment scheduled at the same time each day and strict anti‐flatulent diets with the addition of mild laxatives, to regulate bowels, have also been investigated. Results from these studies suggest that these strategies may have reduced interfraction bowel volume variation for prostate cancer patients. ¹⁴ , ¹⁵ Clinicians could therefore draw from the experience of pelvic cancer treatments and introduce similar supplementary strategies, such as incorporating a ‘standardised bowel preparation patient education’ into the pre‐treatment preparation process for liver SBRT patients. ¹⁴ , ¹⁵ It would also be important to investigate the clinical outcomes associated with reducing variations in bowel volume as part of a clinical study to better understand the clinical impact.

Conclusion

This case series suggests that pharmaceuticals, such as Simethicone, may have some positive effect in reducing bowel volume variation throughout a course of liver SBRT. Minimising the variation in bowel volume and gas throughout liver SBRT treatment has the potential to improve CBCT image quality, improving image matching efficiency and accuracy, and reducing the need for clinicians to bias an image match to avoid treating healthy bowel tissue. The observations from this case series suggest that Simethicone may be beneficial in reducing bowel volume variation; however, this hypothesis would need to be tested in a larger study to understand the clinical impact of these bowel volume variations and other strategies that may be employed to reduce this variation further. This will allow clinicians to continue to improve the quality of liver SBRT treatment delivery and ensure that patients receive high‐quality care with minimal damage to healthy tissue.

Conflicts of Interest

The authors declare no conflict of interest.

Ethical Approval

Institutional ethics approval was granted.

DATA AVAILABILITY STATEMENT

Data available on request from the authors.The data that support the findings of this study are available from the corresponding author upon reasonable request.