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Abstract

Background:

This retrospective cohort study aims to study the changes of the exposed volume of the bladder and rectum under different filling states, and to clarify the influences of the morphing organs on themselves and each other, to provide the basis for reducing the risk of organ damage by intensity-modulated radiotherapy (IMRT) for cervical cancer.

Methods:

A retrospective analysis was performed on 24 patients with cervical cancer who received IMRT. Before radiotherapy, a comfortably full bladder and active defecation was ensured for all patients, and interative cone-beam computed tomography (iCBCT) was performed to delineate the bladder, rectum, and small intestine. The filling degree of the bladder, rectum, and small intestine and their intersection with the planned target volume were recorded.

Results:

83.44% of patients exhibited reduced bladder volume during treatment. When the planned bladder volume was 400–500 cc, the bladder volume changed the least during treatment (F = 58.39, P < .001). The exposed volume of the small intestine was moderately correlated with the degree of bladder filling (r = −.674, P < .01). For every 10% increase in bladder volume, the exposed volume of the small intestine decreased by 24.05% (P < .01). Furthermore, 45.83% patients had an increase in rectum volume during treatment. The exposed volume increased by 9.47% for every 10% increase in rectum volume (P < .01).

Conclusion:

Comfortable bladder and active defecation regimens may not keep bladder and rectal stability. Targeting a planned bladder volume of 400 to 500cc minimizes intrafraction variability. Strategic bladder filling optimization may mitigate small intestine exposure.

Keywords

Cervical cancer intensity-modulated radiation therapy bladder/rectal fullness correlation volume of exposure

Introduction

Cervical cancer is a common gynecological malignancy, and its morbidity and mortality rank fourth among all women’s cancers in the world.¹ Radiation therapy is the main treatment method for cervical cancer. With the development of technology, intensity-modulated radiotherapy (IMRT) is increasingly used in cervical cancer radiotherapy.^2-4 Intensity-modulated radiotherapy is characterized by a steep dose gradient at the edge of the target volume, while administering sufficient dose coverage to the target volume. Therefore, special attention should be paid to the organs that are prone to physical deformation during treatment, a slight change in position may make them fall into the high-dose area, resulting in serious toxic and adverse effects.^5,6 The deformation of the bladder, rectum, and other organs can cause problems such as target coverage and changes in the exposure volume of organs at risk (OARs) in IMRT for cervical cancer. While image-guided radiotherapy (IGRT) can solve the problem of target coverage through online correction, but it is difficult to take into account the changes in the exposure volume of OARs.^7,8 At present, most studies only focus on the effect of organ deformation on the target area,⁹ and there are few studies on the changes in the exposure volume of the OAR and its mutual influence. This study retrospectively analyzed the changes of the exposed volume of the bladder and rectum under different filling states to clarify the influence of the deformable organs on themselves and each other and provide a basis for reducing damage to the OAR by IMRT in cervical cancer.

Materials and Methods

Inclusion and exclusion criteria

This study was reported according to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for cohort studies (von Elm et al¹⁰). A retrospective cohort analysis was conducted using iCBCT data from cervical cancer patients. The inclusion criteria included newly diagnosed cervical cancer. The exclusion criteria were the tumor invades the pelvis, or infiltrates the bladder mucosa or rectal mucosa, or has distant metastasis. Between April and November 2021, 24 patients with cervical cancer receiving radical radiotherapy at Sun Yat-sen University Cancer Center were randomly selected. The age of the patients ranged from 29 to 80 years, with a median age of 58 years. The tumor stages of the patients were from stage IB2 to stage IIIC1(FIGO,2018). This study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (approval no. B2023–116–01).

Immobilization

Before patient immobilization, the patients were instructed to empty the bladder and rectum, then drink 500 cc of water. When reported a strong urge to urinate while being able to maintain urinary retention for at least 30 minutes prior to immobilization. All patients were placed in the head forward supine (HFS) position and immobilized with a negative pressure vacuum pad. A CT simulation positioning was performed after a second bladder-filling training session was conducted. The scanning range of CT simulation (Brilliance^TM Big Bore CT, PHILIPS, The Netherlands) positioning was from the top of the diaphragm to the level of the perineum, and the scanning slice thickness was 5 mm. After scanning, the CT image was transmitted to the Eclipse planning system (Varian, USA), and the clinician delineated the target area and OAR refered to the guidelines published by the American Society for Radiation Oncology. The gross tumor volume (GTV) of primary tumors refers to the lesions and metastatic lymph nodes that cannot be covered by post-loaded radiotherapy. The clinical target volume (CTV) includes the GTV, cervix, uterine body, parametrium, paravaginal soft tissue, and lymphatic drainage area. The planned target volume (PTV) was the CTV + 5 mm. OARs include the small intestine, bladder, rectum, bilateral femoral heads, and spinal cord. The prescribed dose was 50 Gy, once a day, 5 days a week. All patients were treated with Halcyon linear accelerator (Varian, USA), 6MV-X irradiation and Dynamic IMRT technology.

Image processing and data acquisition

Patients were instructed to prepare their bladder and rectum as they did during the positioning process before the threatment. Patients would receive simple post-treatment instructions:Maintain urine output or adjust by ±100 to 300 cc if too low/excessive after the radiotherapy session. After precise positioning was performed by 2 therapists according to the positioning marks, an iCBCT scan was performed. The scanning range was from the second lumbar vertebra to the lower border of the pubic symphysis. The obtained iCBCT images were all online registered with the localization CT images, so that the target volume and position of the OAR meet the clinical requirements. After the registration results were reviewed and confirmed by a competent doctor, radiotherapy was initiated. After registration, the iCBCT images with the target structures were all sent back to the planning system. The doctor who delineates and locates the CT image outlines the structures of the bladder, rectum, and small intestine on the iCBCT image, which were named Bladder_c, Rectum_c, and Smallintestine_c, respectively. The actual illuminated volume of the above organ is its intersection with PTV, which was named And_Bladder, And_Rectum’, and And_{Smallintestine}, respectively. The structures of the bladder, rectum, and small intestine in the planned images were named Bladder_p, Rectum_p and Smallintestine_p, respectively. The intersection of the above organs and PTV was taken as the planned exposure volume, which was named And_Bladder’, And_Rectum’, and And_{Smallintestine’}. The bladder, rectum, and small intestine filling (cc) of each iCBCT image and planned CT image were recorded, and named as V_Bladderi, V_Rectumi, V_{Smallintestinei}, and V_Bladder’, V_Rectum’, and V_{Smallintestine’}, respectively. Changes in planned filling degree, similarity, and exposure volume were defined as △V_xi = (V_xi-V_x’)/V_x’, DSC_xi = 2(V_xi∩V_x’)/(V_xi + V_x’), and △And_xi = (And_xi-And_x’)/And_x’. (X = bladder, rectum, small intestine; i represents the first, second,. . . ., nth iCBCT) (Figure 1).

Figure 1.

The structures of the bladder, rectum, and small intestine in iCBCT images.

Statistical analysis

Statistical processing was performed using SPSS 20.0 statistical software. If the data conformed to a normal distribution, they were described as mean ± standard deviation (X ± s); otherwise, they were described as the median. Dice Similarity Coefficient (DSC) represents the degree of coincidence between the iCBCT image structure and the corresponding planned image structure. The closer the DSC is to 1, the better the degree of coincidence. Correlation analysis was performed using Pearson’s or Spearman’s correlation. A multiple regression analysis model was constructed, and R2 evaluated the interpretability of the regression model. R² > 0.5 indicates that the model was well explainable, R² > 0.8 indicates that the model had application value. Analysis of variance (ANOVA) analysis was used to test whether the model was statistically significant, and the significance level was set as α = 0.05.

Results

Changes in bladder capacity during treatment

A total of 561 sets of data were obtained from 24 patients (11 patients 22 sets;4 patients 23 sets;8 patients 25 sets;1 patient 27 sets). The planned bladder volume of 24 patients was 338.04 ± 108.97 cc. During the treatment period, 20 patients (20/24) had decreased bladder capacity, ranging from (2.23%-55.81%), with an average decrease of 30.54%; 4 patients (4/24) had increased bladder capacity, ranging from (18.99%-36.88%), with an average increase of 29.39% (Figure 2). The odds of bladder volume change exceeding 10%, 20%, and 50% during treatment were 87.7%, 75.22%, and 37.79%, respectively.

Figure 2.

Comparison of actual bladder volume and planned bladder volume in 24 patients.

The effect of planned bladder volume on bladder-filling stability

The 24 patients were divided into 5 groups according to the planned bladder volume: group 1: 0 to 200 cc; group 2: 200 to 300 cc; group 3: 300 to 400 cc; group 4: 400 to 500 cc; group 5: >500 cc. After non-parametric testing (F = 58.39, P < .001), there were differences in data between groups, and pairwise comparison showed that group 4 had the smallest mean and the highest reliability. Therefore, when the planned bladder volume was 400 to 500 cc, there was minimal change in urine output during treatment.

Factors affecting DSC_bladder

The DSC_bladder was positively correlated with △V_bladder (Spearman’s correlation coefficient = .725, P < .01, Figure 3A). The regression analysis showed that DSC_bladder had an exponential relationship with △V_bladder, Y = 0.87 + 0.08*X − 0.56 *X2 + 0.25 *X3 (Y: DSC_bladder; X: △V_bladder) (Table 1)

Figure 3.

The relationship between the DSC_bladder and △V_bladder (A); the △And_bladder and △V_bladder (B); the DSC_Rectum and △V_bladder, the△V_Rectum (C); the △And_Rectum and V_Bladder, △V_Rectum (D); the △And_{smallintestine} and △V_bladder (E) (DSC_x: Dice Similarity Coefficient; △V_x: Rate of volumetric change; △And_x: Rate of change of intersection with PTV.).

Table 1.

Parameter estimation and statistics of the regression analysis.

Regression Model	R ²	F	P value	Model parameter
Regression Model	R ²	F	P value	Intercept	X	X2	X3	X1	X2
DSC_bladder	.945	3204.238	.00	0.87	0.08	−0.56	0.25
△And_bladder	.887	4288.11	.00	0.042	0.865
△And_Rectum	.622	301.76	.00	0.284				−0.001	0.947
△And_{smallintestine}	.521	207.03	.00	0.733	−2.405

Factors affecting △And_bladder

Different bladder filling states had impact on the intersection between the bladder and the PTV (Figure 4). The△And_bladder’ was positively correlated with △V_bladder’ (Spearman’s correlation coefficient = 0.938, P < .01, Figure 3B). The regression analysis showed that Y = 0.042 + 0.865*X (Y: △And_bladder’; X: △V_bladder’) (Table 1).

Figure 4.

The impact of bladder under filling (A), moderate filling (B), and over filling (C) on the rate of change of intersection with PTV.

Changes in rectum volume during treatment

The planned rectum volume in 24 patients was 46.49 ± 16.09 cc. During the treatment, 13 patients (13/24) decreased the rectum volume, ranging from 9.63% to 42.98%, with an average decrease of 27.36%. Eleven patients (11/24) had increased rectum volume, ranging from 1.61% to 39.19%, with an average increase of 12.64% (Figure 5). During treatment, the probability of rectum volume change exceeding 10%, 20%, and 50% was 73.26%, 51.16%, and 7.66%, respectively. Despite this, there were 11 patients (11/24, 45.83%) who showed rectum volume change rate. In >50% of cases, this phenomenon persists throughout the course of treatment, which shows that the control of rectum changes during treatment is not ideal (Figure 6).

Figure 5.

Comparison of actual rectum volume and planned rectum volume in 24 patients.

Figure 6.

Frequency and distribution of the △V_Rectum exceeding 50% during treatment (△V_Rectum: Volume change rate of the rectum).

Factors affecting DSC_Rectum

The DSC_Rectum was not correlated with △V_bladder’ or △V_Rectum (Figure 3 C).

Factors affecting △And_Rectum

Different rectum filling states had impact on the intersection between the bladder and the PTV (Figure 7). △And_Rectum was associated with V_Bladder’ and △V_Rectum (Spearman’s correlation coefficient = −0.275, 0.701; P < .01, Figure 3D). According to regression analysis, Y = 0.284 − 0.001* X1 + 0.947*X2 (Y: △And_Rectum; X1: V_Bladder’; X2: △V_Rectum), Table 1.

Figure 7.

The impact of rectum under filling (A), moderate filling (B), and over filling (C) on the rate of change of intersection with PTV.

Factors affecting △And_{smallintestine}

△And_{smallintestine} was negatively correlated with the △V_bladder (Spearman’s correlation coefficient = −0.674; P < .01, Figure 3E). The regression analysis showed that Y = 0.733 − 2.405*X (Y: △And_{smallintestine}; X: △V_bladder’) (Table 1).

Discussion

Intensity-modulated radiation therapy can not only concentrate on the high-dose area in the tumor target area but also form a steep dose gradient, maximize the protection of normal tissues, and improve the therapeutic gain ratio.¹⁰ Traditional 4-field whole pelvic radiotherapy (4F-WPRT) has a radiation range from the sacrum to the obturator foramen and does not require high movement of internal organs. By contrast, intensity-modulated whole pelvic radiotherapy (IM-WPRT) increases the therapeutic dose to the tumor target area through complex dose distribution, while reducing the dose to the surrounding normal tissues and reducing the acute and long-term adverse reactions of radiotherapy.^11,12 Good organ motion management is the premise of IM-WPRT. Differences in bladder and rectum preparation during treatment and plan cause the target volume to move, which reduces the accuracy of target volume coverage, and causes the OAR to move, which reduces the impact on organizational protection. Therefore, it is vital to know how to manage organ movement. Dynamic IMRT enables the delivery of a single treatment fraction in just 2.4 to 2.9 minutes, significantly reducing the potential for intra-fractional variations caused by changes in bladder and rectal filling status during treatment.¹³ Varian iCBCT’s advanced algorithm produces high-resolution soft-tissue images, particularly improving visualization of the bladder and rectum compared to standard CBCT.

This study showed that despite strict implementation of the “comfortable full bladder” regimen, the control of bladder changes was not ideal: From 561 groups of iCBCT, the probability of bladder volume changes exceeding 10%, 20%, and 50% were 87.7%, 75.22%, and 37.79%, respectively. Overall, 83.44% patients experienced varying degrees of reduction in bladder capacity during treatment, ranging from 2.23% to 55.81%, with an average reduction of 30.54%, which was similar to the conclusion of Eminowicz et al¹⁴ (30.54% vs 38%). A possible reason for the difference is the difference in planned bladder volume (338 vs 289 cc). Our study shows that when the planned bladder volume is 400 to 500 cc, the bladder capacity changes the least during the treatment period. The DSC_bladder’ is positively correlated with △V_bladder’. Reducing △V_bladder’ can stabilize the shape of the bladder (Figure 3A). Studies have shown that as the volume increases, the irradiated volume of the bladder increases. Ahmad et al¹⁵ believed that with increased bladder filling, part of the bladder would move out of the planned contour. Zhang and Wang¹⁶ found that in cervical cancer helical tomotherapy, when the bladder volume changed more than 300 mL, or the relative change exceeded 40%, the irradiated volume of the bladder increased significantly. Our study further quantified the relationship between increased bladder capacity and increased irradiated volume: △And_b = 0.042 + 0.865*△V_b, that is, for every 10% increase in the bladder, its intersection with PTV increased by 8.65% (Table 1). Therefore, we recommend that the planned bladder capacity is 400 to 500 cc, and the bladder capacity should be kept consistent during treatment. If conditions permit, an ultrasonic bladder scanner can be used.¹⁷

Cervical cancer radiotherapy is often accompanied by rectal complications such as mucous bloody stools and tenesmus, which not only reduce the quality of life of patients but also affect the smooth progress of treatment. Schaake et al¹⁸ reported that rectal toxicity was related to rectum dose volume: rectum bleeding was associated with anorectum (V70), fecal incontinence was associated with external sphincter (V15) and iliococcygeus (V55), and increased stool frequency with iliococcygeal muscle (V45) and levator ANI muscle (V40). Tyagi et al¹⁹ further analyzed that the planned rectum volume <70 cc is more helpful for rectal protection in cervical cancer radiotherapy, Wu et al²⁰ reached similar conclusions. In this study, by analyzing the daily CBCT images of cervical cancer patients, it was found that despite active defecation before radiotherapy, the volume control of the rectum was still unsatisfactory: 45.83% (11/24) patients had a volume change of more than 50%. Moreover, the shape of the rectum had a certain randomness (Figure 3C), which was unrelated with the volume change of the rectum, but may be related with the regularity of intestinal peristalsis.²¹ However, the increase in rectal volume during treatment is not conducive to protection. Our study found that rectum irradiated volume change was positively correlated with rectum volume change, with a 9.47% increase in its intersection with PTV for every 10% increase in rectal volume (Table 1). Therefore, optimal rectum preparation is a passive emptying of the rectum during the plan design and each radiation therapy delivery. Glycerin enema which is colorless and non-toxic can be used clinically, as it, has no adverse reactions, has an obvious and rapid effect, is simple to administer, and has a high degree of patient cooperation.

Studies have shown that the degree of bladder filling is the main influencing factor of acute intestinal adverse reactions: Nijkamp et al²² performed magnetic resonance imaging (MRI) scans on 11 volunteers using different fixation devices and positions and designed a radiotherapy plan. The results show that every 100 cc increase in bladder volume can reduce the V15 of the small intestine by 16%, regardless of the fixation device and body position. The study by Georg et al²³ also arrived at a similar conclusion. The study by Jain et al²⁴ found that bladder filling has the greatest impact on intestinal toxicity, followed by the choice of treatment technology. Evacuating the bladder before radiotherapy significantly increases the probability of acute intestinal reactions. In our study, the degree of bladder filling was moderately correlated with the irradiated volume of the small bowel (r = −0.674, P < .01). To further quantify the relationship between them, we proposed that △Ands = 0.733 − 2.405△Vb, that is, for every 10% increase in the bladder volume, the volume of the small intestine entering the high dose area will decrease by 24.05% (Table 1). However, the R² of this regression equation is low (0.52), which may be due to incomplete independent variables; in this case, the small intestine cannot be scanned completely owing to the limitation of the scanning range of iCBCT, and thus the analysis of small intestinal volume changes is lacking. Thus, it can be seen that the change of the irradiated volume of the rectum during radiotherapy is only related to the change of the rectum volume, and the increase of the bladder volume will increase the irradiated volume of the bladder and reduce the irradiated volume of the small intestine. Given the large difference in the tolerated doses of the bladder and small intestine (TD5/5: 60 vs 50; TD50/5: 80 vs 65) Gy, it is difficult for the bladder volume to be completely consistent with the plan before each treatment. When the urine output is appropriately increased, there is a greater benefit than otherwise.

It is undeniable that, in addition to bladder and rectal filling status, factors such as abdominal adipose distribution, beam incidence angles, and respiratory motion may also compromise target coverage precision and dose distribution to OARs.²⁵ As a small-sample retrospective analysis, this study will be followed by in-depth investigations to systematically evaluate the impact of these variables on radiotherapy target delineation and OAR dosimetry.

Conclusion

For all that, our study quantified the trend of bladder and rectum volume changes and their impact on the exposure volume of OARs in the pelvis, which may better guide the development of IMRT for cervical cancer. The implementation of “comfortable full bladder” and “active defecation” programs may not maintain the stability of the bladder and rectum very well. Ultrasonic bladder scanner and glycerin enema can be used for assistance. Targeting a planned bladder volume of 400 to 500 cc minimizes intrafraction variability. For every 10% enlargement of the bladder, the irradiated volume of the bladder may increase by 8.65%, while the irradiated volume of the small intestine can be reduced by 24.05%. Every 10% enlargement of the rectum can increase the irradiated volume of the rectum by 9.47%. An appropriate increase in urine output is more beneficial to the small intestine than a decrease.

Supplemental Material

sj-doc-1-onc-10.1177_11795549251377910 – Supplemental material for The Effect of Bladder and Rectum Volume Changes on Exposed Organ Volume During Intensity-Modulated Radiotherapy for Cervical Cancer

Supplemental material, sj-doc-1-onc-10.1177_11795549251377910 for The Effect of Bladder and Rectum Volume Changes on Exposed Organ Volume During Intensity-Modulated Radiotherapy for Cervical Cancer by Hui Liu, Zixian Zhang, Xuan Guo, Tong Wang, Jiang Hu, Jianhui Shao, Feng Chi and Huilang He in Clinical Medicine Insights: Oncology

Footnotes

Acknowledgements

Not Applicable.

ORCID iD

Huilang He

Ethical Considerations and Consent to Participate

This present retrospective study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (grant no. B2023-116-1) and exempted informed consent on March 21, 2023. The study complied with the Declaration of Helsinki and China’s Human Genetic Resources Management regulations.

Consent for Publication

Not applicable.

Author Contributions

HL, ZZ, and XG collected data and drafted the manuscript. TW and JH helped to collect the data. HH, FC, and JS designed the study, and revised the manuscript. All authors read and approved the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Medical Science and Technology Research Foundation of Guangdong Province, China (grant no. A2020216).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data are not publicly available because of patient privacy concerns but are available from the corresponding author upon reasonable request.

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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The Effect of Bladder and Rectum Volume Changes on Exposed Organ Volume During Intensity-Modulated Radiotherapy for Cervical Cancer

Abstract

Background:

Methods:

Results:

Conclusion:

Keywords

Introduction

Materials and Methods

Inclusion and exclusion criteria

Immobilization

Image processing and data acquisition

Statistical analysis

Results

Changes in bladder capacity during treatment

The effect of planned bladder volume on bladder-filling stability

Factors affecting DSCbladder

Factors affecting △Andbladder

Changes in rectum volume during treatment

Factors affecting DSCRectum

Factors affecting △AndRectum

Factors affecting △Andsmallintestine

Discussion

Conclusion

Supplemental Material

sj-doc-1-onc-10.1177_11795549251377910 – Supplemental material for The Effect of Bladder and Rectum Volume Changes on Exposed Organ Volume During Intensity-Modulated Radiotherapy for Cervical Cancer

Footnotes

Acknowledgements

ORCID iD

Ethical Considerations and Consent to Participate

Consent for Publication

Author Contributions

Funding

Declaration of Conflicting Interests

Data Availability Statement

Supplemental Material

References

Supplementary Material

Factors affecting DSC_bladder

Factors affecting △And_bladder

Factors affecting DSC_Rectum

Factors affecting △And_Rectum

Factors affecting △And_{smallintestine}