Implications of interfractional bladder volume variations in proton beam therapy for rectal cancer

Johanna Färlin; Bruno Sorcini; Karin Söderkvist; Alexander Valdman

doi:10.3857/roj.2024.00654

Radiation Oncology Journal > Epub ahead of print

Färlin, Sorcini, Söderkvist, and Valdman: Implications of interfractional bladder volume variations in proton beam therapy for rectal cancer

Original Article

Radiation Oncology Journal 2025; roj.2024.00654.

Published online: June 9, 2025

DOI: https://doi.org/10.3857/roj.2024.00654

Implications of interfractional bladder volume variations in proton beam therapy for rectal cancer

Johanna Färlin¹

, Bruno Sorcini², Karin Söderkvist¹, Alexander Valdman^3,⁴

¹Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden

²Department of Radiotherapy Physics and Engineering, Medical Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden

³Department of Radiation Oncology, Karolinska University Hospital, Stockholm, Sweden

⁴Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden

Correspondence: Johanna Färlin Department of Diagnostics and Intervention, Oncology, Umeå University, 901 87 Umeå, Sweden
Tel: +46-705574924 E-mail: johanna.farlin@umu.se

Received October 4, 2024 Revised March 12, 2025 Accepted March 13, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

This study evaluated interfractional bladder volume variations and the resulting dosimetric changes during short-course radiotherapy (SCRT) 5 × 5 Gy (relative biological effectiveness) in patients with locally advanced rectal cancer.

Materials and Methods

Twenty patients received either protons or photons with daily cone-beam computed tomography (CBCT). All patients received the same drinking instructions prior to the planning computed tomography (CT) and each fraction. For each patient, volumetric modulated arc therapy (VMAT) and proton beam therapy (PBT) plans were generated. The bladder was delineated on each CBCT which were registered to the planning CT in the treatment planning system. The baseline bowel bag structure was adjusted accordingly for each bladder volume. Volumetric and dosimetric data for the bladder and bowel bag were then analyzed.

Results

Baseline bladder volumes were on average 71 cm³ larger than the average volume during treatment (95% confidence interval, 15 to 126). No significant difference was detected during treatment. Mean bladder doses decreased significantly from baseline to during treatment for both VMAT and PBT treatment plans (p = 0.021 and p = 0.002, paired two-sided t-test). Compared to baseline, the dose to the bowel bag adjusted for daily bladder volume increased by 3.8% for VMAT (t = –2.56, p = 0.019, two-tailed) and 18.7% for PBT (t= –2.415, p = 0.026, two-tailed).

Conclusion

We report consistently smaller bladder volumes during SCRT compared to baseline. This resulted in lower-than-expected mean bladder doses during the treatment course and consequently an increase in dose to bowel bag. Variations in bladder volume resulted in larger changes in delivered dose to bladder and bowel bag in PBT compared to VMAT.

Keywords: Bladder, Bladder volume, Proton beam therapy, Rectal cancer

Introduction

Proton beam therapy (PBT) has the potential to reduce side effects compared to conventional photon therapy due to the proton’s physical properties with the characteristic Bragg Peak [1]. Organs distal to the intended target can potentially be spared from dose due to this effect. This contrasts with conventional photon therapy where the exit dose is unavoidable. By reducing radiation dose to the organs at risk (OAR) and normal tissue surrounding the intended target, less side effects can be expected. Dosimetric studies have repeatedly shown that PBT in many cases can reduce radiation dose to OAR [2-4]. However, clinical benefits of such dose reduction in terms of reduced side effects remain largely unclear due to lack of clinical data, especially from randomized trials. This was recently confirmed by the Particle Therapy Cooperative Group gastrointestinal subcommittee [5]. The physical properties of PBT make it susceptible to changes in the anatomy and as a result, even a small displacement of organs i.e., the bladder or bowel, may considerably affect the dose distribution. This effect is less pronounced in conventional photon therapy [1].

Variability in bladder volume represents a clinical challenge in pelvic radiotherapy. The variations in volume can subsequently affect the surrounding organs by dislocating them [6,7]. Pelvic radiotherapy studies show that a small bladder volume on many occasions predicts a higher dose than expected at planning to the intestine [8]. Furthermore, a full bladder might result in larger dose to the bladder itself [9]. As a result, the advantages of PBT may be limited due to these daily treatment uncertainties.

Several methods have been described to control the variability of the bladder during the treatment course. However, previous studies have shown a limited effect of bladder-filling instructions [10-12].

To investigate the possible clinical advantages of PBT for patients with locally advanced rectal cancer (LARC) the prospective randomized PROtons compared to photons in high-risk RECTal cancer (PRORECT) trial was initiated in 2021 (NCT04525989). The primary endpoint in PRORECT is the incidence of acute preoperative gastrointestinal toxicity associated with PBT vs photon therapy. Patients eligible for short-course radiotherapy (SCRT) are randomized between PBT or conventional photon therapy (volumetric modulated arc therapy [VMAT]). The prescribed dose for all patients is 5 Gy relative biological effectiveness (RBE)* ×5 (* applies to all doses in Gy mentioned in future text) [1]. Bladder-filling instructions were included in the trial for all patients. A dosimetric analysis of the first 20 patients including detailed information on the treatment planning procedures was described previously [4].

The aim of the present study is to analyze the bladder variability and its consequences on the delivered dose using the same cohort [4]. We investigated possible differences between the pre-planned and the actual delivered dose to the bladder and bowel due to daily bladder volume variations during SCRT for LARC. In addition, we compare the difference in delivered dose between PBT and VMAT.

Materials and Methods

1. Randomized phase II trial PRORECT

From May 2021 to June 2022 20 consecutive patients (8 females and 12 males) aged 36–73 years with a mean clinical target volume of 812 cm³ were treated in the ongoing randomized phase II trial PRORECT (NCT04525989). More information regarding the patient characteristics of this initial cohort and the methods of the PRORECT study, including detailed information on the treatment planning procedure, was described previously [4]. We report the dose parameter “mean dose” to bladder and bowel bag according to the clinical goals in the PRORECT trial, in keeping with “as low as reasonable achievable” principles. The dose constraint to bowel bag is that the volume receiving 18 Gy should be equal or less than 450 cm³.

2. Summary of clinical procedures

PBT have been delivered at the Swedish national proton facility Skandionkliniken. The delivered dose was 25 Gy in five fractions with daily cone-beam computed tomography (CBCT) used for setup verification at each treatment fraction. A planning computed tomography (CT) was conducted and used for dose planning and dose calculations. Both a PBT and a VMAT treatment plan were generated for all 20 patients in Eclipse Treatment Planning System (version 16.01.10, Varian Medical Systems, Palo Alto, CA, USA).

To minimize bladder volume variability, all patients were subjected to the following procedure: after voiding, the patients were asked to drink 300 mL of liquid, preferably water. The CBCT was performed 45–60 minutes after this procedure. The same procedure was performed before the planning CT and before each treatment fraction. The anatomical structures of interest were reviewed online on daily CBCT-images. Daily feedback to the patient was delivered with instructions to adjust the preparations accordingly.

3. Daily volume and dose distribution in the bladder and bowel bag

The CBCT scans were taken approximately one minute prior to radiation delivery. All CBCT scans were uploaded to the Eclipse Treatment Planning System (Varian Medical Systems). A total of 100 CBCTs were included in this study. To minimize the interobserver uncertainties, all structures were delineated by a single oncologist with 10 years of experience in radiation oncology (JF). The bladder was manually delineated on five CBCT scans for each patient, representing the bladder volume of each treatment fraction (Fig. 1). Delineated structures were then referred to the planning CT using rigid registration relative to the bony anatomy. Daily dose distribution in each CBCT bladder volume was subsequently extracted from the original dose-volume histogram (DVH) for both PBT and VMAT treatment plans, respectively. The structure “bowel bag” was delineated on planning CT according to the Radiation Therapy Oncology Group guidelines [13]. To investigate the dosimetric impact of daily bladder volume variations on the bowel bag, the following approach was implemented: the bladder delineated in each CBCT scan was referred to the planning CT. For each daily bladder volume, the original bowel bag structure was manually adjusted, creating five daily bowel bag volumes. Daily dose distribution of bowel bag was subsequently extracted from the original DVH for both PBT and VMAT treatment plans.

4. Statistical analysis

Statistical analyses were made in SPSS version 28 (IBM Corp., Armonk, NY, USA). Two-sided t-test was used to compare average baseline and average bladder volumes and bowel bag volumes. Pearson correlation coefficient was employed to measure correlations. Intra-patient mean bladder volume variation over five treatment fractions was analyzed with one-way repeated measured analysis of variance (ANOVA). p-values of less than 0.05 were considered statistically significant.

Results

1. Bladder volume evaluation

Fig. 2 presents differences in volume between baseline volume derived from the planning CT (Vo) and average volume of the five CBCT scans (Vavg) in each patient, respectively.

In the entire cohort, bladder volumes ranged between 33.5–658.9 cm³ with an overall baseline mean volume (Vo, standard deviation [SD]) of 274.0 ± 166.1 cm³. The overall average bladder volume during the treatment, Vavg was 203.8 ± 91.7 cm³. Mean Vo and mean Vavg were strongly correlated (r = 0.71, p < 0.001). The 25.7% decrease from Vo to Vavg was significant (paired two-sided t-test, p = 0.016). Average bladder volume at first treatment fraction was numerically largest (Fig. 3). When changes in intra-patient bladder volumes over five CBCT measurements were analyzed with one-way repeated measured ANOVA, as presented in Fig. 3, no significant time effect on mean bladder volumes measured at five different timepoints was found (F(4, 16) = 2.7, p = 0.068). Further analysis of intra-patient variations during the 5 days of treatment revealed that the largest variation in bladder volume in a single patient was 597.9 cm³ (min 61.0–max 658.9 cm³). Near-empty bladder (<70 cm³) was observed in 12 of the CBCT scans. Four patients presented with near-empty bladder once (3 female and 1 male), and another four presented it twice (1 female and 3 male) during treatment. In four out of 12 occasions (33.3%), near-empty bladders were observed on second treatment fraction, and in 11/12 near-empty bladder observations (91.7%), bladder volume on the following treatment fraction was not near empty.

2. Bowel bag volume evaluation

For each patient, the baseline bowel bag volume (BowVo) and the average bowel-bag volume over five CBCT scans (BowAvg), was extracted. Baseline mean BowVo (SD) in the entire cohort was 966.5 ± 427.0 cm³. The mean BowAvg (SD) in the cohort was 1,027.2 ± 404.0 cm³. The difference in volume was significant (paired t-test, p = 0.002).

3. Dose evaluation for bladder

The mean absolute bladder dose at baseline (Do) was derived from the PBT and VMAT treatment plans, respectively. The average dose to the bladder during 5 treatment days (Davg) represents the average mean absolute dose derived from five daily CBCT scans registered to the planning CT as illustrated in Fig. 1. Fig 1 also illustrates the general reduction in the bladder volume included in the isodose volume as previously demonstrated [4]. The differences in dose are presented in Fig. 4.

For VMAT, the mean Do and Davg (SD) were 14.5 (±2.6) Gy and 13.8 (±2.6) Gy, respectively. Corresponding numbers for PBT were 9.0 (±3.6) Gy and 7.8 (±3.5) Gy. There was a significant difference between Do and Davg for both VMAT and PBT treatment plans (p = 0.021 and p = 0.002, respectively, paired two-sided t-test). The resulting average relative dose reduction from Do and Davg for VMAT and PBT was 4.8% and 13.3%, respectively.

In the female cohort (n = 8) the Do was 14.36 Gy for VMAT and 9.8 Gy for PBT. The corresponding numbers for males (n = 12) were 14.63 Gy and 8.47 Gy, respectively. Davg in the female cohort was 13.61 Gy for VMAT and 8.4 Gy for PBT. Corresponding numbers were 14.06 Gy and 7.32 Gy in males. No significant differences in dose to the bladder were found between sexes.

4. Bowel bag dose evaluation

The mean absolute dose to bowel bag at baseline (BowDo) was derived from the VMAT and PBT treatment plans, respectively. The mean BowDo for the entire cohort for VMAT was 10.42 Gy and for PBT the mean BowDo for the entire cohort was 4.79 Gy. The average dose to bowel bag during 5 days of treatment (BowDavg) represents the average mean dose derived from the five daily bowel bag structures adjusted for the daily bladder volume in the treatment plan. The mean BowDavg for the entire cohort was for VMAT 10.82 Gy and for PBT 5.69 Gy respectively. The increase in dose to bowel bag during treatment compared to the dose expected at planning was significant. For VMAT the 3.8% increase in dose was significant (t = –2.56, p = 0.019, two-tailed) For PBT the 18.7% increase in dose was significant (t = –2.415, p = 0.026, two-tailed).

No significant correlation was observed between mean daily bladder volume (Vavg) and mean daily dose to the bowel bag (BowDavg) across the cohort.

For VMAT, Pearson’s correlation coefficient yielded r = –0.43 with a p-value of 0.057. For PBT, the corresponding values were r = –0.39 and p = 0.087.

In the subject with numerically largest change in bladder volume during treatment (max–min range), the bladder volume varied from 658.9 cm³ (day 1) to 61.0 cm³ (day 2). For VMAT, the larger bladder volume on day 1 corresponded to a daily dose to bowel bag of 15.39 Gy, while the lower volume on day 2 resulted in a VMAT dose of 13.47 Gy. For PBT, the corresponding doses were 9.06 Gy (day 1) and 8.19 Gy (day 2).

Discussion and Conclusion

We report an in-depth analysis of image guided PBT in treatment for LARC, focusing on the bladder volume variability and its dosimetric consequences. The bladder volumes in our cohort were relatively stable during 5-days long radiotherapy. However, average bladder volumes were significantly smaller during the treatment course compared to baseline at treatment planning. Similar findings are described in previous studies conducted in a number of other pelvic malignancies. It is noteworthy that most of these treatments last for a minimum of 25 days. In line with our findings the bladder volume in these studies is reported to be smaller during treatment than on planning CT. However, contrary to our findings the volume throughout the treatment is most often found to be less stable and diminishing towards the end of treatment period [8,11,14,15]. It can be hypothesized that side effects such as urgency and cystitis that often begin after approximately two weeks into the treatment could be a contributing factor to the variation in bladder volumes. In the case of a 5-day long radiotherapy course the side effects largely appear after completed radiotherapy and are not expected to affect bladder volumes during the treatment. Our study indicates that the bladder volume is smaller during treatment than expected from the treatment plan, regardless of the length of treatment. The underlying causes of this finding remain uncertain. Contributing factors may encompass physiological processes such as organ displacement and treatment-induced effects, including urgency. The timing between fluid intake and imaging has been identified as a factor [16]. Compliance with drinking protocols may diminish despite mitigation strategies.

If near-empty bladder was observed, the volume was recovered the following day on nearly every occasion. This observation might be an effect of daily intervention. CBCT bladder volumes are routinely reviewed and feedback to the patient is provided. Previous studies on drinking instructions to maintain stable bladder volume and treatment plan robustness are inconclusive. Some indicate that verbal instructions might be sufficient [11,17] while others report that the procedures give little, or no effect [10,15]. This study indicates that instructions and feedback is a contributing factor to the rapid recovery of the bladder volume during SCRT. This makes the treatment more robust since the bladder volume can be adjusted promptly if needed and the volume of bladder can be maintained as stable as can be expected considering the natural variations in the human body. However, despite these efforts it is unclear if the instructions are clear enough for the patients to follow and if there are other contributing factors affecting participants’ ability to comply with the instructions as intended, but this is not the scope for the present trial.

Reduction in bladder volume during the treatment resulted in a significant although minor lowering in mean dose to the bladder. However, the decrease in bladder dose was larger in PBT treatment plans compared to VMAT, confirming the fact that PBT is more sensitive to changes in patient anatomy [1]. As expected from the previous analysis [4], the mean dose to the bladder delivered with PBT was significantly lower than with VMAT. These results are consistent and even more pronounced when considering the daily bladder volumetric changes. The clinical implications of these observations will be analyzed in the ongoing PRORECT trial. Additionally, these results could be of value when considering other PBT treatment regimes in the pelvic area when dose to the bladder is of major concern. The observed larger reduction in delivered dose to bladder with PBT may potentially have clinical relevance in future dose-escalation and re-irradiation trials.

Another important aspect is the possible implications of bladder volume variation on dose to the bowel bag. Previous studies have shown that there is a correlation between bladder volume and size and location of the bowel [8,15]. This effect is visible in Fig. 1. When the bladder volume diminishes and dislocates inferiorly, the intestines will usually follow and subsequently move further down into the irradiated area. After adjusting the bowel bag structure for the daily bladder volume variations, we found a significantly higher dose to bowel bag during treatment than expected at treatment planning for both VMAT and PBT plans. The correlation between daily bladder volume and dose to bowel was not statistically significant, however there was a trend towards a negative correlation. The hypothesis that a smaller bladder results in a higher dose to bowel than expected is supported by our findings.

One limitation of the present study is that the quality of CBCT scans for PBT does not allow for accurate dose calculation directly on the scans since it requires detailed stopping power measurements [1]. Furthermore, the CBCT scans for PBT have a limited field of view. The rigid registration procedure assumes that the anatomy of the patient is largely unchanged, which is not always the case. Additionally, deformable registration could not be done in a reliable way for CBCT scans in the PBT planning system.

When selecting patients for PBT in the pelvic region, careful consideration of specific patient cohorts is warranted. Our findings highlight that large variations in bladder volume and substantial internal organ motion may exert a greater influence on PBT compared to VMAT.

There are several promising projects and technical advances on the horizon. One possibility for the imminent future is using information from the original CT in combination with the CBCT scans to make a synthetic CT enabling CBCT-based online adaptive radiotherapy. This workflow is reported feasible for SCRT for rectal cancer [18]. Integrating PBT and magnetic resonance imaging to enable real-time imaging is a promising solution for pelvic PBT in the more distant future [19].

To the best of our knowledge, the variability in bladder volume and its possible effect on the delivered dose to the bladder, as well as its potential impact on the dose to the bowel bag during PBT for LARC, has not been previously investigated. In this study we perform the first comparison of the planned and delivered dose to the bladder and bowel bag during PBT for LARC. Additionally, we present initial results from the first randomized trial using PBT and VMAT regarding dose variability to the bladder. Moreover, we describe the variation of bladder volume during SCRT, a period of 5 days, in contrast to longer fractionation schedules.

The bladder volumes during the treatment course were significantly smaller than expected at the time of treatment planning. In contrast, the volume remained relatively stable throughout the treatment.

The volume reduction compared to baseline translated into lower mean doses to the bladder, and a corresponding increase in mean dose to the bowel bag compared to the anticipated dose at treatment planning.

The analysis of daily volumetric variations in the bladder and the implications for dose delivery substantiates the sustained reduction in dose to OAR observed in PBT compared to VMAT, consistent with previous research findings. Additionally, variations in bladder volume during the treatment course resulted in larger changes in dose to the OARs in PBT compared to VMAT.

Statement of Ethics

The PRORECT-trial has received approval from the Swedish Ethical Review Authority (Dnr 2020–02192). All patients gave written consent before any study procedures were performed.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Acknowledgments

We thank prof. Björn Zackrisson for valuable input and all colleagues at Skandionkliniken for their practical support.

Funding

This project received research grants from Cancerfonden, Sweden; Radiumhemmets Forskningsfonder, Sweden; Region Stockholm, Sweden; and Skandionkliniken, Swedish National Proton Center.

Author Contributions

Conceptualization, JF, KS, AV; Data curation, BS, AV; Formal analysis, AV; Investigation, JF; Methodology, JF; Project administration, AV; Resources, JF, BS, AV; Supervision, KS, AV; Visualization, JF; Writing - original draft, JF; Writing - review, and editing: BS, KS, AV.

Data Availability Statement

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author, JF.

Fig. 1.

The cumulative dose-volume histogram (DVH) of bladder at baseline (red) and fractions 1–5 (yellow) in proton beam therapy treatment plan (top). Structures corresponding to DVH (bottom left). Color wash dose distributions (range, 0 to 25 Gy relative biological effectiveness) (bottom right).

Fig. 2.

Comparative baseline bladder volume (Vo, blue) and average cone-beam computed tomography bladder volumes (Vavg, orange). Error bars indicate ± standard deviation.

Fig. 3.

Average (95% confidence interval [CI]) cone-beam computed tomography bladder volumes for each treatment fraction in 20 patients. Error bars indicate 95% CI.

Fig. 4.

Absolute bladder dose at baseline (Do) and average dose to the bladder during 5 treatment days (Davg) for proton beam therapy (PBT) and volumetric modulated arc therapy (VMAT) plans for 20 patients. RBE, relative biological effectiveness.

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