Abstract
Background/Aim: Many patients with high-risk prostate cancer receive normo-fractionated irradiation. Previously, high-risk cancer and pre-treatment bladder volumes <200 ml were associated with inappropriate bladder filling during the radiotherapy course. A prospective trial will investigate the value of an app reminding patients to drink water before each radiotherapy session. This study provides information regarding magnitude of inappropriate bladder filling and risk factors required for the prospective trial.
Patients and Methods: In 23 patients with high-risk prostate cancer and inappropriate pre-treatment bladder filling, mean and median numbers of radiation fractions with bladder volumes less than 200 ml and potential risk factors were retrospectively investigated.
Results: Mean and median numbers of fractions with volumes less than 200 ml were 29.2±6.6 and 32.0 (interquartile range=24.0-35.0) of 35 fractions. Higher numbers were significantly associated with a lower performance score (p <0.029).
Conclusion: Bladder filling was inappropriate during most radiotherapy fractions and, therefore, must be considered a significant problem. Our results are relevant for a subsequent prospective trial.
Introduction
Definitive radiotherapy is a standard treatment for patients with non-metastatic prostate cancer who do not wish to undergo prostatectomy or are not suitable for a surgical approach (1). Radiotherapy regimens include external beam radiotherapy (EBRT) alone, EBRT combined with brachytherapy boost, or brachytherapy alone. The appropriate regimen depends on the risk stage of the prostate cancer. One commonly used risk classification considers the prostate-specific antigen (PSA) level, the Gleason score, and the clinical primary tumor stage, as suggested by D’Amico et al. in 1998 (2). The classification differentiates between low-risk (PSA <10 ng/ml, Gleason score ≤6, and ≤cT2a), intermediate-risk (PSA 10.1-20 ng/ml and/or Gleason 7, and/or cT2b), and high-risk (PSA >20 ng/ml and/or Gleason score ≥8, and/or ≥cT2c) cancer. Patients with low- or intermediate-risk scheduled for EBRT alone are increasingly treated with moderately hypo-fractionated radiotherapy, for example with 20×3.0 Gy over 4 weeks (3, 4). Thus, normo-fractionation with 37-40×2.0 Gy over 7.5 to 8 weeks will likely be used mainly for patients with high-risk cancer who cannot receive brachytherapy.
Both hypo-fractionated and normo-fractionated EBRT of prostate cancer may lead to acute cystitis, which can be burdensome for the affected patients. Radiotherapy-induced cystitis was shown to be more pronounced if the filling of the bladder was insufficient during the course of EBRT. In three previous studies, bladder volumes less than 200 ml (or <180 ml) were associated with a higher incidence of urinary toxicity (5-7). Thus, it is important that the bladder volume is at least 200 ml during as many radiation fractions as possible. In order to achieve this goal, the value of drinking protocols has been evaluated (7-14). However, continuous adherence to such a protocol may require considerable discipline. To support the patients in this context, an app which reminds them to drink water before each radiation fraction, is developed by a project partner of the current Interreg project Health Advancing Technologies for Elderly (HeAT). This app will be tested in a prospective trial very soon. According to the initial study protocol, it was intended to test the app in patients with prostate cancer receiving normo-fractionated EBRT, regardless of the risk stage of the disease (15). However, due to modifications of treatment concepts in the participating centers, normo-fractionated EBRT will be administered almost exclusively to patients with high-risk cancer. As a consequence, the protocol of the prospective trial investigating the app in patients receiving normo-fractionated EBRT needs to be adapted. Only patients with high-risk tumors will be included. Therefore, the present retrospective study was performed focusing on patients with high-risk cancer. The results of this study are very important for proper adaption of the protocol of the prospective trial.
Patients and Methods
Twenty-three patients treated with normo-fractionated irradiation for high-risk prostate cancer between 2021 and 2024 were included in this retrospective study. The modified study protocol was submitted as an amendment to the leading ethics committee in Lübeck, Germany, and approved by this committee under the registration number 2024-447. For inclusion in the present study, patients must have high-risk prostate cancer and a bladder volume less than 200 ml at the time of CT-simulation. Characteristics of high-risk cancer included a PSA level >20 ng/ml, a Gleason score ≥8, and clinical primary tumor stage ≥T2c, of which at least one characteristic must be present (2). All patients received antihormonal therapy.
Total doses of radiotherapy (volumetric modulated arc therapy) ranged between 74 Gy and 80 Gy (median dose=78 Gy), and doses per fraction were always 2.0 Gy. In accordance with our previous study, analyses were performed considering the first 35 fractions. At each of these fractions, the bladder volume was contoured and calculated using the cone-beam computed tomography (CBCT) performed that day. Thus, for the current study, 805 CBCTs were evaluated.
For each patient, we determined the number of radiation fractions (of the first 35 fractions), where the bladder volume was less than 200 ml. The mean number [plus standard deviations (SD)] and the median number [plus interquartile ranges (Q1-Q3)] of fractions with a bladder volume less than 200 ml were calculated. Moreover, seven characteristics were evaluated for potential associations with a higher number of fractions with suboptimal bladder filling of less than 200 ml. These characteristics were age at the start of irradiation (<75 vs. ≥75 years), Karnofsky performance score (KPS 90-100 vs. ≤80), body-mass index (<30 vs. ≥30 kg/m2), pre-radiotherapy prostate volume (<60 vs. ≥60 ml), PSA level (<10 vs. ≥10 ng/ml), Gleason score (≤8 vs. 9), and primary tumor stage (T1 or T2 vs. T3 or T4): Corresponding distributions are summarized in Table I.
Distribution of the seven characteristics.
For the assessment of the location and the dispersion of absolute bladder volumes over time and the number of radiation fractions with a bladder volume less than 200 ml, standard methods of descriptive statistics were applied. Statistical analyses were performed with the SAS 9.4 software (SAS Institute Inc., Cary, NC, USA). In addition, box-Whisker plots were provided. Associations between the seven characteristics mentioned above and the number of radiation fractions with a bladder volume less than 200 ml were evaluated by using Wilcoxon-two-sample tests. p-Values of <0.05 and <0.10 indicated a significant association or at least a trend, respectively.
Results
When considering the distribution of the bladder volumes of the 23 patients at each of the 35 radiation fractions, it becomes obvious that the median bladder volume was always <200 ml (Figure 1). In Table II, we summarized the mean (plus SD) and median (plus Q1-Q3) numbers of radiation fractions with a bladder volume less than 200 ml for the entire cohort and each of the investigated characteristics. In the entire cohort, the mean number was 29.2 (SD=6.6). The median number of radiation fractions with a bladder volume less than 200 ml was 32.0 (Q1Q3=24.0-35.0). The analyses of the seven characteristics (Table III) revealed a significant association between a higher number of fractions with bladder volumes <200 ml and a worse performance score, i.e., a KPS ≤80 (Figure 2, p=0.029). In addition, a trend was found for an association with a Gleason score of 9 (Figure 3, p=0.093).
Box- and Whisker diagrams for bladder volumes (in ml) at each radiation fraction: Mean values (diamonds) plus standard deviations (grey vertical bars) and median values (thin solid line) plus ranges (thin vertical lines) are given.
Mean and median numbers of radiation fractions with a bladder volume less than 200 ml in relation to the investigated characteristics.
Associations between investigated characteristics and the number of radiation fractions with a bladder volume less than 200 ml (Wilcoxon-two-sample tests).
Comparison of Karnofsky performance score 90-100 vs. ≤80 regarding the number of radiation fractions with a bladder volume <200 ml (Wilcoxon-two-sample test).
Comparison of Gleason score ≤8 vs. 9 regarding the number of radiation fractions with a bladder volume <200 ml (Wilcoxon-two-sample test).
Discussion
A considerable number of patients treated with EBRT for prostate cancer experience urinary toxicity, particularly if bladder filling is suboptimal during the administration of radiotherapy. According to previous studies, bladder volumes of at least 180-200 ml were associated with less toxicity when compared to volumes of less than 180-200 ml (5-7). In order to improve the bladder filling during a course of radiotherapy for prostate cancer, several groups suggested the use of drinking protocols motivating the patients to drink a predefined amount of water before CT-simulation and/or each radiation fraction (13, 14, 16-18). However, adherence to a drinking protocol can be challenging for the mainly (very) elderly patients. To support these patients, a reminder app is currently under development as part of the Interreg project HeAT. This app will remind patients to drink 300 ml of water 45 minutes before each radiation fraction. It will be tested prospectively in two prostate cancer trials, one in patients treated with normo-fractionated EBRT and another one in patients treated with hypo-fractionated EBRT (15, 19). Initially, the trial using normo-fractionated EBRT was planned to be performed, regardless of the risk stage of prostate cancer (15). However, since hypo-fractionated EBRT is increasingly used for low- and intermediate risk cancers, centers participating in our prospective trial have very recently modified their treatment strategy and now use normo-fractionated EBRT almost exclusively for high-risk prostate cancer. Therefore, it was decided to adapt the protocol of the prospective trial and focus on patients with high-risk tumors. As a consequence, an additional pre-study is required in order to properly calculate the required sample size for the adapted prospective trial.
The present retrospective study represents the additional pre-study. According to its results, the mean and median numbers of radiation fractions with a bladder volume less than 200 ml were 29.2 and 32.0, respectively. In our previous study of normo-fractionated EBRT for prostate cancer of any risk stage, the corresponding values were 17.8 and 16.5, respectively. This remarkable difference supports the idea of performing a trial focusing on high-risk cancer. Moreover, high-risk cancer, when compared to low- or intermediate-risk cancer, was significantly associated with a larger number of radiation fractions with a bladder volume less than 200 ml during the radiotherapy course (15). In the present study, a larger number of radiation fractions with a bladder volume less than 200 ml was significantly associated with a KPS of ≤80. This may be explained by the fact that patients with a worse performance status may have more difficulties in retaining urine.
In summary, bladder filling was not sufficient during the majority of the first 35 radiation fractions. Therefore, inappropriate bladder filling must be considered as a significant problem for patients with high-risk prostate cancer and a pre-radiotherapy bladder volume <200 ml. The results of this hypothesis-generating study are relevant for a subsequent prospective trial investigating the impact of a reminder app on bladder filling in patients treated with normo-fractionated EBRT for non-metastatic high-risk prostate cancer. However, when designing the prospective trial, the retrospective design of the present study should be kept in mind.
Acknowledgements
This study has been partially funded by the European Regional Development Fund through the Interreg Deutschland-Danmark program as part of the project HeAT (Health Advancing Technologies for Elderly).
Footnotes
Authors’ Contributions
The Authors participated in the design of the study and/or the collection of the data, which were analyzed by a professional statistician. The article, which was drafted by D.R., was reviewed and approved by all Authors.
Conflicts of Interest
The Authors indicate no conflicts of interest related to this study.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received March 27, 2025.
- Revision received April 14, 2025.
- Accepted April 15, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
