Abstract
Background/Aim: Patients irradiated for prostate cancer may experience urinary toxicity, particularly if the bladder volume is small. A mobile application (app) that reminds the patients to drink water prior to each radiation fraction may help avoid small volumes. This study investigating bladder volumes during a radiotherapy course is a prerequisite for a prospective trial testing such a reminder app. Patients and Methods: Frequency of bladder volumes <200 ml and seven potential risk factors were retrospectively evaluated in 72 patients receiving external beam radiotherapy for non-metastatic prostate cancer. Results: The mean and median values of the numbers of radiation fractions with bladder volumes <200 ml were 17.8 (standard deviation=12.0) and 16.5 (interquartile range Q1-Q3=7.5-29.5) fractions, respectively. Higher numbers of fractions with volumes <200 ml were significantly associated with pre-radiotherapy bladder volumes <200 ml (p<0.001) and high-risk prostate cancer (p=0.014). Conclusion: The proportion of bladder volumes <200 ml during the radiotherapy course was high and needs to be decreased. Pre-radiotherapy bladder volume and risk level of prostate cancer were significant risk factors for higher numbers of fractions with volumes <200 ml. These results are important for designing a prospective trial.
Prostate cancer is one of the most common solid malignancies worldwide (1). Most patients with non-metastatic disease receive either prostatectomy or radiotherapy. Radiotherapy is often performed with normo-fractionated (5×2.0 Gy per week) external beam radiotherapy (EBRT) alone or EBRT plus a high-dose rate (HDR) brachytherapy boost (2). Patients with low-risk prostate cancer may also be treated with low-dose rate (LDR) brachytherapy (seeds) alone (2). Selected patients may be candidates for hypo-fractionated EBRT alone, for example with 20×3.0 Gy or 28×2.5 Gy (2). In case of normo-fractionated EBRT alone, the recommended total dose is 74-80 Gy corresponding to 37-40 fractions of 2.0 Gy (2). Radiotherapy of prostate cancer may be associated with significant acute urinary toxicity such as cystitis, particularly if the volume of the urinary bladder is small. Three studies showed that bladder volumes <200 ml or <180 ml, respectively, were associated with increased acute or late urinary toxicity (3-5). In another study, a planned bladder volume >200 ml and daily filling between 82% and 113% were associated with reduced intra-fraction motion of the prostate (6). Moreover, in the study of Smith et al., optimal bladder dose constraints were missed more frequently if the bladder volumes were <200 ml (7). Therefore, it appears important to achieve bladder volumes >200 ml at as many radiation fractions as possible. Several studies investigated the role of drinking protocols (5-16). Patients were asked to drink a certain amount of water prior to the planning computed tomography (CT-simulation) and the radiotherapy sessions. In these studies, the amount of water ranged between 200 and 600 ml and the time interval until CT-simulation or the radiation session between 30 and 60 min (5-16). However, drinking a certain amount of water at a specific point in time may require considerable discipline from the mainly elderly or very elderly patients. These considerations led to the idea of developing a mobile application (app) that reminds the patients 1 h prior to each radiation session of drinking 400 ml of water. The present retrospective study was performed to evaluate the number of radiation fractions with bladder volumes <200 ml and identify corresponding risk factors in a cohort of patients treated with 74-80 Gy of EBRT alone for non-metastatic prostate cancer. These data are mandatory for designing a prospective trial testing the reminder app, which is currently under development.
Patients and Methods
The data of 72 patients with prostate cancer receiving EBRT without a brachytherapy boost in 2022 or 2023 were retrospectively analyzed. The study received approval from the responsible ethics committee at the University of Lübeck, Germany (file 2024-447). All patients had neither lymph node involvement nor distant metastases. Radiotherapy was delivered to the prostate with or without seminal vesicles and performed as volumetric modulated arc therapy with median 37 fractions (range=35-40 fractions) of 2.0 Gy (normo-fractionation). In this study, only patients receiving normo-fractionated EBRT were included, since this reduced the risk of a selection bias due to different dose-fractionation regimens of radiotherapy. For better comparability, the first 35 fractions of each patient were used for the analyses. At each fraction, the bladder volume was determined in the corresponding cone-beam computed tomography (CBCT). In two patients, no CBCT was performed for one fraction each, resulting in 34 evaluable fractions. Thus, the total number of radiation fractions included in the analyses was 2,518 fractions.
The number of radiation fractions with bladder volumes <200 ml was calculated for each patient. Mean values plus standard deviations (SD) and median values plus interquartile ranges (Q1-Q3) were determined. In addition, seven potential risk factors for bladder volumes <200 ml were investigated. These factors included the initial (pre-radiotherapy) bladder volume (<200 vs. ≥200 ml), age (<75 vs. ≥75 years), Karnofsky performance score (70-80 vs. 90-100), body-mass index (<30 vs. ≥30=obesity), prostate volume prior to radiotherapy (<60 vs. ≥60 ml), risk group of prostate cancer (low to intermediate vs. high), and antihormonal therapy prior to and/or during the course of radiotherapy (no vs. yes) (Table I). Standard methods of descriptive statistics were applied to evaluate the location and dispersion of absolute bladder volumes over time, absolute changes of bladder volumes from baseline over time, and number of fractions with bladder volumes <200 ml. Box- and Whisker diagrams were created for graphical illustrations. The potential impact of risk factors on the number of fractions with bladder volumes <200 ml was assessed using Wilcoxon-two-sample tests. A p-value of <0.05 was considered significant. For the statistical analyses, the SAS 9.4 software (SAS Institute Inc, Cary, NC, USA) was used.
Distribution of the investigated potential risk factors.
Results
The distribution of bladder volumes at each radiation fraction is shown in Figure 1. At 18 of the 35 fractions (51.4%), the median bladder volume was less than 200 ml. Fifteen of these values were found in the second half of the radiotherapy course, i.e., between fractions 20 and 35. When considering the change of the bladder volume compared to pre-radiotherapy baseline, a considerable number of extreme values (increase or decrease by more than 200 ml) was found, particularly a decrease by more than 200 ml (Figure 2).
Box- and Whisker diagrams for urinary bladder volumes (given 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 shown.
Box- and Whisker diagrams for change of urinary bladder volumes (given in ml) at each radiation fraction in relation to pre-radiotherapy (baseline) volumes. Mean values (diamonds) plus standard deviations (grey vertical bars) and median values (thin solid line) plus ranges (thin vertical lines) are shown.
Mean values (plus SD) and median values (plus Q1-Q3) of the numbers of radiation fractions with bladder volumes <200 ml related to each of the seven potential risk factors are summarized in Table II. Mean and median values of the numbers of radiation fractions with bladder volumes <200 ml were 17.8 fractions (SD=12.0) and 16.5 fractions (Q1-Q3=7.5-29.5), respectively. In the analyses of potential risk factors (Figure 3), higher numbers of radiation fractions with volumes <200 ml were significantly associated with pre-radiotherapy bladder volumes <200 ml (p<0.001) and high-risk prostate cancer (p=0.014).
Descriptive analysis of the numbers of radiation fractions with bladder volumes <200 ml of the seven investigated potential risk factors.
Comparison of the potential risk factors with respect to the number of radiation fractions with bladder volumes <200 ml. Potential risk factors include initial (pre-radiotherapy) bladder volume, body-mass index (BMI), age, prostate volume prior to radiotherapy, Karnofsky performance score, risk group of prostate cancer, and antihormonal therapy. The p-values were obtained from the Wilcoxon-two-sample test.
Discussion
Many elderly and very elderly men develop prostate cancer (1). Considerable research is carried out in all areas of treatment including surgery, radiotherapy, and systemic therapy to improve the prognoses of these patients (17-21). Many of these patients receive radiotherapy that can be associated with several types of acute toxicity. Three previous studies revealed that smaller bladder volumes were associated with increased urinary toxicity (3-5). In the retrospective study of Pisani et al. that included 280 patients receiving EBRT for prostate cancer, bladder volumes <200 ml at CT-simulation were significantly associated with higher rates of acute grade ≥2 urinary toxicity (p=0.018) (3). Moreover, late urinary toxicity was related to acute grade ≥2 toxicity (p=0.004) On multivariate analysis, bladder filling was an independent predictor of grade ≥2 urinary toxicity (p=0.009). In the prospective study of Pinkawa et al., 80 patients were asked to complete a validated questionnaire regarding several urinary and other functions prior to and at the last day of radiotherapy, as well as at median 2 months (range=6 weeks to 6 months) and median 16 months (range=12-24 months) after their radiotherapy course. Patients with initial bladder volumes <180 ml reported significantly more acute and late urinary symptoms (4). In the study of Grün et al., 193 patients irradiated for prostate cancer received specific training via a biofeedback mechanism to achieve a reproducible bladder volume of 200-300 ml at CT-simulation and each radiation fraction (5). According to their results, it was important to achieve a bladder volume of at least 180 ml during each radiation fraction in order to reduce the rate of grade ≥2 urinary toxicity. These three studies demonstrated that bladder volumes should be ≥180 ml or ≥200 ml at the time of CT-simulation and ideally also at each radiation fraction.
Several studies explicitly emphasized the importance of bladder filling protocols (11, 13, 16, 22, 23). In additional studies that investigated the bladder filling status in patients irradiated for prostate cancer the patients were asked to drink a certain amount of water prior to CT-simulation and radiotherapy sessions (5-16). However, this procedure may require considerable discipline from the patients. Possibly, an app reminding the patients to drink water at a specific point in time prior to CT-simulation and each radiation session may lead to an improved bladder filling status. Such an app is currently under development and will soon be tested in a prospective trial. For proper design of this trial, the frequency of radiation fractions with bladder volumes <200 ml and corresponding risk factors need to be identified. According to the results of the present study, mean and median values of the numbers of fractions with bladder volumes <200 ml were 17.8 and 16.5 fractions, respectively. Moreover, higher numbers of fractions with volumes <200 ml were significantly associated with bladder volumes <200 ml at CT-simulation and high-risk prostate cancer. The importance of bladder volumes at CT-simulation was previously described, although it was not investigated as a potential risk factor of lower bladder volumes during the course of radiotherapy (3-5). High-risk prostate cancer represents a more advanced disease, which requires larger (boost) volumes, which may be associated with increased urinary symptoms including urgency (2). However, since risk factors regarding the frequency of radiation fractions with bladder volumes <200 ml were not previously reported, it is very difficult to compare our results to those of other studies. Moreover, during the interpretation of our results, the retrospective nature of the study including the risk of a hidden selection bias should be considered. Our study is hypothesis-generating and will contribute to the design of a prospective trial.
In summary, we determined the frequency of bladder volumes <200 ml in a cohort of patients receiving EBRT without brachytherapy for non-metastatic prostate cancer. Pre-radiotherapy bladder volumes <200 ml and high-risk prostate cancer were identified as significant risk factors for higher numbers of bladder volumes <200 ml during the radiotherapy course. These results are important for designing a subsequent prospective trial that will test a reminder app in patients irradiated for prostate cancer.
Acknowledgements
This study received partial funding from the European Regional Development Fund through the Interreg Deutschland-Danmark program (project HeAT, number 01-1-23 2).
Footnotes
Authors’ Contributions
All Authors participated in the design of the study and the collection of the data that were analyzed by a professional external statistician. D.R. drafted the article, which was reviewed and approved by all Authors.
Conflicts of Interest
The Authors indicate no conflicts of interest related to this study.
- Received August 5, 2024.
- Revision received August 26, 2024.
- Accepted August 27, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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).
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