Abstract
Background/Aim: Hypo-fractionated radiotherapy (HF-RT) is gaining popularity in prostate cancer treatment. HF-RT can lead to cystitis, particularly in cases with small bladder volumes. This study evaluated the bladder volume during a course of moderate HF-RT. This knowledge is required for the protocol of a prospective trial. Patients and Methods: Seventy-six patients receiving HF-RT (20×3.0 Gy) for prostate cancer were retrospectively evaluated. The number of HF-RT sessions with a bladder volume <200 ml and corresponding risk factors were investigated. Results: Mean and median numbers of sessions with a bladder volume <200 ml were 13.4 (±6.7) and 16.0 (interquartile range=8.0-19.0), respectively. Higher numbers of radiotherapy sessions with a bladder volume <200 ml were associated with a pre-radiotherapy volume <200 ml (p<0.001). Mean numbers of sessions with a bladder volume <200 ml were 16.0 (±5.5) in patients with a pre-radiotherapy bladder volume <200 ml and 7.9 (±5.9) in patients with a bladder volume ≥200 ml, respectively. Conclusion: Bladder volume was <200 ml during many HF-RT sessions. Patients with a pre-radiotherapy bladder volume <200 ml may benefit from an app reminding them to drink water before their HF-RT sessions.
A considerable number of patients with prostate cancer receive external beam radiation therapy alone (1). In many of these patients, radiotherapy is performed using conventional fractionation with doses per fraction of 2.0 Gy and total doses of between 74.0 Gy and 80.0 Gy (1). Since these regimens take quite a long time, namely 7.4 to 8 weeks, several prospective randomized trials have investigated shorter radiation regimens using moderate hypofractionation, i.e. doses per fraction of >2.0 to 3.4 Gy (2). In 2016, the 5-year results of the conventional or hypofractionated high-dose intensity-modulated radiotherapy in prostate cancer (CHHiP) trial were published (3). This non-inferiority trial included 3,216 patients irradiated for localized prostate cancer who were randomized to receive either conventionally fractionated radiotherapy (CF-RT) with 37×2.0 Gy over 7.4 weeks, moderate HF-RT with 20×3.0 Gy over 4 weeks, or moderate HF-RT with 19×3.0 Gy over 3.8 weeks. When compared to CF-RT, non-inferiority regarding biochemical or clinical failure at 5 years was shown for HF-RT with 20×3.0 Gy but not for that with 19×3.0 Gy (3). Long-term adverse events were similar in patients receiving HF-RT when compared to those treated with CF-RT. Another randomized non-inferiority trial, the prostate fractionated irradiation trial (PROFIT), compared CF-RT using 39×2.0 Gy over 8 weeks to HF-RT with 20×3.0 Gy over 4 weeks in a total of 1,206 patients with intermediate-risk prostate cancer (4). In this trial, HF-RT was not inferior to CF-RT regarding biochemical or clinical failure at 5 years. Moreover, HF-RT did not lead to increased late toxicity.
Two other randomized trials used different HF-RT regimens. The hypofractionated irradiation for prostate cancer (HYPRO) trial compared 39×2.0 Gy over 8 weeks and 19×3.4 Gy over 3.8 weeks in a total of 804 eligible and assessable patients with intermediate or high-risk prostate cancer (5-7). The authors concluded that, since HF-RT was not shown to be superior to CF-RT regarding relapse-free survival at 5 years (primary endpoint), HF-RT with 19×3.4 Gy cannot be considered a new standard dose-fractionation regimen for intermediate or high-risk prostate cancer. The NRG Oncology/Radiation therapy Oncology Group 0415 trial compared CF-RT of 41×1.8 Gy over 8.2 weeks to HF-RT with 28×2.5 Gy over 5.6 weeks in 1,092 eligible patients with low-risk prostate cancer (8, 9). HF-RT was not inferior in terms of 5-year disease-free survival. However, in the original publication from 2016, the authors reported an increase in gastrointestinal and genitourinary adverse events in patients who received HF-RT (8). In July 2024, long-term results of this trial were published (9). HF-RT was not found to be inferior to CF-RT with respect to disease-free survival at 12 years and was in fact superior regarding the cumulative incidence of biochemical failure. Moreover, late grade ≥3 gastrointestinal and genitourinary adverse events were not significantly different after HF-RT or CF-RT. When summarizing the results of these four randomized trials, moderate HF-RT appears a reasonable option for selected patients with localized prostate cancer, preferably for patients with low- or intermediate-risk cancer (2-9).
Both CF-RT and HF-RT may lead to symptomatic radiation cystitis, particularly if the urinary bladder volume is small. It has been shown that volumes <180-200 ml are associated with increased radiation-induced urinary toxicity (10-12). Thus, it seems important that the bladder volume is >200 ml during as many radiation sessions as possible. The potential benefit of drinking protocols aiming to increase the intake of fluid (water) before each radiation session or computed tomography (CT)-simulation has already been investigated. In the corresponding studies, the intake of water and time until radiation treatment or CT-simulation ranged between 200 and 600 ml and between 30 and 60 min, respectively (11, 13-23). Since adherence to a drinking protocol requires a certain discipline from patients, they may need support, possibly from a mobile application (app) that would remind them to drink a certain amount of water before each radiation session. The present retrospective study evaluated the number of radiation sessions in which patients had a bladder volume <200 ml and potential risk factors for a volume <200 ml in a cohort of patients treated with HF-RT for prostate cancer. It focused on moderate HF-RT in order to reduce the risk of a potential selection bias introduced by different dose-fractionation regimens. The present study was required for proper design of a prospective trial that will test an app reminding patients with prostate cancer receiving HF-RT to drink water before each of their treatment sessions.
Patients and Methods
A total of 76 patients treated with HF-RT for localized prostate cancer between 2022 and 2024 were included in this retrospective multi-center study, which was approved by the Ethics Committee of the University of Lübeck in Germany (approval number 2024-447_1). HF-RT was administered after CT-simulation using volumetric-modulated arc therapy. The HF-RT regimen included 20 fractions of 3.0 Gy (total dose=60 Gy) over 4 weeks, which was used in two previous randomized trials (3, 4). Prior to each radiation session, cone-beam CT was performed in order to allow for very precise delivery of the corresponding radiation fraction. In each cone-beam CT (i.e., 20 times per patient), the urinary bladder was contoured and its volume determined.
For each patient, the number of HF-RT sessions with a bladder volume <200 ml was determined. Subsequently, the mean (plus standard deviation) and the median (plus interquartile ranges Q1-Q3) of these numbers were calculated. Moreover, the impact of 10 potential risk factors for a bladder volume <200 ml was evaluated. Evaluated factors included age at radiotherapy (<75 vs. ≥75 years), pre-radiotherapy bladder volume (<200 vs. ≥200 ml), Karnofsky performance score (60-80 vs. 90-100), body-mass index (<30 vs. ≥30 kg/m2), prostate volume (<60 vs. ≥60 ml), prostate-specific antigen level (<10 vs. ≥10 ng/ml), Gleason score (6-7 vs. 8-9), primary tumor stage [T1 vs. T2 or T3, according to the eighth edition of the TNM classification (24)], risk group of prostate cancer (low to intermediate vs. high), and antihormonal therapy before or during the HF-RT course (no vs. yes). The distributions of these factors are shown in Table I.
Distribution of the potential risk factors analyzed in this study.
For evaluation of location and distribution of absolute bladder volume over time and the number of HF-RT sessions with a bladder volume <200 ml, standard methods of descriptive statistics were used (SAS 9.4 software; SAS Institute Inc, Cary, NC, USA). Moreover, box-whisker plots are provided for the entire cohort, as well as by pre-radiotherapy bladder volume subgroup (<200 ml and ≥200 ml). Analyses regarding associations between potential risk factors and the number of HF-RT sessions with a bladder volume <200 ml were performed with Wilcoxon two-sample tests. For these analyses, p-values less than 0.05 were regarded as indicating significance.
Results
The distribution of bladder volumes at each HF-RT session for the entire cohort (n=76) is shown in Figure 1. The median bladder volume was less than 200 ml at each of the 20 HF-RT sessions (100%). In the subgroups of patients with a pre-radiotherapy bladder volume <200 ml and ≥200 ml, the median bladder volume was less than 200 ml during 20 sessions (100%) and one session (5%), respectively (Figure 1).
Box-and-whisker plots of bladder volumes at each radiation session for the entire cohort (top), the subgroup of patients with a pre-radiotherapy bladder volume <200 ml (middle), and the subgroup of patients with a pre-radiotherapy bladder volume ≥200 ml (bottom). Mean values (diamonds) plus the standard deviation (grey boxes) and median values (solid line) plus the range (whiskers) are shown. The y-axis was truncated at 600 ml.
The mean numbers (plus their standard deviations) and the median numbers (plus interquartile ranges) of HF-RT sessions with a bladder volume <200 ml for the entire cohort and by subgroups of the 10 investigated potential risk factors are given in Table II. Mean and median numbers of HF-RT sessions with a bladder volume <200 ml for the entire cohort were 13.4 (standard deviation=6.7) and 16.0 (interquartile range=8.0-19.0), respectively.
Descriptive analysis of the mean and median numbers of radiation sessions with bladder volumes <200 ml, related to the potential risk factors and in the entire cohort.
The analyses of the impact of the potential risk factors on the number of HF-RT sessions for patients with a bladder volume <200 ml (Figure 2) revealed a significant association between a pre-radiotherapy bladder volume <200 ml and undergoing a higher number of HF-RT sessions with a bladder volume <200 ml (p<0.001). In addition, a more advanced primary tumor stage (T2 or T3) showed a trend for a positive association with the number of HF-RT sessions with a bladder volume <200 ml (p=0.07).
Comparison of potential risk factors regarding the number of radiation sessions with bladder volumes <200 ml. Factors were age at radiotherapy, pre-radiotherapy bladder volume, Karnofsky performance score, body mass index (BMI), prostate volume, prostate-specific antigen (PSA) level, Gleason score, primary tumor stage, prostate cancer risk group, and antihormonal therapy. The p-values were obtained from Wilcoxon two-sample tests.
Discussion
Treatment modalities used for prostate cancer include radiotherapy, surgery and systemic agents (25-29). Many patients with localized disease, particularly patients aged >70 years, receive definitive radiotherapy (1). Patients assigned to radiotherapy who are not suitable for a brachytherapy boost are treated with external-beam radiotherapy with or without androgen deprivation therapy. External-beam radiotherapy is generally performed as CF-RT over a period of 7 to 8 weeks or moderate HF-RT over approximately 4 weeks (1). Both types of radiotherapy can lead to genitourinary toxicity, including radiation cystitis. Previous studies demonstrated that inappropriate filling of the urinary bladder resulting in a smaller bladder volume is associated with increased radiotherapy-induced toxicity (10-12). In two studies from Germany, patients with pre-radiotherapy bladder volumes <180 ml experienced significantly more urinary toxicity (10, 11). In a retrospective study of 280 patients from Italy, a pre-radiotherapy (CT-simulation) bladder volume <200 ml was significantly and independently associated with increased grade ≥2 acute urinary toxicity (12). Thus, achieving a bladder volume >180-200 ml at CT-simulation and during as many radiation sessions as possible appears to be important in reducing the risk of urinary toxicity.
This may be achieved with drinking or bladder filling protocols (11, 13-23, 30, 31). However, adherence to such protocols requires certain discipline from patients. The patients may benefit from being supported by an app reminding them to drink water before each radiation session. Such an app is currently under creation and is planned to be tested in a prospective trial that will start in 2025. For the appropriate design of this trial, determination of the mean and median numbers of radiation sessions with a bladder volume <200 ml and identification of risk factors are important. Both endpoints were evaluated in the present study.
In our previous study of patients with prostate cancer receiving CF-RT with 74-80 Gy in 37 to 40 fractions, the mean and median numbers of treatment sessions with a bladder volume <200 ml were assessed after 35 sessions (32). The median bladder volume was <200 ml at 18 out of 35 sessions (51.4%). Fifteen of these were recorded between CF-RT sessions 20 and 35, i.e. during the second half of the CF-RT course. Thus, the mean and median numbers of treatment sessions with a bladder volume <200 ml may be different between CF-RT (35-40 sessions) and moderate HF-RT (commonly 20 sessions). Therefore, our present study included only patients treated with 20×3.0 Gy of HF-RT.
According to the results of our study, mean and median numbers of HF-RT sessions with a bladder volume <200 ml were 13.4 and 16.0, respectively. A higher number of sessions with a bladder volume <200 ml was significantly associated with a pre-radiotherapy bladder volume <200 ml. Moreover, the mean number of HF-RT sessions with a bladder volume <200 ml was much higher in the subgroup of patients with a pre-radiotherapy bladder volume <200 ml (16.0 vs. 7.9). The same held true for the median number of HF-RT sessions with a bladder volume <200 ml (19.0 vs. 8.0). Thus, it appears very important to achieve appropriate bladder filling resulting in a bladder volume ≥200 ml during as many HF-RT sessions as possible. However, when interpreting or present data, the risk of hidden selection biases due to the retrospective study design need to be considered.
In conclusion, the bladder volume was <200 ml during a large number of radiotherapy sessions in patients treated with HF-RT for non-metastatic prostate cancer. Patients with a pre-radiotherapy bladder volume <200 ml assigned to HF-RT may benefit from an app reminding them to drink water before each of their radiotherapy sessions.
Acknowledgements
As part of the Interreg-project HeAT, the study received partial funding from the European Regional Development Fund through the Interreg Deutschland-Danmark program (reference 01-1-23 2).
Footnotes
Authors’ Contributions
All Authors participated in the design of the study. Data were collected by D.R., C.K. C.V.M., L.S., J.C., and S.J. Analyses of the data were performed by an external statistician. The article was drafted by D.R. and subsequently reviewed and approved by all Authors.
Conflicts of Interest
The Authors indicate that there are no conflicts of interest related to the current study.
- Received December 16, 2024.
- Revision received January 9, 2025.
- Accepted January 13, 2025.
- Copyright © 2025 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).