Dosimetric impact of bladder volume variation on online adaptive radiotherapy for cervical cancer based on cone-beam computed tomography and clinical management strategies

Introduction

Cervical cancer is the fourth most common malignancy in women globally, ranking first among female reproductive system tumors in China (1). Radiotherapy plays a crucial role in cervical cancer management (2). With developments in image-guided radiotherapy (IGRT), cone-beam computed tomography (CBCT) has become the gold standard for interfractional target verification. However, while IGRT reduces setup errors through real-time imaging, it fails to address dosimetric deviations caused by interfractional organ motion and morphological changes. In cervical cancer radiotherapy, rectal volume variations are minimal due to the fixed anatomical position and thus exert limited dosimetric impact (3), bladder filling status exhibits significant interfractional variability, thereby being the primary source of dose uncertainty (4). Interfractional bladder volume fluctuations (200–500 mL) can induce >15-mm displacement of cervical and paracervical targets, compromising target coverage and increasing radiation exposure to normal tissues such as the small bowel and bladder wall (5). Furthermore, excessive bladder emptying or overfilling may alter pelvic anatomy, elevating risks of tumor underdosing or organ at risk (OAR) toxicity (6). Consequently, achieving precise dose delivery amidst dynamic bladder changes remains a critical challenge in cervical cancer radiotherapy.

Online adaptive radiotherapy (ART), an innovative advancement in radiation oncology, enhances treatment precision, target recontouring, and plan optimization (7-9). Unlike conventional IGRT, which only corrects setup errors, online ART dynamically adapts to interfractional organ deformations, thereby reducing planning target volume (PTV) margins to 2–3 mm and minimizing radiation exposure to normal tissues (e.g., the small bowel and rectum) (10). However, the complex workflow of online ART (target delineation, plan design, and plan delivery) typically results in significantly longer single-fraction treatment times as compared to conventional IGRT, potentially exacerbating intrafractional anatomical shifts (11). Although organs such as the rectum exhibit minimal volume changes during ART, the bladder—as a dynamic organ—may experience continuous filling, leading to spatiotemporal dose heterogeneity due to mismatches between optimized plans and actual anatomical states during delivery (12). Thus, intrafractional bladder dynamics and personalized bladder management warrant particular attention in online ART.

Despite the demonstrated superiority of online ART over conventional IGRT, the former’s technical complexity and time-intensive workflow hinder its widespread clinical implementation, highlighting the importance of establishing bladder volume thresholds in traditional radiotherapy. Despite the substantial research conducted on the dosimetric benefits of ART, there are few reports on interfractional bladder volume-dose relationships, intrafractional dose dynamics in online ART workflows, and personalized bladder management strategies for maintaining organ stability throughout treatment. To address these deficiencies, this study analyzed 14 patients with cervical cancer undergoing online ART supported by CBCT imaging and dose reconstruction techniques and systematically completed the following: (I) compared the dosimetric differences between online ART and conventional IGRT under interfractional bladder volume fluctuations to identify a bladder volume management threshold for IGRT; (II) clarified the optimization mechanisms of personalized bladder management protocols for improving bladder stability during ART; and (III) analyze the impact of intrafractional bladder volume dynamics on actual dose distribution. The findings of this study may provide an important theoretical basis for the precise implementation of online ART and dynamic bladder management in cervical cancer radiotherapy. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-867/rc).

Methods

Research participants

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center (Approval No. B2025-214-01). We retrospectively analyzed 14 patients aged from 28 to 75 years with locally advanced cervical cancer treated between December 2023 and July 2024. The histopathological subtypes included squamous cell carcinoma (13 cases) and adenocarcinoma (1 case). All patients underwent pretreatment evaluations and received 25 fractions of online ART. The clinical characteristics of these patients are summarized in Table 1.

Inclusion criteria

The inclusion criteria were as follows: (I) a pathological diagnosis of cervical squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma; planned radical chemoradiotherapy or postoperative adjuvant radiotherapy; (II) an Eastern Cooperative Oncology Group performance status ≤2; (III) good liver and kidney function and good toleration of chemoradiotherapy; (IV) completion of magnetic resonance imaging (MRI) examination; and signed informed consent and voluntarily participation in this study.

Exclusion criteria

The exclusion criteria were as follows: language, limb, or cognitive impairment; difficulty in holding urine or an inability to hold urine; organic diseases or an inability to maintain a supine position for an extended period; a history of other malignant tumors within 5 years of the study period (except thyroid cancer and skin basal cell carcinoma); previous radiotherapy or chemotherapy; severe cardiovascular diseases, lung diseases, or other systemic diseases that could affect the safety of treatment; and refusal to participate in the study.

Patient positioning and simulation

Patients were immobilized in a vacuum fixation bag (Klarity Medical Equipment Co., Ltd., Guangzhou, China) in a supine position with arms elevated and legs slightly abducted. Computed tomography (CT) simulation was performed with a Discovery scanner (GE HealthCare, Chicago, IL, USA) with a scan range from the T10 vertebra to 4 cm inferior to the ischial tuberosity (2.5-mm slice thickness, 120 kV, and 100 mA). Isocenter placement and positioning markers were established prior to scanning.

Contouring and initial treatment planning

Contouring was conducted according to the International Commission on Radiation Units and Measurements (ICRU) standards, with pelvic MRI data being used to delineate OARs and the clinical target volume (CTV) (including cervical tumor, uterus, parametria, partial vagina, and pelvic lymphatic drainage regions) on CT images. The CTV was expanded by 10–15 mm to generate the PTV. For treatment planning, CT images were imported into the Monaco treatment planning system (Elekta, Stockholm, Sweden) for planning the design. The prescribed dose was 45–50 Gy (squamous cell carcinoma: 45 Gy; adenosquamous carcinoma: 50 Gy) in 25 fractions, with ≥95% coverage of the PTV by the prescription dose. After physician review, medical physicists completed validation and prepared for online ART.

Online ART workflow

Bladder preparation strategy

Two different methods were used for the bladder-filling strategy for adaptation to individual patient differences: natural filling (n=7) and personalized drinking water (n=7). In the natural filling group, patients drank 500 mL of water, and when they complained of urgent urination, a urine volume meter was used to measure the bladder capacity. If the urine volume reached more than 300 mL, the patient was deemed ready for online ART. In the personalized drinking water group, patients needed to empty their bladders and bowels 2 hours before each treatment. Under the premise of confirming adequate patient hydration, a baseline water intake of 650 mL was adjusted according to body weight: ±50 mL per ±5 kg change (e.g., 600 mL for patients weighing 50 kg and 700 mL for those weighing 70 kg). Hydration timing was stratified by age: individuals aged ≤50 years were required to finish drinking within 20 minutes at a constant rate, whereas those aged >50 years were required to finish within 30 minutes, with intake divided into four aliquots (150–175 mL per aliquot at 5- to 8-minute intervals). The bladder capacity was monitored with a urine volume meter at a frequency of once every 20 minutes. When the urine volume exceeded 300 mL and the results of three measurements indicated the bladder volume to be stable, the period with the minimum volume change rate after the bladder reached the filling state was delineated as the “window period” (the stabilization period with minimal bladder volume fluctuation) for ART treatment, and the patients were deemed ready for online ART treatment.

Initial CBCT scanning

After precise patient positioning, initial CBCT (CBCT₁) scanning was initiated with parameters set to 120 kV, 50 mA, and 360° rotation angle. Following image acquisition, the clinician selected the registration area to encompass all the PTV, performed preliminary automatic image registration, and refined alignment manually to achieve optimal registration accuracy. Corrections were applied based on system-calculated displacement errors.

ART plan generation

CBCT₁ images were transferred to PVmed contouring software (PV Medical Technology, Guangzhou, China). The system used a cycle generative adversarial network (CycleGAN) framework to correct geometric distortions and scatter noise in CBCT images through deformable registration and nonlocal mean filtering. Following the Hounsfield unit (HU)-to-electron density mapping relationship [compliant with International Atomic Energy Agency (IAEA) TG-46 standards], CBCT grayscale values were converted into CT-equivalent HU values, generating a synthetic CT (sCT) with electron density distribution. After automated OAR contouring, physicians reviewed and modified target and OAR contours to ensure anatomical accuracy. The revised data were imported into the Monaco planning system, and medical physicists employed Monte Carlo algorithms with GPU acceleration for reoptimization, producing the ART plan (sCT-based redesigned treatment plan). The dose limits for the patients in this study are detailed in Table 2. The final plan underwent joint physician-physicist review and approval.

Final ART plan delivery

The ART plan was transferred to the Axesse linear accelerator (Elekta). Clinicians immediately performed a second CBCT (CBCT₂) scan to verify plan delivery accuracy. After physician confirmation of CBCT₂ images, clinicians initiated final plan delivery. Timestamps for all critical workflow steps (ART initiation, plan transfer, CBCT₂ verification, and delivery completion) were meticulously recorded.

Dosimetric parameter evaluation

Dose parameter extraction

Dose parameters were extracted based on the dose-volume histogram (DVH). A target volume coverage index receiving 100% of the prescription dose (PTV-V_100%) was determined. The OAR dose parameters for the bladder included the absolute volume (V; cm³), average dose of the 2 cm³ highest irradiated volume (D2cc; Gy), and volume percentage receiving ≥30 Gy (V₃₀; %); those for the rectum included D2cc (Gy) and the volume percentage receiving ≥45 Gy of irradiation (V₄₅; %); those for the small bowel included V₄₅ and absolute volume ≥40 Gy (V₄₀; cm³); that for the femoral head included bilateral V₃₀; those for the pelvis included V₂₀ and volume percentage receiving ≥10 Gy (V₁₀; %); and that for the spinal cord included the maximum pixel dose (D_max; Gy).

Comparison between plans

The IGRT plan proceeded as follows: CBCT₁ images were imported into the Monaco system. Parameters from the initial reference plan were mapped onto CBCT₁ without reoptimization for the calculation of dose distributions, with the impact of anatomical changes on dose delivery being evaluated. The pretreatment ART plan (ART_end plan) was conducted as follows: CBCT₂ images were transferred to PVmed contouring software. After physician modification and confirmation of contours, images were imported into Monaco. ART plan parameters were mapped onto CBCT₂ without reoptimization for calculation of the actual predelivery dose distribution.

Through dosimetric parameter analysis, this study aimed to examine correlations between interfraction bladder volume variations and dose-volume parameters in ART and IGRT. Based on IGRT planning data with the small-bowel V₄₅ ≥195 cm³ as a radiation toxicity risk indicator (13), a bladder volume threshold was calculated to establish a preparation benchmark for bladder management in conventional radiotherapy, with the dosimetric advantages of ART above and below this threshold range being simultaneously analyzed. Furthermore, we compared the dose discrepancies between the ART plan and ART_end to determine the impact of intrafraction bladder volume changes on the delivered doses.

Analysis of the correlation between intrafractional bladder volume dynamic evolution and dose in ART

Bladder volume change stratification and dosimetric impact on target coverage

Based on the intrafractional bladder volume change in ART (ΔV = bladder volume in ART_end − bladder volume in the ART plan), the treatment fractions were divided into group A (ΔV <50 cm³), group B (50≤ ΔV <100 cm³), group C (100≤ ΔV <150 cm³), and group D (ΔV ≥150 cm³). The dose differences of PTV-V_100% between the ART plan and the ART_end plan in the four groups were compared to assess the impact of different ΔV values on the target volume coverage during the fraction and to obtain the ΔV threshold.

Dynamic analysis of bladder volume

For the initial volume (V₀), the bladder volume corresponded to the ART plan (cm³). The volume change rate (ΔV/t) was calculated as the ratio of ΔV to the time interval (t; min) between CBCT₂ and CBCT₁ (cm³/min). The differences in ΔV between the personalized filling group and the natural filling group were compared. The correlations between V₀ and ΔV, as well as between V₀ and ΔV/t, were analyzed to determine the potential impact of V₀ on volume dynamic changes and its clinical significance.

Statistical methods

Intergroup comparisons

All data were analyzed with SPSS 25.0 (IBM Corp., Armonk, NY, USA). Normality was assessed via the Shapiro-Wilk test. Normally distributed data were analyzed with the paired-samples t-test, while nonnormally distributed data were analyzed with the Wilcoxon signed-rank test. A P value <0.05 was considered to indicate statistical significance.

Correlation analysis

In the correlation analysis, normally distributed data were analyzed via the Pearson correlation coefficient, while nonnormally distributed data were analyzed with the Spearman rank correlation coefficient. The strength of the correlation was classified according to the absolute value of the correlation coefficient (r) as follows: |r|<0.3, no correlation; 0.3≤|r|<0.5, low correlation; 0.5≤|r|<0.8, moderate correlation; and |r|≥0.8, high correlation.

Receiver operating characteristic (ROC) analysis

The capacity of bladder volume to predict small bowel V₄₅ ≥195 cm³ was evaluated. The optimal bladder volume threshold was determined by maximizing the Youden index (sensitivity + specificity −1). The area under the curve (AUC), sensitivity, and specificity were calculated.

Results

Impact of interfractional bladder volume variations on dosimetry

Dosimetric effects of bladder volume changes in ART

Dosimetric analysis of the 14 patients showed that the bladder volume in the ART plan was significantly negatively correlated with bladder V₃₀ (r=−0.50), small bowel V₄₅ (r=−0.49), and V₄₀ (r=−0.51), but it had no obvious correlation with the dose parameters of PTV-V_100% (r=−0.03), D2cc of the bladder (r=0.24), rectum D2cc (r=−0.03), rectum V₄₅ (r=−0.12), femoral head V₃₀ (L: r=−0.15, R: r=−0.10), pelvis V₂₀ (r=0.07), pelvis V₁₀ (r=−0.08), and spinal cord D_max (r=0.09). The correlation between the bladder volume and the ART dose parameters is shown in Figure S1. The online ART process and the average time required for each step are shown in Figure 1.

Figure 1 The online ART workflow and the average time required per step. ART, adaptive radiotherapy; CBCT, cone-beam computed tomography; OAR, organ at risk; QA, quality assurance; sCT, synthetic computed tomography.

Dosimetric effects of bladder volume changes in IGRT

Dosimetric analysis showed that the bladder volume in the IGRT plan was significantly negatively correlated with bladder V₃₀ (r=−0.51) and small bowel V₄₅ (r=−0.54) and V₄₀ (r=−0.55) but had no obvious correlation with the dose parameters of PTV-V_100% (r=0.10) or D2cc of the bladder (r=0.19), rectum D2cc (r=0.11), rectum V₄₅ (r=−0.16), femoral head V₃₀ (L: r=−0.16, R: r=−0.20), pelvis V₂₀ (r=−0.24), pelvis V₁₀ (r=−0.25) and spinal cord D_max (r=−0.12). The correlation between the bladder volume and the IGRT dose parameters is shown in Figure S2.

ROC curve analysis showed that the critical value of the bladder volume of 265 cm³ had significant predictive efficacy, in terms of AUC (0.89), sensitivity (88.6%), and specificity (89.2%), and this threshold was established as the safety boundary for bladder volume management during the IGRT process. The specific manifestations of the above-described dose-volume association characteristics are shown in Figure 2 (ROC curve of the bladder volume and the small-bowel dose).

Figure 2 ROC curve of bladder volume and dose to the small bowel. AUC, area under the curve; ROC, receiver operating characteristic.

Dosage regulation advantages of ART above and below the bladder volume threshold

Stratified analysis of the treatment fractions based on the bladder volume threshold (265 cm³) showed that when the bladder volume was above 265 cm³, ART—through real-time online dose optimization—significantly outperformed IGRT in terms of the OAR dose between fractions (P<0.01).

When the bladder volume was at or below 265 cm³, ART could still significantly reduce the doses received by the OARs (P<0.01), fully demonstrating the unique advantages of ART in optimizing the dose distribution between fractions. Figure 3 illustrates the interfractional dose distributions of a representative patient undergoing ART and IGRT, comparing scenarios above and below the bladder volume threshold. Differences in various dose parameters between ART and IGRT under different bladder volume thresholds are shown in Figure 4 and Table 3.

Figure 3 Dose distributions for ART and IGRT above and below the bladder volume threshold. (A,B) Bladder volume ≤265 cm³ in ART and IGRT. (C,D) Bladder volume >265 cm³ in ART and IGRT. The bladder volume is outlined in light blue, and the PTV is outlined in red. ART, adaptive radiotherapy; IGRT, image-guided radiotherapy; PTV, planning target volume.

Figure 4 Box plot of the differences in fraction-to-fraction dose optimization between ART and IGRT above and below the bladder volume threshold. (A) Bladder D2cc. (B) Bladder V₃₀. (C) Rectum D2cc. (D) Rectum V₄₅. (E) Small bowel V₄₅. (F) Small bowel V₄₀. (G) Femoral head L-V₃₀. (H) Femoral head R-V₃₀. (I) Pelvis V₂₀. (J) Pelvis V₁₀. (K) Spinal cord D_max. (L) PTV-V_100%. ART, adaptive radiotherapy; IGRT, image-guided radiotherapy; IQR, interquartile range; PTV, planning target volume; V_x, volume receiving ≥ x Gy.

Intrafractional bladder volume dynamics in ART

Characteristics of the natural filling group

Patients without standardized bladder management showed significant volume dynamic change characteristics: the ΔV within fractions reached 190.66±69.97 cm³, and the filling rate was 7.47±3.10 cm³/min. The interfractional bladder volume variations in the natural filling group are shown in Figure 5A.

Figure 5 Diagram for pattern of change in bladder volume. (A) Line graph comparing the natural filling group and personalized filling group. (B) Stacked column chart showing distribution of bladder volume changes in the natural filling and personalized filling groups. (C) Box plot comparing volume changes between the natural filling group and personalized filling group. (D) Box plot comparing volume change rates between the natural filling and personalized filling groups. (E) Scatter plot of the correlation between initial bladder volume and volume change. (F) Scatter plot of the correlation between initial bladder volume and volume change rate. IQR, interquartile range.

Efficacy of the personalized filling group

After the intervention of the personalized drinking water scheme, the amplitude of bladder volume fluctuation was significantly reduced to 88.23±27.79 cm³ (P<0.01), and the filling rate decreased by 38.82% (4.57±2.47 cm³/min; P<0.01). The interfractional bladder volume variations in the personalized hydration group are shown in Figure 5A. According to the results of ΔV grouping (Figure 5B), patients in the personalized bladder filling group were mainly concentrated in groups A and B, and the proportion in groups C and D decreased significantly. This distribution characteristic more fully reflected the stable advantages of personalized bladder management within intrafractional variations in ART. Comparative analyses of ΔV and filling rates between groups are presented in Figure 5C,5D. These findings indicate that personalized hydration management effectively reduces variations in bladder volume during ART.

Modulation effects of initial volume

Statistical analysis showed that the initial volume (V₀) was moderately negatively correlated with both ΔV (r=−0.73) and ΔV/t (r=−0.71), suggesting that the larger the initial bladder volume is, the smaller the amplitude and growth rate of the bladder volume fluctuation during the treatment process. The nonlinear regression model further revealed that an initial bladder volume exceeding 400 cm³ was associated with a markedly increased stability in both ΔV and ΔV/t. The correlations between V₀ and intrafractional ΔV and ΔV/t are shown in Figure 5E,5F.

Dosimetric impact of intrafractional bladder volume changes in ART

Target coverage variations

Analysis based on the four-group division of ΔV showed that in group A, there was no significant change in target volume coverage (P=0.56); in group B, the target volume coverage remained stable (P=0.18); and in group C and group D, the target volume coverage decreased significantly (P<0.01). When ΔV was above 100 cm³, the coverage rate decreased from 99.45% to 97.95%. The comparison of target volume coverage between the groups is shown in Figure 6.

Figure 6 Influence of intrafraction bladder volume changes on target volume coverage in ART. (A) Group A. (B) Group B. (C) Group C. (D) Group D. Group A, ΔV <50 cm³; group B, 50≤ ΔV <100 cm³; group C, 100≤ ΔV <150 cm³; group D, ΔV ≥150 cm³. ART, adaptive radiotherapy; IQR, interquartile range; PTV, planning target volume; V_x, volume receiving ≥ x Gy.

Dosimetric changes in OARs

The intrafractional bladder volume increase during ART resulted in distinct dose redistribution patterns. A protection effect was indicated by a decrease in bladder V₃₀ by 6.6% (from 62.82% to 58.65%; P=0.02) and a decrease in small-bowel V₄₀ by 10.7% (from 108.61 to 96.94 cm³; P<0.01). The comparison of dose parameters between ART and ART_end is shown in Figure 7 and Table 4.

Figure 7 Comparison of the dose parameters between ART and ART_end. (A) Bladder D2cc. (B) Bladder V₃₀. (C) Rectum D2cc. (D) Rectum V₄₅. (E) Small bowel-V₄₅. (F) Small bowel V₄₀. (G) Femoral head_L-V₃₀. (H) Femoral head R-V₃₀. (I) Pelvis V₂₀. (J) Pelvis V₁₀. (K) Spinal cord D_max. (L) PTV-V_100%. ART, adaptive radiotherapy; IQR, interquartile range; PTV, planning target volume; V_x, volume receiving ≥ x Gy.

A heat map of ΔV grouping is provided in Figure 8, where the abscissa represents the mean value of the dose parameters, the ordinate represents the ART plan and the ART_end plan of different groups, and “Difference” indicates the difference between the dose parameters of the ART_end plan and the ART plan. According to the heat map, the color distributions of the rectum, bilateral femoral heads, pelvis, and spinal cord in each group were similar, confirming the dose stability during ART. The color changes in the heat maps of the small bowel and bladder suggest a successive increase from groups A to D. This result indicates that the increase in bladder volume during ART led to a decrease in the doses to the bladder and the small bowel.

Figure 8 Heat map of intrafractional bladder volume and dose parameter changes in ART. Group A, ΔV <50 cm³; group B, 50≤ ΔV <100 cm³; group C, 100≤ ΔV <150 cm³; group D, ΔV ≥150 cm³. ART, adaptive radiotherapy; PTV, planning target volume; V_x, volume receiving ≥ x Gy.

Discussion

Through systematic analysis of interfractional and intrafractional dose parameters in online ART for cervical cancer, this study revealed the dynamic impact of bladder volume variations on radiation dose distribution. The results indicate that ART’s online dose optimization effectively compensates for the influence of interfractional bladder volume changes on target coverage while significantly reducing the dose to OARs. However, due to ART’s complex workflow and technical limitations, its widespread clinical adoption remains challenging, and IGRT continues to be the mainstream technique. Therefore, this study suggests a 265 cm³ as a critical bladder volume threshold for ART initiating in conventional IGRT, which can provide important quantitative guidance for traditional radiotherapy. Through comparative analysis of the personalized bladder management cohort and the natural filling cohort, we established quantitative relationships between V₀, ΔV, and ΔV/t while validating the critical importance of implementing personalized bladder management as an interventional strategy. This approach combines initial volume control (400 cm³), personalized intervention, and ART technology to identify the optimal “window period” during bladder volume changes for ART delivery, achieving dynamic balance between target dosing and OAR protection, thereby providing new insights for dosimetric optimization in precision radiotherapy.

Dosimetric advantages of ART in interfractional adaptation

In pelvic tumor radiotherapy, anatomical variations remain the core challenge for precise dose delivery. Conventional radiotherapy addresses uterine displacement by expanding PTV margins, but this strategy inevitably increases normal tissue exposure (14,15). Although IGRT improves delivery accuracy, it cannot adequately manage the dose distribution impact from significant interfractional bladder changes (16). This study demonstrates the transformative value of online ART technology, which through real-time anatomical optimization and dynamic dose redistribution, can effectively reduce the dosimetric impact of bladder volume fluctuations to targets and OARs. The study confirmed that ART, through CBCT-guided real-time target/OAR contouring and Monte Carlo algorithm optimization, transforms bladder volume changes from dose-disrupting factors into controllable optimization variables, achieving simultaneous improvement in both target coverage stability (1.3–2.2% increase) and OAR protection (16.3–22.8% reduction in rectal V₄₅), which is consistent with the findings reported by Sibolt et al. (17) (3–5% coverage improvement and 10–15% rectal V₄₀ reduction). However, due to ART’s high resource demands and technical constraints, its widespread clinical application remains limited. By establishing a bladder volume threshold system, this study provides an innovative quantitative evaluation standard for conventional IGRT. The results indicate that when bladder volume falls below the critical threshold (at or below 265 cm³), it serves both as an early warning indicator for small-bowel radiation injury and as a key trigger point for online ART, echoing findings by Kavanagh et al. (18) (V₄₅ above 195 cc significantly increases the risk of severe small bowel toxicity). In cases where patients exhibit impaired urinary control or difficulty holding urine, the target bladder filling volume may be appropriately reduced to ensure the feasibility and safety of the treatment process. This finding not only validates ART’s core concept of anatomy-responsive radiotherapy but also provides theoretical foundations and practical pathways for optimizing precision treatment paradigms in pelvis malignancies.

Characteristics and control mechanisms of intrafractional bladder dynamics

As a key dosimetric modulator in cervical cancer radiotherapy, dynamic bladder changes directly impact dose distribution accuracy in conventional radiotherapy and optimization efficacy in online ART. In clinical practice, bladder management strategies have become a critical area of interest, but the currently used methods, such as ureteral catheterization with saline infusion (19), introduce significant clinical challenges in their attempt to address anatomical stability, including reduced patient tolerance and increased iatrogenic infection risks. We integrated bladder management strategies proposed by McBain et al. (20) and Sivanandam et al. (21) to develop personalized protocols based on patient’s body contour, age, and weight, which requires bladder and bowel emptying 2 hours prior to treatment, followed by an intake of 600–700 mL of water within 20 minutes. By controlling total volume and intake rhythm, we identified the phase with minimal postfilling volume change rate as the optimal “window period” for ART planning and delivery, where relative bladder stability facilitates precise dose delivery to targets and OARs. Comparative analysis between natural filling and personalized management protocols revealed the critical clinical value of initiating personalized bladder management 2 hours in advance. In the natural filling group, unstandardized management led to excessive intrafractional volume fluctuations (ΔV=190.66±69.97 cm³) and filling rates (7.47±3.10 cm³/min), particularly exposing the risks of compromised target coverage during ART delivery. Postintervention data showed the personalized hydration strategy not only reduced volume fluctuations by 53.7% but also stabilized filling rates at 4.57±2.47 cm³/min, this is consistent with the study by Valencia Lozano et al. (22). Further analysis revealed significant associations between V₀ and intrafractional bladder stability: when V₀ was above 400 cm³, volume fluctuations reached a plateau phase, likely due to nonlinear bladder wall tension-volume relationships inhibiting further expansion. This finding aligns with De Wachter et al.’s (23) results indicating that standardized bladder management reduces volume variations, while extending the concept of individualized control time windows; specifically, the 2-hour pretreatment hydration intervention provided a buffer time for bladder changes and through synergy with ART’s online optimization algorithms, transformed anatomical stability into dose distribution robustness. This study confirms that combining temporal anticipation with individualization in bladder management strategies can effectively overcome dose precision limitations from bladder variations, and we established quantifiable and reproducible bladder volume control standards for online ART. However, this study is limited by its relatively small sample size, and the findings should be interpreted with caution.

Tripartite dosimetric effects of intrafractional bladder changes in ART

Although online ART provides significant dosimetric advantages, its prolonged workflow may introduce spatiotemporal dose heterogeneity due to dynamic bladder changes (24). This study systematically identified three dose effects from intrafractional bladder fluctuations: First, moderate volume expansion physically displaces mobile OARs (e.g., a 10.7% reduction in small-bowel V₄₀), which aligns with the findings from Sukhaboon et al. (25), confirming that bladder filling can serve as a natural dose-shielding structure. Second, Brennan et al.’s (26) dose displacement model was validated—when volume fluctuations exceeded thresholds (ΔV above 100 cm³), anatomical displacement of the bladder-uterus complex caused a 1.5% target coverage reduction, collectively defining the risk-critical window for bladder volume changes. Third, dose parameters for stable organs (the rectum and bony structures) were not affected by bladder fluctuations and suggesting an “anchoring effect” from the skeletal frameworks in dose distribution. Based on this, our proposed dual-threshold management strategy for (V₀ above 400 cm³ and ΔV below 100 cm³) not only extends Bak et al.’s (27) technical approach in prostate ART but also introduces temporospatial dual-control dimensions (initiation of personalized hydration 2 hours pretreatment), transforming the bladder from a passive dose-disrupting factor into an active anatomical modulator. This dynamic balance mechanism can support innovative solutions for online ART systems in addressing the clinical challenge of anatomical variations disturbing dose precision.

Study limitations

This study involved several limitations that should be addressed: First, the small sample size may reduce the statistical power and generalizability of the findings, and thus future larger-scale validation is needed. Second, while quantifying the bladder dynamics’ dose effects, we did not systematically analyze multi-organ interactions (e.g., intestinal gas and rectal filling), suggesting that comprehensive predictive models incorporating dynamic anatomical scenarios should be developed. Finally, future multicenter studies with larger samples can be conducted to validate the universality of the proposed threshold.

Conclusions

Online ART for cervical cancer more effectively compensates for bladder volume-induced dose variations than does conventional IGRT, demonstrating superior dose optimization capabilities. The study confirmed that bladder volume at or below 265 cm³ can serve as both an early warning indicator for small-bowel radiation injury and a critical trigger point for online ART in cervical cancer. Our study produced three principal findings related to intrafractional bladder changes and dosimetric effects: moderate filling reduces mobile OAR doses, excessive fluctuations compromise target coverage precision, and stable organs maintain relatively constant dose distributions. Therefore, we recommend combining ART with personalized bladder management in the clinical management of cervical cancer, which by controlling initial bladder volume and intrafractional fluctuation thresholds, can ensure stable target coverage while minimizing the dose to OARs. Overall, this method can provide reliable anatomical and dosimetric control solutions for ART in cervical cancer.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-867/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-867/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-867/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. It was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center (Approval No. B2025-214-01). Written informed consent was obtained from all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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