Bladder filling protocols are beneficial for radiotherapy planning of cervical cancers in terms of sparing OARs. Various studies have shown that during radiotherapy, bladder volumes obtained during initial planning scans differ from the bladder volumes that are being actually treated on a daily basis. This may be due to the fact that patients on radiotherapy are not able to maintain consistent bladder filling [8, 9]. Variability in bladder filling may lead to a lack of reliable dose constraints for pelvic OARs. The goal of the present study was to analyze the dosimetric impact of the variable bladder filling bladder (100%/70%/50%/EMPTY) on the target volume and OARs.
Variable bladder filling occurs as a result of a constant and dynamic process of urine formation. It depends upon the amount of water intake before bladder emptying, the rate of urine formation during simulation, and the amount of residual urine in the urinary bladder. The amount of saline instilled through the foleys after emptying the bladder as seen in our study is not an accurate depiction of the 100% actual urinary bladder filling “X” ml as there tends to be some residual urine present in the bladder. Likewise, the 70% and 50% bladder filling are not representative of actual bladder volume at that time of normal saline instillation since some urine is being formed during the cast and scan process. Similarly, the empty bladder has some residual urine left which also adds to the bladder volume. So to counter all these variables, the actual urinary bladder volumes of PLAN100, PLAN70, PLAN50, and PLAN0 were calculated from the planning CT scan images of each respective plan.
As in the present study, the maximum comfortable urinary bladder volume value of 100% was taken for each patient and the mean bladder volume was calculated in terms of percentage bladder filling to determine the dosimetrically crucial points beyond which a substantial change in dose to target or OARs was seen. The mean bladder volume for PLAN100, PLAN70, PLAN50, and PLAN0 differed significantly from each other (p < 0.05). Full bladder treatment can lead to 7 to 450% variation in the bladder volume signifying a low reliability despite instructions [10]. The literature review showed a decrease in bladder volume by 56% (p < 0.01) after 40 Gy of pelvic radiotherapy, thereby highlighting the need of adapting to bladder volume during treatment [4, 11]. Further studies confirm the above fact indicating a downward trend for the bladder volume during radiation in comparison to the initial value despite bladder protocols [12, 13].
IMRT technique aims to reduce normal tissue toxicity and provides adequate target volume coverage. Standard population-based margins are given to ensure adequate target coverage. However, these margins may not be sufficient due to the variability and extent of utero-cervical motion [11]. Variable bladder filling led to a considerable displacement of utero-cervical COM in the Y- and Z-axis without compromising the target volume coverage in the present study. In contrast, Jadon et al. [14] reviewed the literature regarding variable organ motions and concluded that a compromise on uterine coverage was noted with variable bladder volumes. Several studies have demonstrated the extent of target motion occurring during radiotherapy with the maximum reported displacement of uterine fundus up to 4.8 cm [15,16,17,18,19]. Huh et al. [15] and Lee et al. [16] compared the magnetic resonance images taken before and during pelvic radiotherapy and noted a significant change in the uterine movement and position due to variable bladder filling. Taylor et al. [17] made an assessment of the inter-fractional uterine and cervical motion in order to estimate the CTV to PTV margins. Taylor et al. noted a mean displacement of 0.70 cm and 0.71 cm in the antero-posterior (Z-axis) and superior-inferior (Y-axis) direction, respectively, which collaborated with our study findings. Often clinicians tend to take generous margins (2.5–4 cm) to account for 90% of cervico-uterine motion, thereby offsetting the benefit achieved with IMRT. These changes can be attributed not only to rectal and bladder filling variations, but can occur due to tumor regression [11, 17, 18, 20, 21]. In order to avoid excessive normal tissue irradiation, reduced margins can be used which can lead to underdosing in patients with large target movement and should thus be avoided.
Association of rectal and bladder filling with utero-cervical mobility has an attractive prospect for adaptive radiotherapy [2]. Despite using strict bladder and bowel protocol, large systematic setup errors especially at the fundus have been reported [2]. It has been observed that the bladder tends to change in shape and position during the course of pelvic radiotherapy [22, 23]. Huang et al. [22] and Roeske et al. [23] noted a 44% and 30% variation in bladder volume, respectively, during the course of fractionated pelvic radiotherapy and noted higher doses being delivered than initially calculated. Bladder volume reproducibility thus cannot be assured during pelvic radiotherapy treatment. Isodose levels as seen on the dose-volume histogram tend to indicate the planning CT scan state and are not relevant for the whole 5 weeks of treatment. Recent studies have also emphasized on the necessity for quicker bladder volume evaluation using either CBCT scans or ultrasonography in order to choose the most suitable plan of the day from the planning library for sparing OARs and ensuring precise radiation delivery [24].
A filled-up bladder is a principal reason for the dose sparing of the OARs concerned. The severity of acute and chronic effects on the bladder tends to increase after an integral radiotherapy dose of > 65 Gy (whole bladder) [25]. In our study, the bladder mean dose showed a slight, but statistically significant declining trend with increasing bladder volume which was in line with the previously published literature (p < 0.05) [18]. Completely filled up bladder decreased the integral bladder dose, while improved reproducibility was seen with the empty bladder at the cost of increased toxicity due to a larger bladder volume being in the high-dose region. Buchali et al. [18] therefore advocated the use of moderately filled bladder during treatment in order to avoid extreme departure from normal utero-cervical mobility. In contrast, the difference was not significant for V50 Gy which can be ascertained to the fact that the filled-up bladder tends to move more superiorly and posteriorly, thereby extending into the PTV volume. This fact may be responsible for minimal difference in V50 Gy value between different plans [19]. It may also indicate need for slightly less than full bladder filling which is a compromise between Dmean and V50 Gy value. Also, a slow gradual rise up to 64.44% (PLAN50) bladder filling followed by a sudden rise in mean and V50 Gy dose was noted. Therefore, at least 64.44% bladder filling was desirable at the time of daily treatment.
Bladder filling tends to displace the rectum outside the high-dose region. Rectal V50 Gy and mean dose showed a minimal absolute change with an increase in bladder emptying. However, the relative increase in dose gradient was maximal between PLAN50 and PLAN0. So, a bladder filling volume at PLAN50 (64.44%) can be considered an optimal lower limit of bladder filling for rectal dosimetry.
Published literature has documented bladder filling variation as an important contributing factor to bowel toxicity. It is therefore recommended to treat patients with a full bladder as it tends to push the small bowel outside the PTV target volume, thereby decreasing the bowel toxicity [4, 24,25,26]. As the bladder emptying increases, the bowel displaces into the pelvis and receives excess irradiation (Fig. 4). Yaparpalvi et al. [12] described the outcome as a result of variable bladder filling and noted a median superior-inferior bowel shift of 12.5 mm on an empty bladder when compared to a full bladder. This shift led to an extra 151 cc of bowel volume of being irradiated [12]. The mean dose and percentage of bowel receiving 45 Gy in our study showed a statistically significant difference between PLAN100 in comparison to other plans. Similar to our findings, treatment with full bladder reduced small bowel irradiation by 72% [27]. Simpson et al. [28] reported a 65% and 33% incidence of greater than or equal to grade 2 gastrointestinal toxicity in patients with bowel receiving V45 Gy > 150 ml or below it, respectively. In addition, our results showed a sharp relative increase in dose gradient up to 78.34% bladder filling, after which the rate of increase slowed down. The percentage increase in V45 Gy and a relative decrease in the bladder filling beyond PLAN50 were noted. In line with our study, a significant correlation between the volume of intestine irradiated and bladder volume was demonstrated by several studies [29]. Thus, a minimum of 64.44–78.34% bladder filling was desirable at the time of daily treatment in order to prevent excess bowel toxicity.
Homogeneity index (HI) is used to analyze as to how uniform the dose distribution and the target volume is, and a value close to zero is considered ideal [30]. HI showed an increasing trend with a decrease in bladder filling. The percentage difference in HI was most marked till 78.34% bladder filling (PLAN70). Additional parameters like conformity index (CI) were also used to analyze the treatment plans and value close to 1 is considered ideal [30]. The CI showed a decreasing trend with a decrease in bladder filling and maximum relative change noted till PLAN50. Thus, it can be considered that it is ideal to maintain a urinary bladder filling of at least 64.44% when compared to maximal comfortable urinary bladder filling.
Treatment with full bladder tends to induce large variations in inter-fractional bladder volume, leading to a potential for dosimetric uncertainties for targets and normal tissues. The consequence of radiotherapy treatment on less than full bladder increases the rate of normal tissue complications. It has become essential to measure the bladder volume using cone beam CT or ultrasound prior to daily radiotherapy treatment. Assuming that the variable bladder filling volume can act as a predictor of target motion and location, pre-treatment CT scan data can be used to create a planning library. After daily verification of bladder volume, a plan of the day may be implemented for each patient. Such an adaptive treatment approach can be opted for to further decrease the dose to normal tissues.
The main limitation of our study was a relatively small number of patients, dosimetric nature of the study, and probable extra exposure to radiation for patients due to daily CBCT for checking bladder filling. In addition, the rectal filling was not taken into consideration in our study.