Observational study of cone beam CT based Inter-fractional urinary bladder filling variation during IGRT in pelvic malignancies
Dr. Manjari Shah- Senior Registrar, Radiation Oncology, Jaypee Hospital, Noida; previously DNB Resident, Max Super Specialty Hospital, Vaishali, Delhi-NCR, India.Email- email@example.com
With advancement, comes limitations. Similarly, in radiotherapy advanced machines and treatment techniques had several associated factors that limits its precision. Organ motion is one of the important factors limiting the precision of advanced radiation techniques, especially for pelvic malignancies. Bladder filling variation has significant impact on the position of target volumes in pelvic malignancies. The inter- and intra- fractional movement of the bladderwall can be as much as 3 cm due to changes in volume of bladder and rectum . If the bladder wall motion is not taken into consideration while planning the treatment, target miss is likely to occur, resulting in reduced local tumour control. Thus, to compensate this the treatment margins were increased for the uncertainty of the bladder wall motion. Increasing the irradiated margins also increases the possibility a critical structure to be irradiated beyond tolerance leading to unacceptable complications. Another approach to reduce the bladder motion influence on the target location is by controlling the bladder volume, a protocol instructing the patient to drink a certain amount of water before starting the treatment, but studies showed that even with detailed instruction, patient were unable to maintain consistent bladder volumes. This study was an effort to maintain a consistent urinary bladder volume after following a strict bladder protocol, which was then analysed by in room CBCT imaging. The bladder volumes and bladder wall dimension in all the three directions were analysed comprehensively thus adding considerable understanding to the bladder wall motions.
AIMS AND OBJECTIVES
The aim of this study is to observe inter-fractional urinary bladder filling volume variation during Image guided radiotherapy in pelvic malignancies with the help of cone beam CT after following strict bladder filling protocol.
MATERIALS AND METHODS
This study was conducted on patients of pelvic malignancies excluding urinary bladder carcinoma who presented to the Department of Radiation Oncology at Max Super Speciality Hospital, Vaishali, Delhi-NCR, India. It was a single institution, non-randomised, prospective study conducted between 1stAugust, 2014 to 31st January, 2015.
- Patient with the histopathological diagnosis of cancer who were taken up for the treatment with curative intent.
- Patients having urine holding capacity for thirty minutes.
- Carcinoma urinary bladder patients
- Patients who earlier have received pelvic radiotherapy
- Patients having metastatic disease
- Patients having Urinary tract infection (Urine examination was done to rule out)
- Patient having Eastern cooperative oncology group (ECOG) performance score of 3 or more
The patients fulfilling the study criteria were individually staged according to their disease. All patients were counselled in detail regarding bladder filling protocol and a pre-test was carried out to confirm that patients were able to hold urine for thirty minutes. All the patients who were included in the study were explained in detail regarding study procedure in their native language and informed consent was taken before starting treatment from all the patient.
The following bladder filling protocol was used in this study:
- The patients were instructed to void the bladder 40 minutes prior to radiation treatment and to drink 600 ml of water within 10 minutes.
- The patients were scanned after 30 minutes of taking last glass of water. Time of last glass of water and CBCT was noted.
- Twice weekly CBCT were done to quantify the volumetric changes of the bladder throughout the treatment period but the bladder filling protocol was followed during the planning CT as well as whole course of radiation treatment.
- Patients were advised not to take tea/coffee/alcoholic beverages one hour prior to coming for radiation treatment.
- No other dietary restriction was advised.
- No routine laxatives were advised unless patients had complaint of constipation.
Statistical analysis was performed using the SPSS program for Windows, version 17.0. Data were checked for normality before statistical analysis. One-way ANOVA (Analysis of variance) was used to determine whether there are any significant differences between means of different patients. For all statistical tests, a p-value less than 0.05 was taken to indicate a significant difference.
Total number of 26 patients of pelvic malignancies were enrolled including cervical cancer, endometrial, prostate and Colo-rectal cancer patients. All patients in the study group underwent planning CT scan then twice weekly CBCT scan, minimum of 10 CBCTs were performed for each patient. Planned sample size was 100 CBCTs/10 patients but we were able to study 26 patients. A total of 300 scans (26 Planning CT + 274 CBCTs) were analysed in these 26 patients. Urinary bladder was contoured in all 300 scans by same radiation oncologist and bladder was then measured in all three maximum dimensions transverse, longitudinal and antero-posterior diameter. Bladder volume measured and time of CBCT were noted. All these parameters were compared with the planning CT scan considering it as baseline.
The study group was heterogeneous as we had patients of all common pelvic malignancies. The females form the 70% bulk of our study group and we had a greater number of cervical and endometrial cancer patients in our group. Cervical cancer forms the major portion i.e. 9 of the 26 patients followed by endometrium (7/26), prostate (5/26) and Colo-rectal cancer (5/26) patients.
All patients underwent minimum of 10 CBCTs, twice weekly CBCTs during the radiation treatment. All 300 (100%) scans were done after 30 minutes. While 57.3% patients (N=172) had their scans as per the study protocol, 41.7% (N=125) patients had CBCT done after 40 minutes but before 50 minutes. Only 1% (N=3) got their CBCT done after 50 minutes of taking 1st glass of water.
Mean and standard deviation of bladder wall transverse diameter is shown in Graph-1. Patients had maximum mean transverse diameter of 10.2 cm and minimum diameter of 5.58 cm. 69% of patients (N=18) fall in between mean of 8-10 cm while 31% (N=8) patients extend beyond this mean.
Graph 1: Mean and Standard Deviation of bladder wall transverse diameter.
As shown in Graph-2 the mean antero-posterior wall diameter in all 26 patients with maximum mean antero-posterior diameter of 10.2 cm and minimum diameter of 4.56 cm. 53.8% (N=14) patients fall in mean of 6-8 cm and 46.2% (N=12) extend beyond this mean
Graph 2: Mean and Standard Deviation of bladder wall Antero-posterior diameter
Maximum mean as observed in longitudinal dimension was 10.04 cm and minimum mean was 2.82 cm with a wide range. 54% (N=14/26) patients fall in mean range of 4-6 cm while 46% (N=12/26) patients extend beyond this mean as shown in Graph-3
The mean bladder volume was noted in all 26 patients and then compared with all other patients of pelvic malignancies. Maximum bladder volume was 475 cc and minimum bladder volume was 62 cc. The mean bladder volume for all 26 patients was 183.07 cc with SD of 90.43 cc and p-value 0.761 which was non- significant. Similarly, the mean time was 40.12 minutes with SD of 2.15 min and p-value 0.059 which was non- significant.
On analysis of all these patients as a group consisting of total of 300 bladder images (26 planning CT scan + 274 CBCTs) the findings are shown in Table-1 with Mean± SD of bladder wall in all three dimensions and its p-value.
Table 1: Mean± SD of bladder wall movements in all 26 patients
Bladder motion is the most debatable topic in pelvic radiation treatment. Most of the studies exploring bladder motion during radiation treatment have been in bladder malignancies [2,3]. There are studies on other pelvic malignancies like cervical, prostate and rectal cancer in which organ motion were observed, these studies have observed the motion of organ of interest and seldom the organ at risk bladder [4,5,6]. Thus it is difficult to extrapolate the results of these studies to find out the bladder motion. Moreover, the studies looking at organ at risk motion have focused on bladder volume changes rather than bladder wall motion per se. To the best of our knowledge and extensive review of literature very few of the studies of pelvic malignancies (excluding bladder carcinoma) has observed the bladder wall motion. 
All patients underwent minimum of 10 CBCTs. Eighteen of the 26 (70%) of patients underwent 10 CBCT. Daily CBCT can increase the concern of increase radiation dose so most of the centre uses once or twice weekly CBCTs. In our institute we do twice weekly CBCTs. In contrast to our study Yee et al conducted the study on 10 bladder cancer patients and did daily CBCT. They obtained 262 CBCTs in 10 bladder cancer patients.  As the dose of CBCT is a concern, it is reasonable to compare the dose of CBCTs to radical dose of radiation. However, we were not able to compare the dose of CBCTs as dosimetric data were not analysed. Wang J et al showed that the dose received by a patient while doing CBCT pelvis is 17.7 mGy which is almost negligible in comparison of radical treatment dose which ranges from (50– 76Gy) .
Table 2: Mean/ range of 26 patients in all 3 dimensions
Urinary bladder wall movements in all 3 dimensions transverse, longitudinal and antero-posterior diameter were analysed. 14 of the 26 (53%) patient showed significant changes in Antero-posterior diameter followed by longitudinal diameter which showed significant changes in 10 of the 26 (38%) patients. In transverse diameter only 6 of the 26 (23%) patients showed significant changes. Though the number of patients with significant changes were more in antero-posterior diameter but variation was seen more in longitudinal diameter with a range of 7.18 cm as compared to antero-posterior diameter which has range of 5.64 cm as shown in Table-2.Yee et al, 2010 quantify daily bladder size and position variations during bladder cancer radiotherapy in ten bladder cancer patients undergoing daily CBCTs . Anterior bladder wall shifted the most (mean = -0.58 cm). In our study patients underwent twice/thrice weekly CBCTs while Yee et al patients underwent daily CBCTs but the results were similar in both the study with antero-posterior bladder wall movement being more. Another study by Fokdal L et al, 2004 on 15 patients of bladder carcinoma showed bladder movement were more pronounced in the anterior and cranial directions .
Jhingran A et al, 2012 observed the movements of fiducial markers implanted on 24 patients of carcinoma cervix patients and showed more movements in antero-posterior direction followed by superior-inferior direction and least in right-left direction . Mean diameter for 26 patients in our study was 8.35, 6.69 and 5.59 cm in transverse, antero-posterior and longitudinal dimension. Standard deviation was 1.039, 1.05 and 1.798 cm in transverse, antero-posterior and longitudinal direction and these results were consistent with above mentioned studies.The number of patients in our study was 26 while it is 24, 15 and 10 in Jhingran et al, Fokdal et al and Yee et al respectively still the results are consistent with these studies. Yee et al and Fokdal et al has done its study in carcinoma bladder patients and Jhingran et al did his study on carcinoma cervix but our study group was heterogeneous but we were able to replicate the results of above-mentioned studies.Majewski W et al estimated bladder movements in the patients of bladder cancer receiving conformal radiotherapy . Bladder movements were mainly observed cranially, similarly in our study cranial movements were more.
Pinkawa M et al observed the variability in bladder filling during pelvic radiotherapy . 50 patients with localized prostate cancer were prospectively evaluated with multiple CT scans.
This study has focused on bladder volume variation and bladder wall displacements during a fractionated pelvis external beam radiotherapy. He showed wall displacement in all 6 directions and observed maximum wall displacements in anterior and superior direction. The standard deviation was 19.3 and 10.3 cm in cranial and anterior direction. The result of this study is consistent with our study as shown in Table-3. The standard deviation in longitudinal direction is 1.79 cm and in antero-posterior direction is 1.05 cm. Despite of variable assessment method for organ motion used in different studies maximum movements occur in antero-posterior and longitudinal direction. Hence it is proved that despite using different assessment technique the results remain same.
Table 3: Comparison of bladder wall displacement in different studies
Similar conclusions were made by the studies mentioned in Table-3. They have also shown similar results with bladder wall movements and these results can be explained well on the basis of anatomical limitation of the urinary bladder. An empty bladder can well expand in posterior and lateral directions. With increasing volume, the lateral movement is limited strongly by the pelvic bones, the posterior bladder wall movements is limited by rectum (including filling and sacral bones). Further expansion is a lot easier in the anterior and superior directions, where soft tissue and bowel loop can be shifted.
The results of our study were in concordance with those of above-mentioned studies. The most important challenging factor in this study was limitation of literature. As already mentioned most of the studies exploring the bladder wall motion have been in bladder cancer patients [2,3]. Contrary to this bladder carcinoma patients were excluded from our study because here it was an organ of interest. We focused on OAR (Organ at Risk) rather than organ of interest. There are studies of other pelvic malignancies like cervical, prostate and rectum but they did not per se observed the bladder wall motion but the volume of bladder [4,5]. Another problem with this study was availability of different methodologies to observe the organ motion.[10,11,12] There were different techniques available for determining organ motion and different studies has used their different techniques so the results were interpreted with the limited studies available with same technique i.e. perimeter displacement technique which we have used in our study.
The finding of this study indicates that the development of technological and clinical aspects in radiation treatment should go hand in hand. The study shows that to use the full potential of Image Guided Radiation Therapy in pelvic malignancies in terms of margin reduction, it is also necessary to implement measures to control the bladder volume by bladder filling protocol. Daily CBCT imaging may not be considered feasible in a routine setting so we can switch to twice/ thrice weekly CBCTs and planar imaging on other days in a week.
This study showed considerable reduction of margin can be done on lateral side as there is less displacement on transverse diameter and more liberal margins should be considered in antero-posterior dimension and longitudinal dimensions. Even if bladder volume is controlled with the bladder filling protocol variation is always expected so the benefit can even be greater while using image-guided radiation therapy. With bladder filling protocol an attempt is made to control the bladder volume but this led to small reduction in variation of bladder volume but did not translate into margin reduction.
The challenges posed by internal organ motion in patient treated with pelvic malignancies can be overcome by image-guidance technologies, of which CBCT is the best modality as it is non-invasive and the most common image-guided radiation therapy (IGRT) method, providing the volumetric-anatomic information and the opportunity to localize target volumes in a few minutes before each treatment fraction. Pre-treatment CBCT has received much attention for its ability to reduce setup error and the required margins, thereby reducing the dose to the organ at risk in external beam radiotherapy.
This prospective study has been done to quantify the variation in bladder wall motion and volume after following strict bladder filling protocol. The aim of our study is to observe interactional bladder filling variation after following strict bladder filling protocol. All the patients followed the bladder filling protocol religiously and no discomfort was reported. Patients showed variation in bladder volume with mean 184 cc and standard deviation of 90 cc which was non-significant. Bladder volumes increases with increasing waiting time. As the volume increases bladder showed asymmetrical change in size and shape with most significant changes observed in antero-posterior dimension followed by longitudinal dimension and least changes were observed in transverse diameter.The purpose of this study was to find a possible answer to a very pertinent question on bladder wall motion and bladder volume variations during different days of radiation therapy. This study has reached the conclusion that bladder filling protocol is necessary to maintain the consistent bladder volume but it is too preliminary to state that it will translate into reduction of margin. Further studies are required specifically for margin reduction if we want to reduce the margins utilizing the information, we have analysed doing this study.
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