Image-guided radiotherapy of bladder cancer: Bladder volume variation and its relation to margins

Transcription

1 Radiotherapy and Oncology 84 (2007) IGRT Bladder Image-guided radiotherapy of bladder cancer: Bladder volume variation and its relation to margins Ludvig Paul Muren a, *, Anthony Thomas Redpath b, Hannah Lord c, Duncan McLaren c a Department of Medical Physics, Aarhus University Hospital, Aarhus, Denmark, b Department of Oncology Physics, Western General Hospital, Edinburgh, UK, c Department of Radiation Oncology, Western General Hospital, Edinburgh, UK Abstract Background and purpose: To control and account for bladder motion is a major challenge in radiotherapy (RT) of bladder cancer. This study investigates the relation between bladder volume variation and margins in conformal and image-guided RT (IGRT) for this disease. Materials and methods: The correlation between the relative bladder volume (RBV, defined as repeat scan volume/ planning scan volume) and the margins required to account for internal motion was first studied using a series of 20 bladder cancer patients with weekly repeat CT scanning during treatment. Both conformal RT (CRT) and IGRT were simulated; in the latter translational movement of the bladder was accounted for by isocentre shifting. Further analysis of bladder volumes and margins was performed using a second series of eight patients with twice-weekly repeat CT scanning. In an attempt to control bladder volume variation these patients were given fluid intake restrictions on alternating weeks during treatment. Results: IGRT gave the strongest correlation between the RBV and margin size (R 2 = 0.75; p < 0.001). Using IGRT, isotropic margins >10 mm were required in only 1% of the situations when the RBV 6 1, whereas isotropic margins >10 mm were required in 55% of the situations when the RBV > 1. Less marked correlation was found using CRT (R 2 in the range , p < 0.001) for four different methods used to assess the margins required in the six directions, although a strong correlation was found for the superior margin (R 2 = 0.63; p < 0.001). Fluid intake restriction gave a small reduction in both bladder volume (average absolute volume reduced from 126 to 121 cm 3 ; RBV from 0.83 to 0.80) and bladder volume variation, but not sufficient to translate into margin reduction. Conclusions: The study showed the potential for a large margin reduction in bladder RT if the bladder volume is controlled and this potential was even greater for IGRT. An attempt to control the bladder volume by restricting fluid intake prior to the treatment session failed to give any reduction in the margins required. c 2007 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 84 (2007) Keywords: Bladder cancer; Conformal radiotherapy; Image-guided radiotherapy; Bladder volume variation; Treatment margins Radiotherapy (RT) is an important treatment option for patients with muscle-invasive urinary bladder cancer and although it is currently used as a definitive treatment for patients unsuitable for radical cystectomy, it also has the potential for playing a key role in an organ-sparing combinedmodality treatment alternative [4,15]. Improvement of RT planning and its delivery are fundamental for broadening the role of RT in the management of this disease. The considerable geometrical uncertainties caused by pelvic organ motion and patient positioning variation represent major challenges in RT of bladder cancer [15]. Until recently, such uncertainties have been accounted for by adding population-specific margins (after accurate quantification of the magnitude of the uncertainties) around the clinical target volume (CTV, defined here as the bladder including tumour) [3,5,12 14,18,20,21]. In these studies, internal bladder motion has been found to be a major source of geometrical uncertainty. An active research area in RT is the technical development of imaging equipment designed to visualise internal anatomy while the patient is in the treatment position, often referred to as image-guided RT (IGRT) [2,22]. These techniques provide methodologies that make it possible to account for the geometrical uncertainties on an individual and adaptive basis. A technical solution that is currently given a lot of attention is conebeam CT imaging (CBCT), where a full 3D CT data set is reconstructed from multiple cone-beam X-ray transmission projections through the patient. These are measured by a flat panel radiation detector situated directly opposed to the X-ray source. Much of the current CBCT development focuses on improving image quality to allow for adequate softtissue contrast. Compared to organs such as the prostate, /$ - see front matter c 2007 Elsevier Ireland Ltd. All rights reserved. doi: /j.radonc

2 308 Bladder volume and margins the bladder appears to have better soft-tissue contrast, both in conventional CT [12] and in CBCT [6], making rapid and accurate target outlining feasible. The bladder also undergoes changes in volume and shape in addition to position and therefore seems to be an appropriate tumour site for an adaptive RT approach using CBCT. In a recent study, we showed that there is considerable theoretical potential in terms of margin reduction resulting from the use of isocentre shifting based on CBCT-guidance in bladder RT [19]. Along with this technological development, the procedures applied to control the bladder volume (and its variation) during treatment are still likely to be of importance for the precision that can be obtained in bladder irradiation. Further knowledge of the relation between bladder volume and margins required is fundamental to the development of the optimal application of IGRT technology, including the selection of technique (e.g. 2D/3D kv/mv imaging or ultrasound), as well as imaging frequency and timing. This study investigates the link between variation in bladder volume and the margins required to account for internal motion within both standard conformal RT (CRT) and image-guided RT. In addition, results are presented for an interventional study aiming to control the bladder volume by fluid intake restriction. Materials and methods Patient and CT data for the correlation analysis of bladder volumes and margins The patient data used for the initial analysis of the relation between bladder volume and margins (Material A) were recruited to an observational investigation of geometrical uncertainties and margins in bladder irradiation [14]. Material A consisted of 20 consecutive bladder cancer patients (16 men, 4 women) treated at Haukeland University Hospital, Bergen, Norway, between January 2000 and October The age at the start of treatment ranged from 58 to 88 years (mean age: 75 years). All patients were scheduled for weekly repeat CT scanning during treatment. Both the initial planning scans and the repeat scans consisted of 5 mm thick contiguous slices throughout the bladder region and were acquired in the supine position. A 70 ml volume of contrast was instilled into the bladder before acquisition of the planning scan and all patients were instructed to empty their bladder prior to each subsequent scanning/treatment session. All repeat scans were registered on bony anatomy to the corresponding planning scan using Advantage Fusion software (GE Medical Systems, Milwaukee, WI, USA), isolating the internal bladder motion only. Subsequently, the bladder volumes were outlined (as the volume within the outer bladder wall) in all relevant slices from dome to apex and these were stored as DI- COM RT structure sets using the same coordinate system as the corresponding planning scan. The patients were treated with a standard four-field CRT technique and prescribed a dose of Gy (five fractions per week, each of 2 Gy) to the whole bladder with a mm isotropic margin. Further details describing Material A have been published previously [14]. The patients in the second material (Material B) were included in an interventional investigation of geometrical uncertainties in bladder irradiation. Material B consisted of eight bladder cancer patients (6 men, 2 women) that were treated at Edinburgh Cancer Centre (ECC), Western General Hospital, Edinburgh, UK, between May 2003 and March Their age at start of treatment ranged from 63 to 81 years (mean age: 74 years). These patients were scheduled for twice-weekly repeat CT scanning and both the planning scan and the repeat scans consisted of 3 mm thick contiguous slices throughout the bladder volume (except for one case with 5 mm). The planning scans were all acquired with an empty bladder and during treatment, all patients were asked on alternating weeks to either drink normally or not to drink during the last 3 h prior to treatment (both oral and written instructions were given). The same procedures for image registration and bladder outlining as used for Material A were also used for these patients (again, registration on bony anatomy allowing for investigation of internal bladder motion only). Pre-treatment uro-dynamic testing that quantified the maximum urine outflow rate, volume passed and residual volume was performed on six of the patients (4 male, 2 female). Patients were treated according to the standard ECC protocol to a dose of 52.5 Gy (20 fractions/4 weeks) to the bladder with a 10 mm isotropic margin using a three-field CRT technique. a conformal, non-igrt setting The planning CT and the related repeat scan bladder structures from Material A were imported into the Helax- TMS planning system where the planning scan bladder volume was also outlined. Using the 3D margin tool of Helax- TMS, the individual margins in the six directions (inferior, superior, left, right, anterior, posterior) that had to be added to the planning scan bladder/ctv to cover each individual repeat scan bladder volume were determined. Further details of this analysis have been described previously [14]. In the current study, the correlation between the relative bladder volume (RBV, defined as the repeat scan bladder volume/planning scan bladder volume) and the resulting margins was investigated by performing a parametric correlation analysis giving the Pearson coefficient, R 2 and its related p-value. This analysis was carried out for each of the six margin directions separately and for three methods that aimed to condense the six margins (along the three orthogonal axes) into one parameter. These were the maximum margin, the geometrical average margin and the cubed average margin (the third root of the average of the sum of the margins cubed), calculated from all six margins. To obtain data that could directly be compared to the IGRT situation, the isotropic margin required to cover each individual repeat scan in a CRT setting was also calculated using the data from Material A. This was performed using in-house written software [19] where isotropic margins, increasing in size in 1 mm steps, were added to the planning CTV until complete coverage of the repeat CTV was obtained. Again, a correlation analysis between the RBV and these isotropic margins was performed.

3 L.P. Muren et al. / Radiotherapy and Oncology 84 (2007) an IGRT setting Margins representing an IGRT situation were determined using the CT and bladder structure data from Material A. Details of this analysis have been presented recently [19], but the relevant points are outlined as follows. Briefly, a process of shifting the isocentre to its optimal position before each treatment session was simulated. This was performed by first of all shifting the repeat scan bladder contour so that its centroid coincided with the centroid of the planning scan bladder volume. Starting from this position, the additional shift required to find the optimal isocentre position of the repeat scan bladder volume was determined as that which resulted in the smallest volume of the repeat scan bladder structure lying outside the planning scan volume. This was found by performing an exhaustive search over all possible additional isocentre shifts (within ±20 mm from the coinciding centroid position) along the three orthogonal axes. Having positioned all repeat scans for all patients in their optimal position, the isotropic margin that had to be added to the planning scan bladder was determined so that the bladder volume from each individual repeat scan was covered. As for the isotropic margins for the CRT situation (described in Bladder volume variation and margins required in a conformal, non-igrt setting), these isotropic margins were determined using software developed in-house [19]. To compare with the CRT situation, the correlation between the RBV and the isotropic IGRT margins was quantified with a parametric correlation analysis. the interventional study To investigate the effect of the fluid intake restriction in the interventional study, the bladder volume structures from the patients in Material B were used. Initially, the absolute bladder volume and the RBV, as well as the variation in these, were compared for the weeks on fluid intake restriction vs. the weeks with no restriction. Subsequently, it was investigated whether the potential reduction in volume obtained by restricting fluid intake also translated into a reduction in margins for bladder motion. This was performed by calculating the margins required for each patient, both for all weeks, and for the weeks on and off fluid restriction separately. A sub-group analysis was performed for the cases with good urinary outflow, defined as having a maximum outflow rate >10 ml/s, a volume passed >100 ml and a residual volume <100 ml. In the initial margin calculations for these patients (Material B), the margins required for a CRT approach (without image-guidance/isocentre shifting) were determined. This was performed using a previously developed optimisation algorithm for margin determination [18] that works on the CTV of the planning scan and on repeat observations of the CTV during treatment (obtained from repeat CT scans). This algorithm derives margins (in the inferior, superior, left, right, anterior and posterior directions) that when applied to the planning CTV minimise the volume of tissue that lies between this expanded CTV and the envelope produced by the superposition of all observed CTV positions for the patient (the CTV envelope). This volume was summed over all patients included where the sum was used as the objective function for the algorithm and was minimised during the optimisation. Starting values for all six margins were chosen so that the expanded planning CTV was sufficiently large to enclose the CTV envelope. The algorithm then used an iterative process where the margins were gradually reduced (in 1 mm steps) and the volume of the expanded CTV was shrunk until the objective function converged to a minimum. In this process, measures were taken to avoid becoming trapped in local minima and to assure that reductions in all six margins were tested with the same frequency. Margins were determined giving absolute coverage of the envelope of observed CTVs as well as margins where exclusion of a 5% volume fraction of each repeat CTV was accepted. Finally, as for the data in Material A, it was also investigated whether there was an effect of fluid restriction in terms of margins required using CBCT-guided isocentre shifts. Again, as for Material A, isotropic margins were determined, following the procedure described in Bladder volume variation and margins required in an IGRT setting. Results a conformal, non-igrt setting There was a large variation in the bladder volume throughout the treatment course for the patients in Material A, with the RBV having values in the range For 12 of the 20 cases, the RBV was less than 1.0 for all repeat scans; for the remaining eight cases, RBV was larger than 1.0 for some (but not all) of the repeat scans. The RBV was found to have an intermediately strong correlation with the margin required in a conformal, non-igrt setting, with the correlation measure R 2 taking values of 0.43, 0.53, 0.44 and 0.53 (p < 0.001) for the maximum margin (Fig. 1), geometric average margin, cubed average margin and isotropic margin (Fig. 2), respectively. Assessing these scatter diagrams visually, the data points could be divided into four areas, separated by RBV = 1 and a margin level giving an acceptable percentage (taken as 65%) of repeat scans not included for RBV 6 1. The results of this analysis are shown in Table 1. Considering the six margin directions separately, a statistically significant correlation with the RBV was found for the superior, left, right and anterior margins. The strongest correlation was found for the superior margin with R 2 = 0.63 (p < 0.001), whereas for the left, right and anterior margins R 2 was in the range (p ). an IGRT setting The correlation between the RBV and the isotropic margin required in an IGRT setting in Material A was even stronger, with R 2 = 0.75 (p < 0.001) (Fig. 3). In this case, an isotropic margin >10 mm was required in only 1% of the situations when the RBV 6 1, whereas an isotropic margin >10 mm was required in 55% of situations when the RBV > 1.

4 310 Bladder volume and margins Maximum margin (mm) R 2 = Repeat scan volume / planning scan volume Fig. 1. The correlation between the RBV and the maximum margin (across the six directions) required in a standard, non-igrt setting Isotropic margin (mm) R 2 = Repeat scan volume / planning scan volume Fig. 2. The correlation between the RBV and the isotropic margin required in a standard, non-igrt setting. Table 1 Fraction of repeat CTVs where the given margin size is not sufficient to account for bladder organ motion in a non-imageguided CRT setting, in situations where the RBV 6 1 and the RBV > 1 (Material A) Margin type Size (mm) Fraction of repeat CTVs not covered (%) RBV 6 1 RBV > 1 Maximum Geometrical average Cubed average Isotropic the interventional study The variation in bladder volume during treatment in the interventional study was also large and comparable to the variation in Material A, with the RBV ranging from 0.36 to Overall, the fluid intake restriction intervention gave a small reduction in the absolute bladder volume, reducing the average (calculated first over the treatment course for each patient and then over all patients) from 126 to 121 cm 3. Looking at individual patients, fluid restriction reduced the absolute bladder volumes for six of the eight cases. For these six cases, the reduction in the absolute bladder volume between weeks off vs. weeks on restriction

5 L.P. Muren et al. / Radiotherapy and Oncology 84 (2007) Isotropic margin (mm) R 2 = Repeat scan volume / planning scan volume Fig. 3. The correlation between the RBV and the isotropic margin required in an IGRT setting. was on average 10 cm 3, ranging from 21 to 1 cm 3. Correspondingly, the RBV was also somewhat reduced by fluid restriction, from an average of 0.83 to 0.80 (again first averaged over the treatment course, then over patients). For the six cases where fluid intake restriction was helpful there was a reduction in the RBV of 0.06 on average, ranging from 0.13 to The fluid intake restriction led to a considerable reduction in the variation in the bladder volumes. The standard deviation of the absolute bladder volume (calculated for the treatment course for each patient and then averaged over all patients) was reduced from 20 to 10 cm 3. Again, the variation decreased in six of eight patients. In a conformal, non-igrt setting, i.e. without isocentre shifts, margins of mm were found to be required for 100% coverage of all repeat CTVs in the superior and anterior directions for the eight patients included in Material B. Margins of mm were required in the left, right and posterior directions whereas margins below 5 mm were required for the inferior direction. For the six cases where outflow function could be properly determined (three had good function and three had poor function) the margins required to cover all CTVs were calculated and also compared to the margins for the weeks on and off fluid restriction, as well as the cases with good and poor outflow function (Table 2, upper part). No apparent differences were found. The same comparison was carried out for the margins after applying the optimal shift in each situation, but again, no striking differences were evident (Table 2, lower part). As it was difficult to disclose potential differences in the margins when considering all six directions at the same time, the isotropic margins required in various situations Table 2 Margins (in mm) required to account for internal bladder motion observed for the patients in the interventional study (Material B), for various scenarios, all with 100% coverage of the included repeat CTVs Situation patients scans Inf Sup Left Right Ant Post Without iso shifts All scans Restricted Unrestricted Good function Poor function With iso shifts All scans Restricted Unrestricted Good function Poor function Table 3 Isotropic margins (in mm) required to account for internal bladder motion observed for the patients in the interventional study (Material B), for various scenarios Situation patients scans 100% coverage of repeat CTV Without iso shifts All scans Restricted Unrestricted Good function Poor function With iso shifts All scans Restricted Unrestricted Good function Poor function % coverage of repeat CTV

6 312 Bladder volume and margins were also compared (Table 3). However, the margins covering both 100% and 95% of each repeat CTV also failed to show any effect of either fluid restriction or urinary outflow function. Finally, the analysis presented in Figs. 1 and 3 for Material A was repeated using the data of Material B and the same pattern was found. As in Material A there was a relatively strong correlation between the RBV and the maximum margin for CRT (R 2 = 0.68; p < 0.001) and an even stronger correlation for the uniform margin using IGRT (R 2 = 0.85; p < 0.001). Discussion This study has investigated the role of bladder volume variation during bladder RT, studying the situation for both conformal and image-guided RT. The main finding was that margin reduction is possible if the bladder volume during treatment can be controlled (i.e. by avoiding that it exceeds the planning scan volume), both for CRT and even more so with IGRT. The second main finding was that restricting the fluid intake prior to the treatment session only gave a small reduction in the bladder volume and not sufficiently to allow for margin reduction. Margins were used as surrogate endpoints in this study but the ideal endpoints are the volumes of normal tissue that will be irradiated [1]. However, these volumes are closely related to the margins. Future studies will investigate further the use of image-guided IMRT by focusing on the impact in terms of normal tissue irradiation. By investigating the relation between bladder volume and margins required, this study has not considered the ideal protocol for bladder voiding/filling in the planning/ CT scanning situation. However, a small contrast volume (70 ml) was instilled into the bladder before the planning scan was acquired for the patients in Material A and these patients were subsequently treated with an empty bladder. No planning scan contrast was used for the patients in Material B and these were therefore both scanned for planning and treated with an empty bladder. The margins required in these two series were comparable [18], indicating that margins of the same magnitude are required around a presumed empty and a slightly filled bladder during scanning. It might be that smaller margins, although not necessarily reduced normal tissue irradiation, will result if scanning patients for planning with a full bladder. However, the current data were based on planning situations with a presumed empty or low-volume bladder and our findings do not necessarily apply for the full bladder situation; also they should probably not be used as a rationale for such an approach. Furthermore, a full bladder situation will be more difficult to standardise and maintain [15,16]. A main finding of this study is that keeping the bladder volume during treatment smaller than during planning will allow for smaller margins and that this effect is most pronounced in an IGRT setting. This is probably explained by the fact that after isocentre shifting, most of the asymmetrical bladder shape variation [12] is accounted for and the remaining bladder wall deflections are suitably encompassed with an isotropic margin. As shown in previous studies, there is room for improvement by using non-isotropic margins also in an IGRT setting [18]. This, however, requires a very active, adaptive approach involving daily re-planning. The modest volume reduction that was obtained by fluid restriction might be explained if the patient had been made aware that a possible deterioration of treatment quality could be linked to fluid intake. Outflow function was measured, but did not seem to identify patients where it was more difficult to control the bladder volume. Other factors that were not controlled might have played a role, such as time of day scheduled for treatment (e.g. early morning vs. late afternoon), amount of fluid intake when drinking normally as well as demographic issues such as travel time/distance to the RT centre. Also, it might be that the study sample was too low to identify the effect and a protocol restricting intake of diuretic fluids (e.g. tea, coffee) and medication prior to treatment together with strict bladder emptying before entering the treatment room should be tested within a larger study population. The findings of this study indicate that the development of technological and clinical aspects in RT should go handin-hand. The study shows that to use the full potential of IGRT in terms of margin reduction, it is also necessary to implement measures to control the bladder volume. To date, there have been a few reports of CBCT application in bladder cancer treatment, all from the Christie Hospital in Manchester [1,6,11]. McBain and colleagues presented their initial CBCT experience (in terms of image acquisition routines, image quality and patient doses) for 30 patients with a range of tumour sites where nine had pelvic tumours, but only one of these in the bladder [11]. They reported that most organ boundaries could be defined, although the pelvic images were those with the largest variation in image quality. Henry and her co-authors presented an off-line clinical feasibility and volume analysis study using repeat CBCT imaging in a series of 20 bladder cancer patients [6]. The CBCT image quality was sufficient to define the bladder in all cases except four, where the bladder could not be outlined due to artefacts caused by the presence of bowel gas. The potential of CBCT imaging to identify patients with large bladder volume variation (>50 cm 3 increase relative to the planning scan) was demonstrated; however, as shown in the present study, a volume increase of less than this amount is still likely to have a considerable impact in terms of margins required. In addition, the bladder volume variation only accounts for a fraction of the total geometrical uncertainties and therefore the margins required. In the study by Burridge et al. [1], a large potential for normal tissue (i.e. intestine) reduction was presented, although, as in the present study, a volumetric reduction in the target volume was used as a surrogate endpoint for the actual intestine volume. Lotz and co-workers have developed a mathematical model that predicts the changes in bladder shape caused by short-term changes in bladder and rectum volume [9]. Using this model, they have studied the short-term increase in bladder volume due to urinary in-flow [10] and have shown that bladder tumour deformations during treatment are limited, in spite of the bladder volume variation [8]. From the same group, Pos et al. have used standard CT imaging to study the possibilities for adaptive RT approaches, simulating a situation where only the bladder

7 L.P. Muren et al. / Radiotherapy and Oncology 84 (2007) tumour is treated [17]. Constructing a PTV based on daily CT scanning over 5 days, they reported a 40% average reduction in the PTV volume compared to the conventional approach where the PTV was based on a single pre-treatment CT scan. Implementing the findings of the current study would imply frequent use of CBCT imaging, possibly in combination with other methods to measure the bladder volume. At present, daily CBCT imaging may not be considered feasible in a routine setting and there is obviously also an issue of additional dose. Ultrasound imaging might be too inaccurate to allow for bladder positioning, but could still provide a means to measure the bladder volume on a daily basis [16]. This could be applied to avoid the situations that mostly lead to large margins, i.e. where the RBV > 1. Also, a combination of ultrasound volume measurement and a reliable and rapid method for tumour visualisation (and localisation) could become an alternative, or at least a supplement, to CBCT imaging. The development of the optimal adaptive RT protocols, including what imaging tools to apply, still remains an open question for bladder cancer. A planning study from our group has shown that there are challenges related to changes in dose resulting from changes in patient anatomy/geometry [19]. The use of CBCT for isocentre repositioning is therefore not only a geometrical problem and one therefore needs to consider the impact in terms of calculated doses, in both the target and normal tissues. Similar findings have recently been presented also for prostate irradiation [7]. These topics are currently under further investigation. In conclusion, this study showed considerable benefit in terms of margin reduction in bladder RT if the bladder volume is controlled and this benefit was even greater for an image-guided RT approach. An attempt to control the bladder volume by restricting fluid intake prior to the treatment session led to a small reduction in bladder volume but did not translate into margin reduction. Acknowledgement The authors acknowledge the contributions of several other staff at the Edinburgh Cancer Centre, Western General Hospital. * Corresponding author. Ludvig Paul Muren, Department of Medical Physics, Aarhus University Hospital, Nørrebrogade 44, Building 5, DK-8000, Aarhus C, Denmark. address: muren@as.aaa.dk Received 1 February 2007; received in revised form 21 June 2007; accepted 28 June 2007; Available online 9 August 2007 References [1] Burridge N, Amer A, Marchant T, et al. Online adaptive radiotherapy of the bladder: small bowel irradiated-volume reduction. Int J Radiat Oncol Biol Phys 2006;66: [2] Dawson LA, Sharpe MB. Image-guided radiotherapy: rationale, benefits and limitations. Lancet Oncol 2006;7: [3] Fokdal L, Honore H, Hoyer M, Meldgaard P, Fode K, von der Maase H. Impact of changes in bladder and rectal filling volume on organ motion and dose distribution of the bladder in radiotherapy for urinary bladder cancer. Int J Radiat Oncol Biol Phys 2004;59: [4] Fokdal L, Hoyer M, von der Maase H. Radical radiotherapy for urinary bladder cancer: treatment outcomes. Expert Rev Anticancer Ther 2006;6: [5] Harris SJ, Buchanan RB. An audit and evaluation of bladder movements during radical radiotherapy. Clin Oncol 1998;10: [6] Henry AM, Stratford J, McCarthy C, et al. X-ray volume imaging in bladder radiotherapy verification. Int J Radiat Oncol Biol Phys 2006;64: [7] Kupelian PA, Langen KM, Zeidan OA, et al. Daily variations in delivered doses in patients treated with radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2006;66: [8] Lotz HT, Pos FJ, Hulshof MC, et al. Tumor motion and deformation during external radiotherapy of bladder cancer. Int J Radiat Oncol Biol Phys 2006;64: [9] Lotz HT, Remeijer P, van Herk M, Lebesque JV, de Bois JA, Zijp LJ, et al. A model to predict bladder shapes from changes in bladder and rectum filling. Med Phys 2004;31: [10] Lotz HT, van Herk M, Betgen A, Pos F, Lebesque JV, Remeijer P. Reproducibility of the bladder shape and bladder shape changes during filling. Med Phys 2005;32: [11] McBain CA, Henry AM, Sykes J, et al. X-ray volumetric imaging in image-guided radiotherapy: the new standard in on-treatment imaging. Int J Radiat Oncol Biol Phys 2006;64: [12] Meijer GJ, Rasch C, Remeijer P, Lebesque JV. Three-dimensional analysis of delineation errors, setup errors, and organ motion during radiotherapy of bladder cancer. Int J Radiat Oncol Biol Phys 2003;55: [13] Miralbell R, Nouet P, Rouzaud M, Bardina A, Hejira N, Schneider D. Radiotherapy of bladder cancer: relevance of bladder volume changes in planning boost treatment. Int J Radiat Oncol Biol Phys 1998;41: [14] Muren LP, Smaaland R, Dahl O. Organ motion, set-up variation and treatment margins in radical radiotherapy of urinary bladder cancer. Radiother Oncol 2003;69: [15] Muren LP, Smaaland R, Dahl O. Conformal radiotherapy of urinary bladder cancer. Radiother Oncol 2004;73: [16] O Doherty UM, McNair HA, Norman AR, et al. Variability of bladder filling in patients receiving radical radiotherapy to the prostate. Radiother Oncol 2006;79: [17] Pos FJ, Hulshof M, Lebesque JV, Lotz H, van Tienhoven G, Moonen LM, et al. Adaptive radiotherapy for invasive bladder cancer: a feasibility study. Int J Radiat Oncol Biol Phys 2006;64: [18] Redpath AT, Muren LP. An optimisation algorithm for determination of treatment margins around moving and deformable targets. Radiother Oncol 2005;77: [19] Redpath AT, Muren LP. CT-guided intensity-modulated radiotherapy for bladder cancer: isocentre shifts, margins and their impact on target dose. Radiother Oncol 2006;81: [20] Sur RK, Clinkard J, Jones WG, et al. Changes in target volume during radiotherapy treatment of invasive bladder carcinoma. Clin Oncol 1993;5:30 3. [21] Turner SL, Swindell R, Bowl N, et al. Bladder movement during radiotherapy for bladder cancer: implications for treatment planning. Int J Radiat Oncol Biol Phys 1997;39: [22] Xing L, Thorndyke B, Schreibmann E, et al. Overview of imageguided radiotherapy. Med Dosim 2006;31: