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Consistency of Organ Geometries during Prostate Radiotherapy with Two Different Bladder and Bowel Regimens

Published:November 17, 2015DOI:https://doi.org/10.1016/j.jmir.2015.09.001

      Abstract

      Background

      The majority of Ontario cancer centres incorporate bladder and bowel preparation protocols for the treatment of prostate cancer with radical radiotherapy. Differing methods are used to achieve a full bladder and empty rectum for planning and treatment. We compared the effects of two different bladder and bowel preparation regimens on bladder, rectum, and prostate +/− seminal vesicle geometries through a course of radiotherapy. An optimal preparation would achieve reliable spatial arrangements and a high therapeutic ratio.

      Methods

      This prospective longitudinal study involved 59 prostate cancer patients treated with radical radiotherapy, of which half followed cohort 1 (laxative cohort) and the other cohort 2 (consistent timing cohort) bladder and bowel preparation regimen. Participants were asked to maintain an empty rectum for both planning and daily treatment appointments in cohort 1 through a fleet enema the morning of the planning appointment, and intake milk of magnesium during daily treatments. No specific bowel preparation was provided to cohort 2 patients. Instead, their appointment times were aligned with their natural bowel habits. This information was collected through a prescreening tool before treatment booking. All cohort 1 and 2 participants were asked to drink 250 mL of water 1 hour before planning and daily treatment appointments. Cohort 2 participants who identified no pre-existing urinary conditions were also asked to drink 2 L of water within 24 hours before the planning session and to continue this during treatment trajectory unless unable to do so because of treatment-induced bladder toxicities later in the treatment. A total of 1,335 structures (bladder, rectum +/− gas, and prostate +/− seminal vesicles) were contoured on the cone beam computerized tomography scans by three radiotherapists. A stringent quality assurance process was performed to assure quality and consistency of contours. Organ volumes were measured and evaluated for consistency over time from planning to completion of radiotherapy. Data analysis included the Fischer exact test and mixed effect modelling for total and subvolumes for bladder, rectum, rectal gas, and prostate +/− seminal vesicles.

      Results

      Baseline total volumes for bladder ranged from 132 mL to 501 mL with means of 325 mL and 315 mL in cohorts 1 and 2, respectively. Bladder volume declined 3.6 mL per fraction and 2.4 mL per fraction in cohorts 1 and 2, respectively. The volume of the bladder structure inside the planning target volume (PTV) on simulation showed no difference by cohort (P = .095) but there was an effect of time (linear P < .0005). Baseline total volumes for rectum ranged from 19.2 mL to 106.3 mL with means of 52.0 mL and 54.7 mL in cohorts 1 and 2, respectively. The volume of the rectum inside the PTV on simulation showed no difference by cohort (P = .12) or time (P = .30) during the treatment course. Volume of gas in the rectum did not vary by cohort (P = .6) or time (P = .08). Baseline total volumes for the clinical prostate +/− seminal vesicles target ranged from 37.1 mL to 167.5 mL with means of 76.2 mL and 66.0 mL in cohorts 1 and 2, respectively. The clinical target decreased by 3% in total volume during the course of radiotherapy in both cohorts, with similar rates of the target falling outside the planned PTV structure.

      Conclusions

      No significant difference was found between cohorts for rectal volume, gas volume, target coverage, and rectal and bladder volumes in the PTV. Hence, patients should be offered a choice between cohort 1 and 2 bowel preparation regimens to allow for patient preference customization. Cohort 2 bladder preparation regimen was shown to be superior for consistency with slightly larger volume over time.

      Résumé

      Contexte

      La majorité des centres d'oncologie en Ontario incorporent des protocoles de préparation de la vessie et de l'intestin pour le traitement du cancer de la prostate avec la radiothérapie radicale. Différentes méthodes sont utilisées pour obtenir un rectum vide et une vessie pleine pour la planification et le traitement. Nous avons comparé les effets de deux régimes différents de préparation de la vessie et de l'intestin sur la géométrie de la vessie, du rectum et de la prostate avec ou sans les vésicules séminales tout au long d'un cycle de radiothérapie. Une préparation optimale permettrait d'obtenir des arrangements spatiaux fiables et un ratio thérapeutique élevé.

      Méthodologie

      Cette étude prospective longitudinale a été menée sur 59 patients atteints d'un cancer de la prostate et traités par radiothérapie radicale et dont la moitié a suivi le régime de préparation de la vessie et de l'intestin de la cohorte (cohorte laxative) et l'autre celui de la cohorte 2 (cohorte de routine constante). On a demandé aux participants de maintenir un rectum vide pour les rendez-vous de planification et de traitements quotidiens par l'utilisation d'un lavement fleet le matin du rendez-vous de planification et la consommation de lait de magnésie durant les traitements quotidiens. Aucune préparation spécifique de l'intestin n'a été demandée aux patients de la cohorte 2. Au lieu de cela, leurs rendez-vous ont été alignés avec leurs habitudes intestinales naturelles, une information obtenue grâce à l'outil de pré-triage avant l'ordonnancement des traitements. On a demandé à tous les participants des deux cohortes de boire 250 ml d'eau une heure avant les rendez-vous de planification et de traitement quotidien. Les patients de la cohorte 2 qui n'ont signalé aucun problème urinaire préexistant ont aussi été invités à boire deux litres d'eau dans la période de 24 heures précédant le rendez-vous de planification et de poursuivre ce régime durant la trajectoire de traitement, à moins d'en être incapables en raison de toxicités de la vessie induites par le traitement plus tard durant le traitement. Au total, 1 335 structures (vessie, rectum avec ou sans gaz et prostate avec ou sans vésicules séminales) ont été contourées sur les images de tomodensitométrie à faisceau conique par trois radiothérapeutes. Un processus strict d'assurance de la qualité a été appliqué afin d'assurer la qualité et l'uniformité des contours. Le volume des organes a été mesuré et évalué afin d'assurer l'uniformité dans le temps à partir de la planification jusqu’à la conclusion du traitement de radiothérapie. L'analyse des données a été faite selon la méthode exacte de Fisher et la modélisation à effets mixtes pour le volume total et les sous-volumes pour la vessie, le rectum, le gaz rectal et la prostate avec ou sans les vésicules séminales.

      Résultats

      Le volume de base total pour la vessie allait de 132 cc à 501 cc avec une moyenne de 32,5 cc et de 31,5 cc respectivement pour les cohortes 1 et 2. Le volume de la vessie a diminué de 3,6 cc par fraction et de 2,4 cc par fraction respectivement pour les cohortes 1 et 2. Le volume de la structure de la vessie à l'intérieur du volume cible de planification dans la simulation n'a affiché aucune différence entre les cohortes (p = 0,095), avec cependant un effet de temps (p linéaire <0,0005). Le volume de base total pour le rectum à l'intérieur du volume cible de planification dans la simulation n'a affiché aucune différence entre les cohortes (p = 0,12) ou selon le temps (p = 0,30) pendant la durée du traitement. Le volume de gaz dans le rectum n'a pas varié entre les cohortes (p = 0,6) ou selon le temps (p = 0,08). Le volume de base total pour la prostate clinique avec ou sans les vésicules séminales allait de 37,1 cc à 167,5 cc avec une moyenne de 76,2 cc et de 66,0 cc respectivement pour les cohortes 1 et 2. Le volume total de la cible clinique a diminué de 3 % durant le traitement pour les deux cohortes, avec des taux similaires de cible hors de la structure de volume de planification cible prévue.

      Conclusions

      Aucune différence significative n'a été notée entre les deux cohortes pour le volume rectal, le volume de gaz, la couverture de cible et le volume du rectum et de la vessie dans le volume cible de planification. Par conséquent, les patients devraient avoir le choix entre les régimes de préparation des intestins des deux cohortes afin de tenir compte des préférences des patients. En ce qui concerne la préparation de la vessie, le régime de préparation de la cohorte 2 s'est avéré supérieur en termes d'uniformité, avec un volume légèrement supérieur au fil du temps.

      Keywords

      Introduction

      In Canada, approximately 24,000 men are diagnosed with prostate cancer annually [], with half receiving curative radiotherapy [
      • Washington C.M.
      • Leaver D.
      Principles and practice of Radiation Therapy.
      ]. The therapeutic ratio for radiotherapy is determined by radiation dose distributed to the target and organs at risk (OARs). Targeting of the prostate requires stable shape, size, and accurate localization of target with imaging tools such as cone beam computed tomography (CBCT). To spare OARs, such as rectum and bladder, as well as avoid a geographic miss of the target volume, one needs an optimum and consistent geometry meeting all dose constraints. Therefore, geometric stability from planning through the entire treatment course is desirable.
      Literature indicates that bladder and bowel preparation can influence the geometries of both organs and so affect dose exposures and toxicities. Therefore, an empty rectum and full bladder during the radiotherapy planning scan and all daily treatments is recommended [
      • Stasi M.
      • Munoz F.
      • Fiorino C.
      • et al.
      Emptying the rectum before treatment delivery limits the variation of rectal dose—volume parameters during 3DCRT of prostate cancer.
      ,
      • Ogino I.
      • Uemura H.
      • Inoue T.
      • Kubota Y.
      • Nomura K.
      • Okamoto N.
      Reduction of prostate motion by removal of gas in rectum during radiotherapy.
      ,
      • Pinkawa M.
      • Asadpour B.
      • Gagel B.
      • Piroth M.
      • Holy R.
      • Eble M.
      Prostate position variability and dose–volume histograms in radiotherapy for prostate cancer with full and empty bladder.
      ]. Several studies suggest that an empty rectum prevents organ motion and is ideal [
      • Stasi M.
      • Munoz F.
      • Fiorino C.
      • et al.
      Emptying the rectum before treatment delivery limits the variation of rectal dose—volume parameters during 3DCRT of prostate cancer.
      ,
      • Ogino I.
      • Uemura H.
      • Inoue T.
      • Kubota Y.
      • Nomura K.
      • Okamoto N.
      Reduction of prostate motion by removal of gas in rectum during radiotherapy.
      ,
      • Pinkawa M.
      • Asadpour B.
      • Gagel B.
      • Piroth M.
      • Holy R.
      • Eble M.
      Prostate position variability and dose–volume histograms in radiotherapy for prostate cancer with full and empty bladder.
      ,
      • Webber C.
      • Brundage M.D.
      • Siemens D.R.
      • Groome P.A.
      Quality of care indicators and their related outcomes: a population-based study in prostate cancer patients treated with radiotherapy.
      ,
      • Jain S.
      • Loblaw D.A.
      • Morton G.C.
      • et al.
      The effect of radiation technique and bladder filling on the acute toxicity of pelvic radiotherapy for localized high risk prostate cancer.
      ]. However, De Creviosier et al found that variations in rectal filling results in prostate displacement [
      • De Crevoisier R.
      • Tucker S.L.
      • Dong L.
      • et al.
      Increased risk of biochemical and local failure in patients with distended rectum on the planning CT for prostate cancer radiotherapy.
      ]. A full versus empty bladder has less or no impact on prostate position [
      • Pinkawa M.
      • Asadpour B.
      • Gagel B.
      • Piroth M.
      • Holy R.
      • Eble M.
      Prostate position variability and dose–volume histograms in radiotherapy for prostate cancer with full and empty bladder.
      ], but a bladder over 150 mL can ensure that overall organ dose constraints are met [
      • Nakamura N.
      • Shikama N.
      • Takahasi O.
      • et al.
      The relationship between the bladder volume and optimal treatment planning in definitive radiotherapy for localized prostate cancer.
      ] with reduced bladder toxicities [
      • Webber C.
      • Brundage M.D.
      • Siemens D.R.
      • Groome P.A.
      Quality of care indicators and their related outcomes: a population-based study in prostate cancer patients treated with radiotherapy.
      ,
      • Jain S.
      • Loblaw D.A.
      • Morton G.C.
      • et al.
      The effect of radiation technique and bladder filling on the acute toxicity of pelvic radiotherapy for localized high risk prostate cancer.
      ] and reduced small bowel exposure [
      • Pinkawa M.
      • Asadpour B.
      • Gagel B.
      • Piroth M.
      • Holy R.
      • Eble M.
      Prostate position variability and dose–volume histograms in radiotherapy for prostate cancer with full and empty bladder.
      ]. Practical methods to produce consistency in rectal and bladder volumes vary. In 2012, we requested that all 14 cancer centres in Ontario share their bladder and bowel preparation guidelines for prostate cancer patients. Eleven cancer centres responded and, although they all indicated that they required a full bladder and empty rectum for treatment, their practices of achieving this varied greatly. For example, some centres used milk of magnesia to ensure an empty rectum, while others used Dulcolax (bisacodyl) or enemas. The amount of water required was anywhere between one and two cups, 15 minutes–1 hour before treatment. Similar inconsistencies are reflected in the literature [
      • Jain S.
      • Loblaw D.A.
      • Morton G.C.
      • et al.
      The effect of radiation technique and bladder filling on the acute toxicity of pelvic radiotherapy for localized high risk prostate cancer.
      ,
      • Nakamura N.
      • Shikama N.
      • Takahasi O.
      • et al.
      The relationship between the bladder volume and optimal treatment planning in definitive radiotherapy for localized prostate cancer.
      ,
      • Yahya S.
      • Zarkar A.
      • Southgate E.
      • Nightingale P.
      • Webster G.
      Which bowel preparation is best? Comparison of a high-fibre diet leaflet, daily microenema and no preparation in prostate cancer patients treated with radical radiotherapy to assess the effect on planned target volume shifts due to rectal distension.
      ,
      • Munoz F.
      • Fiandra C.
      • Franco P.
      • et al.
      Tracking target position variability using intraprostatic fiducial markers and electronic portal imaging in prostate cancer radiotherapy.
      ,
      • Ki Y.
      • Kim W.
      • Nam J.
      • et al.
      Probiotics for rectal volume variation during radiation therapy for prostate cancer.
      ]. Further research is needed to determine the effects of different bowel and bladder preparations on rectal, bladder, and prostate +/− seminal vesicles geometries through a course of radiation. An optimal preparation would achieve reliable spatial arrangements and a high therapeutic ratio.
      We undertook this study to directly compare two methods of bladder and rectal preparation for the outcomes of consistency of prostate targeting and avoidance of the rectum and bladder. Daily pretreatment CBCT imaging with on-line matching provides geometric information while volumetric modulated arc therapy for radiation delivery is more efficient and associated with less geometric relaxation caused by intrafraction motion than other delivery methods [
      • Munoz F.
      • Fiandra C.
      • Franco P.
      • et al.
      Tracking target position variability using intraprostatic fiducial markers and electronic portal imaging in prostate cancer radiotherapy.
      ,
      • Park S.S.
      • Yan D.
      • McGrath S.
      • et al.
      Adaptive image-guided radiotherapy (IGRT) eliminates the risk of biochemical failure caused by the bias of rectal distension in prostate cancer treatment planning: clinical evidence.
      ,
      • Thornqvist S.
      • Muren L.P.
      • Bentzen L.
      • et al.
      Degradation of target coverage due to inter-fraction motion during intensity-modulated proton therapy of prostate and elective targets.
      ]. The combination provides an opportunity to explore geometries in the context of different patient preparations.

      Methods

       Patient Characteristics

      This prospective, longitudinal study was approved by the Trillium Health Partners Research Ethics Board. Fifty-nine men with newly diagnosed adenocarcinoma of the prostate, low-to-intermediate risk, and without distant metastases and who were proceeding to radiotherapy at the Carlo Fidani Regional Cancer Centre were consented. Patients with any comorbidity that would hinder or impair their written communication were excluded from the study.

       Bladder and Bowel Preparations

       Cohort 1–Laxative Cohort

      Cohort 1 bladder and bowel preparation was the existing departmental practice, developed by the genitourinary disease site team in July 2010. These guidelines were in place before September 1, 2013. The bowel preparation was achieved through maintaining an empty rectal state from planning session to treatment delivery. Therefore we included all prostate cancer patients treated with radical radiotherapy performing a fleet enema on the morning of their planning simulation appointment. No rectal balloon or any other form of rectal preparation was used. As per the genitourinary disease site team, the purpose of the enema was to try to decrease the number of rescans at CT simulation. To achieve this empty rectal state, throughout their course of treatment, starting 3 days before the first radiation treatment, patients were asked to take 2 tbsp of milk of magnesia unless otherwise instructed to stop (eg, for arising diarrhoea). Patients were instructed to empty their bladder 1 hour before simulation and treatment appointments and then drink 500 mL of water without voiding until after the appointment, for the purpose of attaining a full bladder.

       Cohort 2–Consistent Timing Cohort

      After September 1, 2013, a new set of bladder and bowel preparation guidelines were introduced. These new guidelines were developed by the genitourinary disease site team, with the input of radiation therapists, nurses, and oncologists. The new guidelines are a patient-friendly alternative with the goal of improved patient comfort and compliance. In addition, the previous patient focus group indicated the use of milk of magnesia and enemas was quite costly and uncomfortable. For cohort 2, hydration instructions appropriate to the patient, collected through a questionaire designed around the American Urological Association Symptom Score Index (AUASI), were added to the bladder preparation instructions. Patients were asked to drink 2 L of water and/or other fluids over a period of 24 hours before their planning simulation appointment time and to continue hydration while on treatment (as opposed to only drinking 500 mL before treatment), with the exception of patients with significant pre-existing urinary issues. To achieve consistency in patient's rectal filling from planning to treatment sessions, patients were asked a series of questions to determine their bowel habits. The simulation and daily treatment appointment times were then aligned to be within the period between 3 hours after their most consistent daily bowel movement and before their next meal. For those patients who could not identify a consistent bowel habit, simulation and treatment appointment times were simply kept consistent within +/− 1.5 hours throughout the course. Patients did not use fleet enemas or milk of magnesia, and therefore, incurred no extra expenses. To achieve an empty rectum, the team chose the least intrusive approach of aligning the treatment appointments with the patient's natural bowel habits over artificial interventions (eg, enema, milk of magnesia, and rectal balloons). By keeping the preparation instructions the same for CT simulation and treatments, it might be easier for patients to follow, fit better with their established daily routine, and might improve geometric consistency of organs from planning to completion of treatments.

       Treatment Planning

      A Philips big bore CT scanner was used to obtain planning simulation images at 2-mm slice thickness.
      The planning process began with delineation of organs and volumes using Varian Medical System's Eclipse, version 10. Bladder volumes were contoured by dosimetrists and checked by the primary radiation oncologist. The clinical target volume, which includes the prostate +/− proximal seminal vesicles and the rectum (from anus to sigmoid flexure), was contoured by the primary oncologist and peer-reviewed by another oncologist. A planning target volume (PTV) margin of 1 cm around the clinical target volume, except 7 mm posteriorly, was applied to all cases. As per departmental policy Varian Rapid Arc (VMAT) optimization technique was used along with AAA v 10 (anisotropic analytical algorithm) dose calculation algorithm and a calculation grid size of 2 mm. Density override was used if excess transient air was present around target volumes.
      Treatment was delivered by RapidArc on the Varian Clinac iX Linear Accelerator. Plan geometry included two 6 MV arcs, 1 full and 1 partial, angle 240–120 clockwise.

       Patient Position Verification

      Forty-one patients underwent gold seed fiducial marker insertion. The others were not candidates for fiducial markers or had calcifications (at least 2 mm in all dimensions) suitable for use as a prostate surrogate [
      • Zeng G.
      • McGowan T.S.
      • Larsen T.M.
      • et al.
      Calcifications are potential surrogates for prostate localization in image-guided radiotherapy.
      ].
      Daily pretreatment CBCT scans were acquired for patients without fiducial markers. Patients with fiducial markers only had CBCT scans on days 1–3 and weekly thereafter. CBCT was acquired with the Varian On-Board Imager, version 1.4. A “pelvis spot light” preset (125 kV, 80 mA, 25 ms, full-fan bow tie filter, partial gantry rotation) was used. Image registration was performed using either fiducial markers as prostate surrogates with soft tissue matching on CBCT days or calcification(s) with soft tissue matching.

       CBCT Contouring

      CBCT images were imported into the Varian Eclipse planning system. Prostate +/− seminal vesicles, bladder, rectum (extending 3 slices superior and inferior to PTV), and gas (if present 3 slices above or below the PTV using windowing level that provided the highest contrast) were contoured on all the CBCTs (see Figure 1). The bladder was fully contoured in all dimensions, except if it extended more than 8 cm anterior of the isocenter because of poor image quality attributed to CBCT ring artifact. In some cases, the superior aspect of bladder was not captured in the CBCT scan due to the length limitation of the CBCT (16 cm) and an inferiorly positioned isocenter, in which case the bladder was only contoured to the superior limit of CBCT. Where bladder contour was truncated on CBCT, the same rule was applied to the planning bladder contour volume.
      Figure thumbnail gr1
      Figure 1Prostate, bladder, rectum, and gas contours. PTV, planning target volume.
      CBCT contouring and recording was done by three radiotherapist investigators. To minimize interobserver variability within patient contours, each patient's specific organ was contoured by the same therapist on all CBCT scans. Ten completed therapist-contoured patient data sets were randomly chosen for quality assurance by an oncologist with prostate cancer expertise. This process yielded rules for a second therapist investigator to review all contour sets. This robust process was designed to assure accuracy and consistent contouring methods.
      Boolean structures were created to measure volumes of bladder and rectal structures within the planned PTV structure and any volume of the prostate +/− seminal vesicles structure falling outside the planned PTV structure (see Figure 2).
      Figure thumbnail gr2
      Figure 2Overlaps between bladder and planning target volume (PTV) and between rectum and PTV. Image from Varian Medical System's Eclipse, v10.

       Statistical Analysis

      Statistics included Fischer exact test for tables or proportions, and mixed effect modelling for repeated measures panel or longitudinal data, for total and subvolumes for bladder, rectum, rectal gas, and prostate +/− seminal vesicles. Second-order terms and interactions were assessed during modelling, and only relevant models and P values are provided in the Results section. Figures for panel data display cohort means and standard errors of the means. Statistical significance means P < .05.

      Results

       Patient Numbers

      This study includes 35 prostate-only radiotherapy and 24 two-phase pelvis–prostate radiotherapy patients. Baseline characteristics are listed in Table 1. Age and pre-treatment prostate specific antigen (PSA) score were not statistically different between cohorts.
      Table 1Baseline Characteristics
      Baseline VariableCohort 1 (n = 31)Cohort 2 (n = 28)P Value
      Age, yMean, 73.3; SD, 5.7Mean, 71.5; SD, 5.9.23
      StageFor T = 0.65
       T1119
       T21718
       T331
       T400
       N03028For N = 1.00
       N110
       (All) M031 (All)28 (All)n/a
      Gleason score
       <786.45
       71510
       ≥8812
      PSAMedian, 7.0; range, 2.9–46.5Median, 10.2; range, 1.7–103.00.1, using 1/sqrt, T-test of transformed data
      High risk?.29
       No2115
       Yes1013
      GSI.57
       GSI2318
       Non-GSI810
      Treatment.19
       Single phase2114
       Two phase1014
      GSI, gold seed insertion.
      Cohort 1 (n = 31) included patients who underwent treatment imaging between February and August 2013; however, three cases were later dropped due to poor CBCT quality. Cohort 2 (n = 28) included patients who underwent treatment imaging between December 2013 and July 2014. The total number of baseline simulations was 56, one per case. In cohort 1, one case was missing a single CBCT, and seven cohort 2 cases were missing some CBCT's (P = .05). Of 446 available image sets (simulation and CBCT), only 3 CBCT had artefact precluding contouring rectum, so there was a total of 1,335 structures (prostate +/− seminal vesicles, bladder, and rectum) contoured.

       Consistency Avoiding Bladder

      Baseline total volumes for bladder ranged from 132 mL to 501 mL, with means of 325 mL and 315 mL in cohorts 1 and 2, respectively (P = .75). Mixed effects panel analysis for total bladder volume showed a difference by cohort (interaction P = .048 for cohortXfraction, linear effect P = .9; and combined P = .04), so bladder volume in cohort 1 declined 3.6 mL per fraction, and in cohort 2, declined only by 2.4 mL per fraction. The final volume in cohort 1 was estimated to be lower than that in cohort 2 by 46 mL, with the actual observed difference being 37 mL. The volume of the bladder structure inside the PTV on simulation ranged from 7.0 mL to 41.4 mL with means of 23.9 mL and 19.9 mL in cohorts 1 and 2, respectively (P = .07). In regression, there was no difference by cohort (P = .095), but there was an effect of time (both linear P < .0005 and quadratic P = .002; combined P = .0004). The decline in both cohorts was 1.1 mL over the course of treatment. In conclusion, the bladder was more consistent in size in cohort 2 (see Figure 3A ).
      Figure thumbnail gr3
      Figure 3Bladder (A) and rectal (B) volume trend. Solid line, cohort 1; dotted line, cohort 2; Z, standard error of the mean.

       Consistency Avoiding Rectum

      Baseline total volumes for rectum ranged from 19.2 mL to 106.3 mL, with means of 52.0 mL and 54.7 mL in cohorts 1 and 2, respectively (P = .62). Mixed effect panel analysis for total rectum volume showed no difference by cohort or time (all P > .25). The volume of the rectum inside the PTV on simulation ranged from 1.7 mL to 16.4 mL, with a mean of 6.8 mL in both cohorts (P = .9). There was no effect of either cohort (P = .12) or time (P = .30) on this volume during the treatment course. Volume of gas in the rectum varied from 0 mL to 45 mL, with a mean of 2 mL, and by regression, this did not vary by cohort (P = .6) or time (P = .08). In conclusion, the rectum (and any gas) was consistent in size in both cohorts and was not different (see Figure 3B).

       Consistency on Clinical Target

      Baseline total volumes for the clinical prostate–seminal vesicles target ranged from 37.1 mL to 167.5 mL, with means of 76.2 mL and 66.0 mL in cohorts 1 and 2, respectively (P = .15). By mixed effects panel analysis, the total target volume decreased per fraction of radiation by 0.056 mL (P = .001) for a net decline of 2.2 mL over the course of radiotherapy, but with no difference by cohort (P = .12). During the course of treatments, in 14 of 398 CBCTs the clinical target fell partly outside the PTV, with volumes of 0.1 mL to 0.23 mL outside in 13 of 14 and 1.52 mL in 1 of 14. By cohort, 6 of 216 CBCTs were classified as “outside” in cohort 1, confined to 3 of 28 cases; and 8 of 174 in cohort 2, confined to 5 of 28 cases (P = .4 for CBCT; P = .7 for cases). In conclusion, the clinical target decreased by 3% in total volume (2.2 mL) during the course of radiotherapy in both cohorts, with similar rates of the target falling outside the planned PTV structure.
      There was no statistical difference in target (prostate and seminal vesicles) coverage between cohorts. With adequate planning margins and pretreatment image guidance, maintaining an empty rectal state appears not to be required to ensure acceptable target coverage. However, variations in rectal and bladder volume can affect daily positioning of the seminal vesicles [
      • Mak D.
      • Gill S.
      • Paul R.
      • et al.
      Seminal vesicle interfraction displacement and margins in image guided radiotherapy for prostate cancer.
      ]. Although direct displacement of seminal vesicles due to rectal and bladder filling was not measured in our study, the seminal vesicle and prostate volume on CBCT was assessed to be inside or outside the planned PTV. In a very small percentage of the total CBCT data sets, despite daily pretreatment image registration, the seminal vesicles were still found to be outside, or in the periphery of, the PTV. In cohort 2, the seminal vesicles were displaced more posteriorly when there is less rectal filling compared with that of planning scan. In contrast, the seminal vesicles were displaced anteriorly outside the PTV in cohort 1.

      Discussion

      This prospective study has assessed geometric stability of organ volumes over the course of radiotherapy with two different bladder and bowel preparation regimes.

       Bladder

      Both cohorts had similar total bladder volumes at baseline, and these declined over time in a divergent manner. Because the incremental decline in bladder volume was smaller in cohort 2, and the volume of bladder inside the PTV declined equally in both cohorts, it is concluded that the hydration approach for cohort 2 bladder filling method is more effective in achieving consistency in bladder size from planning to treatment. We believe the reason for consistency in cohort 2 to be twofold. First, the bladder filling requirements in CT simulation were less stringent in cohort 2, requiring the full bladder to only extend 3 cm superior of the base of the prostate, rather than superiorly beyond the femoral heads, as was the case in cohort 1, thus making it easier for patients to achieve a sufficient bladder filling. The bladder size requirement in cohort 2 is designed to achieve the necessary small bowel displacement from high dose region based on our planning margins and planning protocols. Second, cohort 2 guidelines required hydration, a healthy lifestyle change that could be easily incorporated into patients' daily routine. Hydration levels can vary from day to day for one individual and also across individuals. The rate of bladder filling is affected by hydration levels. Previous studies have demonstrated that bladder volume reduces by up to 51% from start of the treatment to 4–5 weeks after onset of radiation treatment [
      • Zellers R.
      • Robertson P.
      • Strawderman M.
      • et al.
      Prostate position late in the course of external beam therapy: patterns and predictors.
      ]. This appears to differ by type of preparation, so we recommend the cohort 2 bladder preparation regimen for less decline, and so greater consistency.

       Rectum and Gas

      Previously, the planning scan was done with an empty rectum, thus simulating the “worst case scenario” where the rectum is collapsed; consequently, a larger volume of the rectum will receive a higher dose. The assumption was that if the plan met the dose/volume constraints, the actual total dose delivered to the rectum would not exceed the planned dose [
      • Stasi M.
      • Munoz F.
      • Fiorino C.
      • et al.
      Emptying the rectum before treatment delivery limits the variation of rectal dose—volume parameters during 3DCRT of prostate cancer.
      ].
      Because no difference was found between cohorts in rectal volumes, patients could be offered to choose from the rectal preparations for both cohorts without negatively affecting their treatment. Therefore, we recommend a patient-centred approach that offers patients a choice between the two bowel preparation methods, thus engaging the patient in their care and improving overall patient experience.
      In both cohorts, the aim is to achieve a consistent rectal state from planning to daily treatment, rather than an empty rectal state. Cohort 1 attempts to induce a consistently emptier rectum state via medicinal interventions, whereas cohort 2 capitalizes on the patient's natural bowel evacuation schedule or alignment of CT and treatment appointment times. Neither preparation was successful in achieving a consistent rectal state in every patient. For cohort 1, this may be because of the difficulties patients had in following preparation guidelines, or perhaps the body's ability to adjust its natural bowel status, or the inconsistency in the time of their treatment appointments. In cohort 2, operational issues such as delays, scheduled, and unscheduled downtime affected our ability to keep the patients' appointment times as consistent as we had intended. Also, a few patients opted to have their treatment appointments at a time they preferred for personal reasons rather than aligning with their normal bowel habits.
      In addition, this article only investigated the volume of the rectum and did not examine any changes of shape. Previous research has shown that rectal volume varies most at the superior portion and least at the inferior portion of the rectum [
      • Kupelian P.A.
      • Langen K.M.
      • Zeidan O.A.
      • et al.
      Daily variations in delivered doses in patients treated with radiotherapy for localized prostate cancer.
      ]. Future research may investigate the relationship between volume, shape, and dose–volume histograms of the rectum.

       Target Coverage and Biochemical Failure

      Although infrequent, in a hypofractionated treatment regimen, the impact of having the seminal vesicles displaced outside or in the periphery of the PTV could be detrimental to the therapeutic ratio. With early identification, interventions such as replanning with adjusted margins or daily monitoring of seminal vesicles position can be done. Standard practice guidelines for contouring seminal vesicles, margins, and pretreatment image registration can preclude such events. Further research investigations are required.

       Strengths and Weaknesses

      Although the literature does support using CBCTs for contouring [
      • Yaver M.
      • Foo A.
      • Fineberg H.
      • Larsen T.
      • Jones G.
      Investigating variations in rectal size on CT planning data set and CBCT for patients undergoing radiation therapy to their prostate/prostate bed during the first thirteen days of treatment.
      ,
      • Nishioka K.
      • Shimizu S.
      • Kinoshita R.
      • et al.
      Evaluation of inter-observer variability of bladder boundary delineation on cone-beam CT.
      ], interobserver variability is greater on CBCTs because of their poorer quality [
      • Lutgendorf-Caucig C.
      • Fotina I.
      • Stock M.
      • Potter R.
      • Goldner G.
      • Georg D.
      Feasibility of CBCT-based target and normal structure delineation in prostate cancer radiotherapy: multi-observer and image multi-modality study.
      ]. However, by undergoing extensive training with a radiation oncologist and applying a rigorous quality assurance process to ensure proper contouring, we turned a weakness of the study into strength. After reviewing 1,335 structures, the investigators found that they became comfortable contouring on CBCTs, the oncologist involved in the research felt that the contours had been drawn appropriately. Nevertheless, we do recognize that occasionally, CBCTs cannot be used to contour on. However, only three cases were dropped due to poor CBCT quality and only three CBCTs were discarded due to artefacts. Also as per the departmental contouring policy, only the proximal seminal vesicles are contoured by the primary oncologist. The prospective study design and consistency in application are additional strengths.
      A weakness of the study is the exclusion of dose analysis as it relates to the geometric findings presented in this article. In general, the primary strategy to obtain a desirable therapeutic ratio is to ensure that dose constraints are met during planning. However, literature consistently reports that planned dose is not the same as the delivered dose due to organ motion or altered shape(s) [
      • Thor M.
      • Apte A.
      • Deasy J.O.
      • et al.
      Dose/volume-response relations for rectal morbidity using planned and simulated motion-inclusive dose distributions.
      ,
      • Thor M.
      • Apte A.
      • Deasy J.O.
      • Muren L.P.
      Statistical simulations to estimate motion-inclusive dose-volume histograms for prediction of rectal morbidity following radiothery.
      ,
      • Hatton J.A.
      • Greer P.B.
      • Tang C.
      • et al.
      Does the planning dose-volume histogram represent treatment doses in image-guided radiation therapy? Assessment with cone-beam computerised tomography scans.
      ]. Although through daily imaging dose delivery to prostate seems to be satisfactory, large variation in delivered dose to rectum and bladder was observed because of varying shape or volume [
      • Kupelian P.A.
      • Langen K.M.
      • Zeidan O.A.
      • et al.
      Daily variations in delivered doses in patients treated with radiotherapy for localized prostate cancer.
      ]. In some instances, observed dose to both bladder and rectum was noted to be greater than what the initial plan had predicted [
      • Thor M.
      • Apte A.
      • Deasy J.O.
      • Muren L.P.
      Statistical simulations to estimate motion-inclusive dose-volume histograms for prediction of rectal morbidity following radiothery.
      ]. The next step is to investigate the impact effect of a change in geometry and anatomy on delivered dose.

       Future Research

      This article presents results from a portion of a larger project to study the journey of a patient with prostate cancer undergoing curative radiotherapy. The patient experience consists of many facets of their journey from therapeutic ratio, adverse events, biochemical control, use of patient-reported outcomes, and overall patient satisfaction, which will be the scope of future studies.

      Conclusions

      The study compared the impact of two different bowel and bladder preparation regimes for prostate cancer patients undergoing radical radiotherapy on patient satisfaction, target reliability, and geometric consistency of the bladder and rectum. Findings showed no significant difference between cohorts for rectal volume, target coverage, gas volume, rectal volume in the PTV, and bladder volume in the PTV. Consistency in bladder size was better in cohort 2, with slightly larger volume over time suggesting that cohort 2 bladder filling regimen is superior over that of cohort 1. In conclusion, patients should be offered a choice between cohort 1 and cohort 2 bowel preparation, thus engaging them in their care and allowing customization based on their needs and preferences (eg, appointment times). The cohort 2 bladder filling regimen has been proven to be advantageous over cohort 1 in terms of therapeutic ratio.

      Acknowledgements

      The authors of this study would like to acknowledge the Radiation Oncology program Genitourinary Disease Site Team and the Radiation Therapy department at the Carlo Fidani Regional Cancer Center.

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