Radiotherapy and Oncology 113 (2014) 398–403

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Radiotherapy and Oncology

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IMRT in prostate cancer

Rectal toxicity after intensity modulated radiotherapy for prostatecancer: Which rectal dose volume constraints should we use?

http://dx.doi.org/10.1016/j.radonc.2014.10.0140167-8140/� 2014 Elsevier Ireland Ltd. All rights reserved.

⇑ Corresponding author at: Ghent University Hospital, Department of RadiationOncology and Experimental Cancer Research, De Pintelaan 185, 9000 Ghent,Belgium.

E-mail address: Valerie.fonteyne@uzgent.be (V. Fonteyne).

Valérie Fonteyne a,⇑, Piet Ost a, Frank Vanpachtenbeke a, Roos Colman b, Simin Sadeghi a, Geert Villeirs c,Karel Decaestecker d, Gert De Meerleer a

a Ghent University Hospital, Department of Radiation Oncology and Experimental Cancer Research; b Ghent University, Biostatistics Unit, Department of Public Health,Faculty of Medicine and Health Sciences; c Ghent University Hospital, Department of Radiology; and d Ghent University Hospital, Department of Urology, Belgium

a r t i c l e i n f o

Article history:Received 14 May 2014Received in revised form 19 October 2014Accepted 31 October 2014Available online 28 November 2014

Keywords:Prostatic neoplasms/radiotherapyRadiotherapy/intensity modulated/adverseeffectsRectum/radiation effects

a b s t r a c t

Background: To define rectal dose volume constraints (DVC) to prevent Pgrade2 late rectal toxicity (LRT)after intensity modulated radiotherapy (IMRT) for prostate cancer (PC).Material and methods: Six hundred thirty-seven PC patients were treated with primary (prostate mediandose: 78 Gy) or postoperative (prostatic bed median dose: 74 Gy (adjuvant)–76 Gy (salvage)) IMRT whilerestricting the rectal dose to 76 Gy, 72 Gy and 74 Gy respectively. The impact of patient characteristicsand rectal volume parameters on Pgrade2 LRT was determined. DVC were defined to estimate the 5%and 10% risk of developing Pgrade2 LRT.Results: The 5-year probability of being free from Pgrade2 LRT, non-rectal blood loss and persistingsymptoms is 88.8% (95% CI: 85.8–91.1%), 93.4% (95% CI: 91.0–95.1%) and 94.3% (95% CI: 92.0–95.9%)respectively.There was no correlation with patient characteristics. All volume parameters, except rectal volumereceiving P70 Gy (R70), were significantly correlated with Pgrade2 LRT. To avoid 10% and 5% risk ofPgrade2 LRT following DVC were derived: R40, R50, R60 and R65 <64–35%, 52–22%, 38–14% and 5%respectively.Conclusion: Applying existing rectal volume constraints resulted in a 5-year estimated risk of developinglate Pgrade2 LRT of 11.2%. New rectal DVC for primary and postoperative IMRT planning of PC patientsare proposed. A prospective evaluation is needed.

� 2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 113 (2014) 398–403

High dose external beam radiotherapy (EBRT) is an excellenttreatment option for patients with prostate cancer (PC), both inthe primary [1] and postoperative setting [2,3]. Long-term dataon clinical outcome and toxicity have been published and areencouraging [1–3]. However, even with the use of modern EBRT,the incidence of severe rectal toxicity is still not negligible and ham-pers quality of life [4]. Several clinical factors have been associatedwith rectal toxicity [5–7]. Based on both retrospective [8–11] andprospective data [12–15] a clear dose response relationship for rec-tal toxicity after 3D-conformal radiotherapy (3D-CRT) has beenestablished. The latter has lead to the development of rectal dosevolume constraints (DVC) that are implemented worldwide.

The implementation of intensity modulated radiotherapy(IMRT) techniques in the treatment of PC patients is emerging.

Compared to 3D-CRT, IMRT generates an inhomogeneous dose dis-tribution with tight dose gradients and concave dose distributions(‘‘horse-shoe’’-shaped). As a result, the dose to the prostate can beincreased with better sparing of the organs at risk (OAR) from highdose areas. In contrast, at the level of the surrounding and OARthere will be more spreading of the low and intermediate doseregions when IMRT is used. Despite this different dose distribution,centres using IMRT for PC have implemented rectal DVC derivedfrom 3D-CRT series.

Therefore we evaluated late rectal toxicity and analysed theimpact of patient characteristics and rectal dose volume parame-ters on the development of rectal toxicity after high dose IMRT ina large patient group. The goal is to provide rectal DVC that canbe applied in the IMRT planning of PC patients in order to preventPgrade 2 late rectal toxicity.

Materials and methods

Since 1998, patients with PC at the Ghent University Hospitalare treated with IMRT. Since then, 1347 patients with PC were

V. Fonteyne et al. / Radiotherapy and Oncology 113 (2014) 398–403 399

treated with IMRT in the primary or postoperative setting. For allthese patients, data concerning medical history, PC characteristicsand IMRT characteristics and toxicity were prospectively enteredin a database (Table 1). Only patients with a minimal follow upof 18 months were included in this analysis. As there was no signif-icant difference in the incidence of Pgrade 2 late rectal toxicitybetween patients treated in the primary or postoperative setting,the toxicity data of these patients were pooled (Table 2). Finally637 patients were included in this trial.

Details on pre-treatment imaging, patient preparation, treat-ment planning and delivery have been published [16]. In the pri-mary setting, the clinical target volume (CTV) consisted of theprostate and seminal vesicles. If the probability of seminal vesicleinvasion was <15% [17] the latter were excluded from the CTV at50 Gy. In the postoperative setting, the CTV contained the prostaticand seminal vesicular bed. The PTV was created using a 3-dimen-sional, isotropic expansion of the CTV of 4 (primary setting) or7 mm (postoperative setting). No patient was irradiated to the pel-vic lymph nodes. Patients were instructed to have a comfortablyfilled bladder at the time of planning CT and treatment. All patientswere instructed to drink ±750 cc of water starting 1 h prior to theirplanning CT and therapy.

Prior to the planning CT a fleet enema was used to obtain anempty rectum. The rectum was thereafter defined as rectal wall(excluding remaining air and faeces) and delineated from the analverge caudally up to the anatomic transition to the sigmoid coloncranially.

Sigmoid colon, bladder, small bowel and femoral heads weredelineated separately as organs at risk [16].

The dose was prescribed as median dose to the PTV. A maximalrectal dose was used as planning objective. In the primary setting 3different dose levels were implemented over time: from December1998 to 2002, patients were treated to a median dose (Dmed) of74 Gy (PTV) with a hard constraint on maximum rectum dose(Rmax) of 72 Gy. Between 2002 and 2003, patients were treated toa Dmed of 76 Gy to the PTV with a hard constraint on Rmax of74 Gy. In 2003, we initiated a third dose level: Dmed of 78 Gy tothe PTV with a hard constraint on Rmax of 76 Gy. This is still thecurrent prescription in the primary setting.

In the salvage and adjuvant setting, the prescription was as fol-lows: 76 Gy (PTV) and 74 Gy (rectum) and 74 Gy (PTV) and 72 Gy(rectum) respectively [3].

Over time different rectal DVC have been applied:

– Period 1: 1998–2004: maximal volume of the rectum in %receiving 50 Gy (R50), R60, R65 and R70 was restricted to100%, 60%, 50% and 30% of the rectal volume respectively.

– Period 2: 2004–2006: R50, R60 and R70 was limited to 60%, 50%and 30% respectively while there was no longer a constraint onR65.

Table 1Patient characteristics for all patients and per radiotherapy type. Abbreviations: IBS, irritabrackets represent percentages.

Characteristics All patientsN = 637

Primary radiotherapN = 405

Age 66 (41–85) 67 (41–85)Median follow up 60 (18–168) 60 (18–168)Presence of Crohn or colitis 3 (1) 2 (1)Presence of diabetes 59 (9) 50 (12)Nicotine consumption 136 (21) 100 (25)Presence of haemorrhoids 157 (25) 96 (24)Presence of abdominal surgery 376 (59) 206 (51)Presence of IBS 23 (4) 15 (4)Use of adjuvant hormonal therapy 415 (65) 281 (69)

– Period 3: 2007–today: DVC were applied based on an analysispublished in 2007 resulting in 2 separate sets of DVC: 1 to pre-vent grade P2 (R40 <84%, R50 <69%, R60 <59% and R65 <48%)and another to prevent grade P1 (R40 <64%, R50 <46%, R60<35% and R65 <34%) late rectal toxicity respectively [18].

A 3–7 beams set-up was used for planning. Patient positioningwas controlled daily by portal imaging (EPID) (1996–2010), 3Dultrasound system (SonArray™ Zmed, Ashland, USA) (2001–2007) or cone beam CT (CBCT) (2006–today). All plans underwenta standardized control by our physics before being released forclinical use.

During treatment, patients were instructed to have a comfort-ably filled bladder. A daily suppository was administered to over-come a critical rectal distension that can be seen during the firstdays/weeks of treatment. The use of suppositories during therapyinstead of fleet enemas was recommended to reduce the risk ofrectal irritation and injury due to repeated administration of rectalfleet enemas. Rectal and bladder filling was evaluated on ultra-sound and CBCT imaging pre therapy.

A questionnaire was used to register the medical and surgicalhistory (Crohn’s disease, colitis, irritable bowel disease, diabetes,nicotine consumption, haemorrhoids and previous – non-pros-tate-related – abdominal surgery) and pre-treatment rectal symp-toms of each patient [16].

Patients were seen following a fixed schedule: every 3 monthsfor the first year, 6-monthly from 2 till 5 years and yearly thereaf-ter [16]. Late rectal and lower intestinal toxicity was defined as anyincrease of rectal toxicity lasting more than 3 months after the endof IMRT, or occurring for the first time later than 3 months after theend of IMRT. The grade of late rectal toxicity was scored accordingto the RTOG toxicity scale [19], combined with rectal urgency andincontinence as determined by Yeoh [20] and by an in-housedeveloped scoring system [16]. All together, this was defined as‘Radiotherapy Induced Lower Intestinal Toxicity’ (RILIT) system.In total 8 different lower intestinal symptoms were recorded: diar-rhoea, rectal blood loss (RBL), mucus loss, faecal incontinence,abdominal cramps, urgency, stool frequency and anal pain. Foreach symptom, the maximal toxicity score was registered.

Statistical analysis

Statistical analyses were performed in SPSS version 22.0 soft-ware (Chicago, ILL, USA) and SAS version 9.4. Significance levelwas set at P = 0.05.

Chi-square or Fisher’s exact test (categorical variables) andKruskal–Wallis-test (continuous variables) were used to comparethe pre-treatment characteristics.

A Kaplan Meier curve was used to describe the overall probabil-ity of developing Pgrade 2 late rectal toxicity, Pgrade 2 non-RBLand Pgrade 2 persisting symptoms (using the LIFETEST procedure).

ble bowel syndrome. Data are presented as absolute numbers. The numbers between

y Adjuvant radiotherapyN = 110

Salvage radiotherapyN = 122

P-value

64 (51–77) 65 (42–76) NS48 (18–144) 48 (18–156) <0.001

1 (1) 0 (0) NS4 (4) 5 (4) <0.001

14 (13) 22 (18) <0.00129 (26) 32 (26) NS81 (74) 89 (73) <0.001

4 (4) 4 (3) NS62 (56) 72 (59) 0.015

Table 2Late toxicity per grade for all patients and per treatment group separately.

Toxicity All patientsN = 637

Primary radiotherapyN = 405

Adjuvant radiotherapyN = 110

Salvage radiotherapyN = 122

P-value

Late rectal grade 1 toxicity Yes 318 (50) 215 (53) 51 (46) 52 (43) 0.091No 319 (50) 190 (47) 59 (54) 70 (57)

Late rectal grade 2 toxicity Yes 68 (11) 45 (11) 12 (11) 11 (9) NSNo 569 (89) 360 (89) 98 (89) 111 (91)

Late rectal grade 3 toxicity Yes 6 (1) 3 (1) 1 (1) 2 (1) NSNo 631 (99) 402 (99) 109 (99) 120 (99)

400 Rectal dose volume constraints for IMRT

Log rank tests were applied to compare the probability of devel-oping Pgrade 2 late rectal toxicity between categories. Followingvariables were analysed:

– Radiotherapy type i.e. primary versus adjuvant versus salvageradiotherapy

– Radiotherapy prescription i.e. median dose to the PTV of 78 Gy,76 Gy or 74 Gy

– Positioning modality i.e. CBCT versus EPID or ultrasound– Crohn’s disease or colitis– Irritable bowel disease– Diabetes– Nicotine consumption– Haemorrhoids– Previous – non-prostate-related – abdominal surgery– Adjuvant hormonal therapy

The estimated effect of continuous predictors (age, R40, R50,R60, R65, R70, mean rectal dose (V mean) and rectal volume (R vol-ume)) on the probability of developing Pgrade 2 late rectal toxic-ity and the corresponding 95% confidence intervals weredetermined by applying Cox proportional hazards regression(using the PHREG procedure). The same analysis was performedfor volume of the rectum in cc receiving a dose of 40 Gy, 50 Gy,60 Gy, 65 Gy and 70 Gy (V40, V50, V60, V65 and V70 respectively).

In order to derive rectal DVC, rectal dose volume cut-off valuespredictive for developing Pgrade 2 late rectal toxicity were deter-mined. Two cut off values per variable were defined as the valuefor which the estimated probability of being free of Pgrade 2 laterectal toxicity was at least 90% and at least 95%.

Fig. 1. Kaplan Meier curves for Pgrade 2 late rectal toxicity, Pgrade 2 non-RBL symradiotherapy. Abbreviations: RBL, rectal blood loss.

Results

Median follow up of all patients was 60 months (range: 18–168 months).

Patient characteristics and overall incidence of late grade 1–3rectal toxicity per group (primary, adjuvant and salvage radiother-apy) are presented in Tables 1 and 2.

The only grade 3 toxicity that we observed was RBL in 4 andanal pain in 2 patients. Late grade 2 RBL, increased stool frequencyand diarrhoea were recorded in 3% of the patients (n = 17, n = 18and n = 21 respectively). Thirteen (2%) patients experienced lategrade 2 rectal urgency. Ten, 9, 8 and 7 patients had late grade 2 fae-cal incontinence, abdominal cramps, anal pain and mucus loss.Most frequently observed late grade 1 rectal toxicity was rectalurgency (n = 126, 20%), mucus loss (n = 116, 18%) and frequency(n = 109, 17%).

Our main interest was the incidence rate of late Pgrade 2 rectaltoxicity at 60 months. At 60 months, 287 patients are still at risk.For all patients (N = 637) the probability of being free from latePgrade 2 rectal toxicity is 88.8% (95%CI: 85.8–91.1%) at a follow-up time of 60 months resulting in a cumulative percentage of latePgrade 2 rectal toxicity in patients at risk of 11.2% (95% CI: 8.9–14.2%) at 60 months (Fig. 1). At 60 months the probability of beingfree from non-RBL symptoms and persisting symptoms was 93.4%(95% CI: 91.0–95.1%) and 94.3% (95% CI: 92.0–95.9%) respectively.

The results of the risk analysis of developing Pgrade 2 late rectaltoxicity for categorical (log-rank test) and continuous (Cox propor-tional hazard regression model) variables are presented in Supple-mentary Table. In brief, radiotherapy prescription and positioningmodality (p = 0.0086 and 0.0350 respectively, log rank analysis) as

ptoms and Pgrade 2 late persisting symptoms. Time: months after the end of

Table 3Cut-off values for an estimated 95% and 90% probability of being free of late rectalPgrade 2 toxicity. Presentation of the hazard ratios and there 95% CI for an increase of10% of the volume of the rectum irradiated up to a certain dose.

Variable Estimated risk of 65% for developing Pgrade 2 late rectal toxicityat 60 months

Cut-off value 95% confidence interval for the estimated risk

R40 35 1.8–8.2%R50 22 1.9–7.9%R60 14 2.1–7.6%R65 5 1.9–8.1%

Estimated risk of 610% for developing Pgrade 2 late rectal toxicityat 60 months

Cut-off value 95% confidence interval for the estimated risk

R40 64 7.2–12.5%R50 52 6.1–12.5%R60 38 7.2–12.3%R65 29 7.2–12.5%

Hazard ratio for an increase of 10% of the volume of the rectumirradiated

R40 1.28 (95% CI: 1.08–1.51)R50 1.27 (95% CI: 1.1–1.48)R60 1.35 (95% CI: 1.14–1.59)R65 1.35 (95% CI: 1.11–1.64)

V. Fonteyne et al. / Radiotherapy and Oncology 113 (2014) 398–403 401

categorical variables and R40, R50, R60, R65 and R average(p = 0.0041, 0.0015, 0.0004, 0.0027 and 0.0051 respectively, Coxproportional hazard regression model) as continuous variableswere significantly correlated with developing Pgrade 2 late rectaltoxicity. After correcting for R60 (as most predictive volume param-eter), there was no longer a significant effect of radiotherapy pre-scription (P = 0.17) or positioning modality (P = 0.13) on latePgrade 2 rectal toxicity (multiple cox proportional hazardsregression).

To derive rectal DVC for a 5% and 10% estimated risk of develop-ing late Pgrade 2 rectal toxicity at 60 month, cut-off values werecalculated for the different volume parameters that were signifi-cantly correlated with late Pgrade 2 rectal toxicity. The resultsare presented in Table 3.

Most precise estimated risk of developing late Pgrade 2 rectaltoxicity was obtained for the variable R60. R70 was not consideredbecause the effect on developing late Pgrade 2 rectal toxicity wasnot significant.

Discussion

Late rectal toxicity is one of the major concerns after EBRT forPC and has therefore been examined extensively. Despite the mul-tiplicity of data that are available it is, so far, unclear which factorsare and are not responsible for developing severe rectal toxicity.

Conflicting results have been reported regarding the role ofpatient characteristics. According to Huang et al. [8] and Valdagniet al. [6], a history of haemorrhoids was correlated with anincreased risk of developing rectal toxicity. In contrast, based ontoxicity data of 298 patients, Goldner et al. concluded that thereis no evidence to support the hypothesis that patients with endo-scopic findings such as haemorrhoids, present in 35% of theirpatients, are at increased risk of having acute or late rectal toxicity[21]. In this prospective phase II trial a rectoscopy was performedprior to and 1 and 2 years after the end of radiotherapy [21]. Thereported incidence of grade 2 late rectal toxicity, mainly RBL, was17% after a median follow up of 14.5 months [21].

Also the impact of anticoagulants on rectal toxicity is debatable.Choe et al. reported a threefold risk increase of developing grade 3

RBL in patients using anticoagulants [22]. On the contrary, the useof anticoagulants was protective in the Valdagni-nomogram [6].Both studies agreed on the protective effect of androgen depriva-tion on the incidence of rectal toxicity [6,22]. Other factors thathave been suggested to be correlated with rectal toxicity are diabe-tes [6], prior abdominal surgery [23] and inflammatory bowel syn-drome [7]. However, Barnett et al., did not find a significantassociation between late rectal toxicity and either the presenceof diabetes mellitus or prior pelvic surgery [7]. Also in our studynone of the patient characteristics predicted for late Pgrade 2 rec-tal toxicity. However this can be due to a combination of a smallnumber of events and a limited number of patients presenting withexamined comorbidities.

On the other hand, the correlation between rectal dose param-eters and rectal toxicity is well recognized. Several groups haveproposed rectal DVC to reduce the incidence of late rectal toxicity,most particularly RBL. Many of these recommendations are basedon studies in which 3D-CRT was used as a radiation technique[8,9,14,24–26]. For PC it is known that the delivery of higher radio-therapy doses results in better biochemical relapse free survival,decreased local failure, distant metastasis free survival and pros-tate cancer specific mortality [27]. However when using 3D-CRT,increasing the dose to the prostate has led to increased incidenceof late rectal toxicity [1]. In IMRT planning, beams with differentintensity are used, resulting in an inhomogeneous dose distribu-tion. This allows us to deliver high doses at the level of the prostatewhile lowering the dose to the OAR. This has resulted in excellentlong-term results, combining excellent tumour control and lowtoxicity [28].

IMRT shifts away the high dose area from the rectum at the costof an increased volume of the rectum treated to intermediate andlower doses. This is not the case for 3D-CRT. It seems therefore notlogic to use 3D-CRT derived DVC in IMRT planning when DVC fromIMRT studies are available. Moreover, 3D-CRT series focus on thehigh dose region and RBL as the main contributor to rectal toxicity.However other debilitating symptoms such as rectal urgency andfaecal incontinence are mainly correlated with the intermediaterectal dose areas, which are more prominent in IMRT planning[13,14,29]. There is, as Fig. 2A demonstrates, a good correlationbetween our IMRT DVC and the ones derived from 3D-CRT plan-ning (14, 24, 26) when a 10% risk of developing late Pgrade 2 rec-tal toxicity is allowed. On the contrary, when a reduction ofdeveloping late Pgrade 2 rectal toxicity to 65% is the aim, the3D-CRT DVC are not strict enough and could be replaced by theones that we propose.

Based on data coming from 3D-CRT, Swanson et al. [30] andChan et al. [25], proposed more stringent rectal DVC to be imple-mented in IMRT planning. Those DVC are very much in line withour 5% DVC [30] (Fig. 2B).

Although there is evidence, coming from dosimetric studies,that IMRT is superior to 3D-CRT in reducing exposure of the rectumand bladder from high dose areas without hampering the dose tothe prostate, further research is required to demonstrate that thisdosimetric advantage translates into improved clinical outcome[31]. Moreover, based on the results presented in Table 3 one canconclude that, although there is a higher risk for developingPgrade 2 late rectal toxicity by increasing the rectal dose for a cer-tain level of dose, this, rather small risk, has to be weighted againsta potential risk of creating an underdosage of the prostate. Theimplementation of the proposed rectal DVC should therefore beevaluated prospectively to prove the safety of it.

Another issue of debate is the delineation of the rectum: bothdelineating the rectum as a total volume (including its content)and delineating only the rectal wall (excluding its content) areused. Our DVC are derived from ‘‘rectal wall only’’ delineations,yet they are quite similar to those derived from studies delineating

Fig. 2. Rectal dose volume constraints (DVC). Rectal DVC comparing our DVC proposal (95% and 90% probability of being free from late rectal Pgrade 2 toxicity) with DVCfrom studies implementing DVC based on 3D-CRT data (2A), DVC for IMRT proposed by others (2B), DVC defined on rectum volume in toto (2C) and DVC defined on rectal wallvolume. Abbreviation: GUH: Ghent University Hospital.

402 Rectal dose volume constraints for IMRT

the rectum as a total volume (Fig. 2C and D) [8–10,13–15,25,26]. Apossible explanation might be the application of a strict protocol toobtain an empty rectum on planning’s CT. Consequently the vol-ume difference between rectal volume in toto or rectal wall is lesspronounced and might even become negligible. The importance ofan empty rectum both on the toxicity profile as well as clinical out-come has been reported [32,33].

In an attempt to decrease the incidence of rectal toxicity fur-ther, studies have been initiated to evaluate the advantages ofusing endorectal balloons during radiotherapy in controlling rectalfilling and prostate motion [34,35]. Unfortunately, the endorectalballoon itself can alter the shape of the prostate resulting in aninferior PTV coverage [36]. A further reduction in rectal toxicitymight be expected from the application of rectal spacers. Smallstudies have proven the stability and safety of using these rectalspacers [37,38]. Longer follow up is however warranted beforedrawing conclusions regarding long-term toxicity.

Caution is needed when interpreting our data, as the reportedincidence of toxicity is not based on patients’ self-assessments. Ithas been proven that physicians often underreport patient’s symp-toms [39].

Strengths of our study are: the large patient cohort size (morethan 600 patients) and long median follow up of 5 years. Many otherstudies evaluated rectal toxicity after a median follow up of630 months [9,12,13,40]. Although severe rectal toxicity is mostprominent within the first 3 years after EBRT, the follow up of thesestudies might not be long enough to draw conclusions as was sug-gested by the recent data from the prospective AIROPROS 0102study. The updated results revealed that, after a median follow upof 7 years, the clinical factors that predicted for rectal blood loss at3 years were no longer significant with longer follow up [29].

In our analysis the rectal toxicity data of patients treated in theprimary and postoperative setting were pooled since there was no

significant difference in late Pgrade 2 rectal toxicity betweenthese groups. The proposed rectal DVC can consequently also beapplied in the planning of PC patients after radical prostatectomy.So far doses up to 60–66 Gy are delivered in the postoperative set-ting, however there is evidence that the same dose response rela-tionship is present for postoperative radiotherapy as it is forprimary radiotherapy [41]. IMRT is a safe way to deliver thesehigher doses [42,43].

In conclusion, our results confirm that the implementation ofpreviously reported rectal DVC in the treatment planning of PCpatients is safe making high dose IMRT for prostate cancer well tol-erated. Since IMRT gives a different dose distribution when com-pared to 3D-CRT, stricter DVC can be applied to reduce evenfurther the incidence Pgrade 2 late rectal toxicity.

All examined rectal volume parameters, except for R70, werecorrelated with Pgrade 2 late rectal toxicity, with R60 being mostpredictive. New rectal DVC were proposed for IMRT planning of PCpatients. A prospective evaluation is needed to prove the safety ofthese DVC.

There was no correlation between patient characteristics andPgrade 2 late rectal toxicity.

Conflict of interest

None declared.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.radonc.2014.10.014

V. Fonteyne et al. / Radiotherapy and Oncology 113 (2014) 398–403 403

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