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Comparison of rectal volume definition techniques and their influence on rectal toxicity in patients with prostate cancer treated with 3D conformal radiotherapy: a dose-volume analysis

Comparison of rectal volume definition techniques and their influence on rectal toxicity in... Background: To evaluate the impact of four different rectum contouring techniques and rectal toxicities in patients with treated with 3D conformal radiotherapy (3DCRT). Methods: Clinical and dosimetric data were evaluated for 94 patients who received a total dose 3DCRT of 70 Gy, and rectal doses were compared in four different rectal contouring techniques: the prostate-containing CT sections (method 1); 1 cm above and below the planning target volume (PTV) (method 2); 110 mm starting from the anal verge (method 3); and from the anal verge to the sigmoid flexure (method 4). The percentage of rectal volume receiving RT doses (30–70 Gy) and minimum, mean rectal doses were assessed. Results: Median age was 69 years. Percentage of rectal volume receiving high doses (≥ 70 Gy) were higher with the techniques that contoured smaller rectal volumes. In methods 2 and 3, the percentage of rectal volume receiving ≥ 70 Gy was significantly higher in patients with than without rectal bleeding (method 2: 30.8% vs. 22.5%, respectively (p = 0.03); method 3: 26.9% vs. 18.1%, respectively (p = 0.006)). Mean rectal dose was significant predictor of rectal bleeding only in method 3 (48.8 Gy in patients with bleeding vs. 44.4 Gy in patients without bleeding; p = 0.02). Conclusion: Different techniques of rectal contouring significantly influence the calculation of radiation doses to the rectum and the prediction of rectal toxicity. Rectal volume receiving higher doses (≥ 70 Gy) and mean rectal doses may significantly predict rectal bleeding for techniques contouring larger rectal volumes, as was in method 3. Background Those findings support the suggestion that enhanced sur- Prostate cancer is a radio-responsive tumor with a well- vival rates may be achievable with an improvement in defined dose-response relationship [1,2]. Higher radio- local control. However, the use of higher RT doses is lim- therapy (RT) doses have been associated with better bio- ited by an increased risk of complications in adjacent nor- chemical control rates and fewer distant relapses [1,3]. mal tissues. In this setting, more sophisticated techniques Page 1 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:14 http://www.ro-journal.com/content/4/1/14 such as three dimensional conformal RT (3DCRT), inten- mens were scored with the Gleason grading system. sity modulated RT (IMRT), and tomotherapy allow more According to our current protocol, all patients were precise treatment planning with better sparing of the nor- treated with 3 months of neoadjuvant total androgen mal tissues [4], which yields higher local control with sig- blockage prior to planned irradiation. Baskent Univer- nificant reduction in both acute and late complications[5] sity's Institutional Review Board approved this study Nevertheless, the use of higher RT doses beyond the con- design. ventional doses has been demonstrated to cause a moder- ate increase in the dose-limiting, late rectal toxicity, Treatment Planning mainly manifested by rectal bleeding [6,7]. As part of treatment planning, all patients underwent a CT scan with 2.5-mm slice thickness. During the scan, The major predictor of rectal bleeding is the volume of the patients were in supine with their feet fixed in a commer- rectum included in the high dose region [8,9], and the cially available knee support device, an emptied rectum, correlation between rectal bleeding rates and the irradi- and comfortably full bladder. Patients were asked to ated rectal volume has been well established [9-12]. Fur- empty their rectum before treatment, no enema or other thermore dose-volume histograms (DVH) served as useful laxatives were used before planning CT and during treat- tools in demonstrating this significant relationship. ment. The CTV was defined as the entire prostate and sem- Despite its extreme importance, no universally accepted inal vesicles. A 1-cm margin was added to the CTV to method has been established for rectal contouring in RT define the planning target volume (PTV). The treatment planning for prostatic carcinomas. The length of rectum volume included an additional 0.7-cm margin for beam contoured has been defined in different ways by different penumbra in all directions, except for the posterior mar- authors. Examples of these definitions include: 1 cm gin, which overlaps the rectum; thus, posteriorly, a 0.5-cm above and below the planning target volume margin was added for reducing rectal toxicity. The iso- (PTV)[13,14], the length of the rectum in prostate-con- center was positioned in the center of the PTV and beams taining tomography sections [15], 110 mm of rectum were shaped with multi-leaf collimators (MLC; Varian starting from anal verge [12,16], or the anal verge to the DHX 3323, Varian Medical Systems, Palo Alto, California, rectosigmoid flexure [10,17-19]. USA). One important drawback of using different rectal defini- The exposed rectum was defined in four different ways for tions and contouring methods is the resultant difficulty in all 94 patients as depicted in Table 1. All target and organ interpreting the outcomes of different studies. Thus, we at risk volumes were defined and contoured by the same planned to compare four different rectal volume defini- physician. Intra-observer variability was also assessed on tion techniques and dependent irradiated percent rectal randomly selected 10 sample patients by a blind repeti- volumes on predicting rectal toxicity in patients with tion of rectum contouring on randomly chosen CT scans. localized prostate cancer treated with 3DCRT, which will The mean intra-observer variability was 0.7 mm in the cra- be a guide for evaluating the rectal toxicity wherein the nial and 0.9 mm in the caudal directions, respectively. rectal contouring technique used. All treatments were planned with a six-field technique Methods using a treatment planning system (Eclipse , Varian Med- Patient Data ical Systems, Palo Alto, California, USA). A total of 70 Gy A total of 118patients with histological proof of prostate (2 Gy/fr, daily, Monday through Friday) was delivered adenocarcinoma was treated with 3D-CRT between Janu- using 18-MV photons. Portal images obtained from the ary 2007 and February 2008 in the Department of Radia- anterior set-up and two lateral fields on the first treatment tion Oncology at Baskent University. We analyzed clinical day and once weekly, or more (if necessary), during the RT and dosimetric data of 94 eligible patients. Eligibility cri- period, were used to confirm field verifications by com- teria were as follows: Eastern Cooperative Oncology paring them with digitally reconstructed radiographs. The Group performance status (PS) of 0 to 2; age between 18 portal images were reviewed by the treating physician. and 70 years; non-prostatectomised; no prior chemother- apy or abdominal irradiation; no distant metastasis; no Table 1: Rectum contouring techniques contraindication for RT. Invariably, all eligible patients Methods Techniques were treated with the same technique and the same doses, and any deviations from either the technique or dose were 1 All prostate-containing CT sections reasons for exclusion from the study. The clinical and 2 1 cm above and below PTV-containing sections dosimetric records of patients with stage T1c-T3 (Ameri- 3 110 mm of rectum starting from the anal verge can Joint Committee on Cancer, 1997 staging system) 4 Anal verge to the sigmoid flexure prostate cancer were used in this analysis. Prostate speci- Page 2 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:14 http://www.ro-journal.com/content/4/1/14 DVH Analysis were compared for both dosimetric assessment and their The dose distribution of each plan for each patient's rec- predictive value on rectal toxicity. The Fisher's exact test tum was established and the doses were re-calculated for was used to compare qualitative variables and the Stu- the different rectal volumes lengths. The DVHs created for dent's t means comparison test was used for continuous each patient and methods were used to perform inter- variables. The median values of these differences were method comparisons. Our analysis included the percent compared using the Wilcoxon signed rank test to evaluate volume of rectum irradiated with certain dose levels (30 if they were significantly different from zero. A p ≤ 0.05 to 70 Gy, in 10 Gy increments) evident on DVHs created (two-sided) was considered significant for all statistical for each method, and their possible predictive role on rec- tests. tal toxicity incidence and severity. All doses represent total doses that have not been corrected for fractionation. Results Total 94 of 118 eligible patients were evaluated. 26 Toxicity Score patients were excluded from the study, because, 16 Side effects manifested within 90 days from the initiation patients were treated after radical prostatectomy, 6 of RT were considered "acute", and "late" those manifest patients were treated with pelvic box technique because of thereafter. Rectal toxicities were graded according to the lymph node metastasis, and 2 patients did not finish the Radiation Therapy Oncology Group (RTOG) toxicity sheduled treatment (1 with myocardial infarction, 1 with scores [20]. The rectal toxicity grades are: grade 1 = minor no reason). The patient and disease characteristics are symptoms requiring no treatment; grade 2 = symptoms summarized in Table 2. All 94 patients were eligible for that respond to simple management; grade 3 = distressing toxicity analysis and no patient was lost to follow-up; the symptoms affecting lifestyle and necessitating hospital median follow-up interval was 13.1 months (range: 3– admission; grade 4 = symptoms necessitating a major sur- 21.6 months). The treatment protocol was well tolerated gical procedure (laparatomy, colostomy, long stay in hos- in general with no report of grade 4 or 5 acute or late tox- pital); and grade 5 = death. Grades 1 and 2 rectal bleeding icity. Sixteen patients (17%) completed the treatment is defined as incidental or intermittent bleeding requiring without any significant complications. Rectal toxicities of no treatment or responding to simple outpatient manage- grade 1 to 3 were reported in 34 (36%), 36 (38%), and 8 ment, respectively; grade 3 rectal bleeding is defined as (9%) patients, respectively. Rectal bleeding was reported bleeding that requires a blood transfusion or laser cauter- in 13 (14%) patients, and were graded as grade 2 in 12 ization. (13%), and grade 3 in the remaining 1 (1%). This latter th patient was presented at the 9 month after 3DCRT and During the RT course, all eligible patients were evaluated fared well following two courses of laser cauterization. on the same day of the week for toxicity scoring, unless a patient required more frequent visits. In the medical The median prostate and seminal vesicle volumes were 38 3 3 3 records, the type of toxicity and its grade, the time of cm (range: 18–111.7 cm ) and 13 cm (range: 4.8–28.8 occurrence, as well as the prescribed medications and cm ), respectively. The median prostate, seminal vesicle, doses were systematically reported. and PTV doses were 69.7 Gy (range: 68.5 – 71.3 Gy), 69.8 Follow-up Table 2: Patient characteristics. The length of follow-up was calculated from the first date of 3DCRT. According to the medical records, follow-up Patients visits included a thorough physical examination, serum total and free prostate specific antigen (PSA), and testo- Age (years) Median 69 sterone levels, complete blood count and serum biochem- Range 48–82 istry, and pelvic MRI every 6 months. At each visit, Pretreatment PSA n (%) detailed genitourinary and gastrointestinal system toxici- ≤ 10 ng/mL 37 (39) ties were assessed. The patients were first seen 6 weeks > 10 ng/mL 57 (61) after the completion of RT and every 3 months or more Gleason score n (%) frequently, if necessary, thereafter. 6 55 (59) 7 30 (32) 83 (3) Statistical Analysis 96 (6) The dosimetric variables considered were rectal volume, Stage n (%) maximum and mean dose to the rectal volume (Dmax T1 12 (13) and Dmean, respectively), and volumes (percentage and T2 63 (67) absolute) of rectum receiving 30 Gy, 40 Gy, 50 Gy, 60 Gy, T3 19 (20) and 70 Gy. For each patient and each technique, DVHs Page 3 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:14 http://www.ro-journal.com/content/4/1/14 Gy (range: 68.4 – 72.0 Gy), and 70.0 Gy (range: 68.7 – umes those received ≥ 70 Gy were 30.8% and 22.5% for 71.5 Gy), respectively. patients with and without rectal bleeding (p = 0.03), respectively. Similarly in method 3, the percentage of rec- Table 3 shows the median rectum volumes using the dif- tal volume that received ≥ 70 Gy was 26.9% and 18.1% in ferent contouring techniques. As expected, compared to patients with and without bleeding (p = 0.006). The mean methods 1 and 2, relatively larger rectum volumes were rectal dose was found to be a significant predictor of rectal contoured in methods 3 and 4. Table 4 shows the compar- bleeding only in method 3; mean rectal doses were 48.8 ison of rectum minimum, maximum and mean doses and Gy and 44.4 Gy for patients with and without bleeding (p percentage of rectal volumes receiving different doses = 0.02). No significant correlation was found for low or based on these different techniques. The mean rectal moderate dose levels. doses and percentage of rectal volumes receiving different dose levels were higher with contouring techniques that Discussion resulted in small rectal volumes (method 1) than with In this study, four different rectum contouring techniques contouring techniques that resulted in average and large were assessed, and the impact of the contouring tech- rectal volumes (method 3). Thus, for example, the mean niques on DVH and acute rectal toxicity and rectal bleed- rectum dose and V70 were higher in method 1 (57.5 Gy ing was evaluated. We clearly demonstrated that mean and 32.9%, respectively) than in method 3 (49.6 Gy and rectal dose and rectal volume receiving a high dose (≥ 70 24.3%, respectively). Gy) are the most important predictive factors for acute rec- tal toxicity and rectal bleeding, and varies according to rec- The comparison of rectal minimum and mean doses, V30, tal contpuring techniques. This significance was assessed V40, V50, V60 and V70 Gy revealed significantly higher in this study with different rectum contouring techniques, doses for method 1 compared to the other methods; the and especially the method 3 revealed a significant correla- lowest mean rectal doses and percentage of rectal volumes tion. at different dose levels were obtained with the technique used in method 3. The minimum and mean rectal doses The primary aim of 3D-CRT in prostate carcinoma is to significantly differed in each method. Similarly, statisti- maximize the therapeutic ratio to deliver an effective dose cally significant differences were established for the per- to the tumor while maintaining an acceptable dose to the centage of rectum volumes receiving 30 Gy, 40 Gy, 50 Gy, neighboring normal tissues. In this manner, better control 60 Gy, and 70 Gy, respectively. of the local tumor and reduction of distant metastatic rates can be achieved by escalating the dose beyond that Acute rectal toxicity was closely associated with the mean of conventional doses without additional toxicities rectum doses and V30 Gy, V40 Gy, V50 Gy, V60 Gy and [9,21,22]. However, toxicities such as late rectal bleeding, V70 Gy points for all contouring techniques. As shown in which is one of the dose-limiting complications, may pre- Table 5 mean rectal doses and V70 Gy were significantly vent escalation of the dose and therefore adversely affect higher in patients with Grade 2 or more rectal toxicity treatment outcomes. The volume of the rectum included compared to patients with or without Grade 1 rectal tox- in the high dose region is the major determinant for pre- icity. The mean rectal dose in patients with Grade 2 or dicting late rectal bleeding. In recent years a number of more rectal toxicity was lowest in method 3 (52.4 Gy) and studies evaluated the relationship between rectal toxicity highest in method 1(61.0 Gy). Likewise V70 Gy values and rectal irradiation, and for this purpose rectal DVHs, were higher in methods 1 and 2 (42.3% and 37.3%) com- dose wall histograms (DWHs), and dose surface histo- pared to methods 3 and 4 (32.5% and 33.4%), respec- grams (DSHs) have been used. However, the definitions tively. of the affected rectum varied widely among the research- ers [10,12-14,16-19,23], and no universally accepted, When rectal bleeding was evaluated Wilcoxon test conclusive result has been obtained with respect to revealed that, in method 2, the percentage of rectal vol- whether DVH, DSH, or DWH is the best predictor of rectal complications, including late rectal bleeding. Nor has such a result been obtained to determine which length of Table 3: The Median Rectum Volumes the contoured rectum provides the best predictor of com- Methods Volume in cm (min-max) plications. In this current study, we compared mean rectal doses and percentage of rectal volumes receiving particu- Rectum lar doses (30–70 Gy) via DVHs in most commonly used 1 43.6 (22.0–147.3) four rectal contouring techniques to an effort to deter- 2 54.7 (29.8–161.4) mine the best contouring technique for prediction of rec- 3 63.0 (36.5–175.3) tal toxicity. 4 60.5 (30.5–176.2) Page 4 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:14 http://www.ro-journal.com/content/4/1/14 Table 4: Median Dose-Volume Histogram and Dose-Wall Histogram data for the patients treated with 3DCRT. Method 1 Method 2 Method 3 Method 4 p Min dose (Gy) 8.2 3.2 1.5 1.9 0.01 Mean dose (Gy) 57.5 54.0 49.6 51.1 <0.001 Max dose (Gy) 75.1 75.1 75.1 75.1 NS V30 Gy (%) 86.7 84.5 80.6 82.1 <0.001 V40 Gy (%) 78.1 73.3 68.6 70.7 <0.001 V50 Gy (%) 70.9 64.2 55.3 59.8 <0.001 V60 Gy (%) 55.6 48.4 41.7 45.1 <0.001 V70 Gy (%) 32.9 27.9 24.3 26.5 <0.001 The use of different rectal contouring techniques with dif- regardless of contouring techniques (Table 5). Also a sig- ferent rectal lengths and volumes yield various radiation nificant correlation was found between rectal bleeding doses, which may result in a variety of toxicity probabili- and rectal volume receiving ≥ 70 Gy for rectum contoured ties. This issue has been addressed by various authors. in methods 2 and 3. One of the most important predictors of acute rectal tox- icity and rectal bleeding is the rectal volume receiving a The mean rectal dose is another dosimetric factor that pre- high dose (60–80 Gy) [19,24,25]. Koper et al. found that dicts rectal morbidity. Zapatero et al. demonstrated that the risk of rectal bleeding increased from 10% to 63% the mean rectal dose and V60 Gy were closely correlated when the irradiated rectal volume increased from 25% to with grade 2 or worse rectal bleeding in 107 patients with 100% [17]. In that study, the rectum was contoured from prostate cancer treated with 3DCRT [25]. They found that the anal verge proximally to the sacroiliac joint. Michalski patients with rectal bleeding had a mean rectal dose of 57 et al., in the preliminary report of toxicity from an inter- Gy compared with 46 Gy for those without bleeding (p < group trial, observed that the relative risk of developing 0.0005). The rectum was contoured over 150 mm, from late gastrointestinal system toxicity was two-fold greater if the anus (at the level of the ischial tuberosities) to where the total rectal volume receiving radiation dose exceeded the rectosigmoid flexure could be identified. In the cur- 100 cm ; the rectum was contoured as a solid organ rent study, we found a statistically significant correlation extending from the anus to the rectosigmoid flexure [21]. between rectal bleeding and mean rectal doses only when In a randomized trial, Pollack et al. reported a significant the rectum was contoured over 110 mm starting from the increase in rectal toxicity in patients treated with 78 Gy anus (method 3: 48.8 Gy for patients with rectal bleeding compared to 70 Gy [16]. The DVH calculations were per- and 44.4 Gy for patients without rectal bleeding (p = formed with respect to the rectal volumes within a 11-cm 0.02)). The fact that this correlation was significant only cranio-caudal segment, with no specification as to in method 3 may be due to the fact that this technique whether the rectal contents were included. The authors contours larger rectal volumes than the other techniques demonstrated that the 5-year risk of grade ≥ 2 rectal toxic- that we used. The rectum contoured in the study of Zapa- ity was 37% in patients with > 25% of the rectum receiv- tero et al. was even longer and the rectal volume larger ing ≥ 70 Gy compared to 13% for patients with < 25% of compared to those in method 3 of our study. Thus, mean the rectum receiving ≥ 70 Gy. In addition, all grade 3 com- rectal doses may significantly predict rectal bleeding for plications occurred when V70 exceeded 30% of the rectal techniques contouring larger rectal volumes. volume [9]. In this current study, we clearly demonstrated that all grade ≥ 2 acute rectal toxicities were seen in In one of the first studies that evaluated the rectal contour- patients with > 30% of the rectum receiving ≥ 70 Gy ing problem, Geinitz et al. concluded that a uniform def- inition of the rectal volume should be established to Table 5: Mean rectal doses and percentage of rectal volume achieve equivalent DVH results [26]. Boehmer et al. com- receiving 70 Gy (V70 Gy) values according to acute rectal pared two different rectal contouring techniques: one toxicity grade groups. technique included the rectum bounded by two CT slices above and below the PTV; the other technique included Mean Rectal Dose (Gy) V70 Gy (%) the rectum from the anal verge to the sigmoid colon [27]. Grade Grade p Grade Grade p Furthermore, the posterior half of the rectum was con- 0–1 ≥ 2 0–1 ≥ 2 toured for both volumes. The first technique resulted in Method 1 53,4 61,0 < 0.001 27,2 42,3 < 0.001 significantly higher minimum and mean rectal doses than Method 2 49,8 58,4 < 0.001 23,0 37,3 < 0.001 did the second technique. The authors concluded that dif- Method 3 44,5 52,4 < 0.001 19,8 32,5 < 0.001 ferent ways of rectal contouring significantly influence cal- Method 4 46,1 54,7 < 0.001 20,7 33,4 < 0.001 culated doses to the rectum. In another study, Liu et al. Page 5 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:14 http://www.ro-journal.com/content/4/1/14 compared 6 different ways of contouring the rectum in 10 touring of the target volume and organs at risk; ET and MY patients with prostate cancer treated with a four-field box- collected the samples; AY gave advise on the work and technique with a total dose of 70 Gy. They concluded that helped in the interpretation of the data; EE and SS made absolute rectal wall volume, in addition to percent rectal the treatment planning; CO wrote the paper together with volume, should be used in analyzing late rectal toxicity ET. [24]. Acknowledgements This study was accepted as oral presentation at 7th Congress of Balkan Our study also demonstrates that the rectal DVHs vary Union of Oncology from 15 to 19 October 2008. considerably with different rectum delineation tech- niques. 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Fiorino C, Vavassori V, Sanguineti G, Bianchi C, Cattaneo GM, Piaz- zolla A, Cozzarini C: Rectum contouring variability in patients treated for prostate cancer: impact on rectum dose-volume histograms and normal tissue complication probability. Radi- other Oncol 2002, 63:249-255. 24. Liu M, Berthelet E, Patterson K, Dick K, Kwan W: Various tech- niques of contouring the rectum and their impact on rectal dose-volume histograms. Med Dosim 2003, 28:189-192. 25. Zapatero A, Garcia-Vicente F, Modolell I, Alcantara P, Floriano A, Cruz-Conde A, Torres JJ, Perez-Torrubia A: Impact of mean rec- tal dose on late rectal bleeding after conformal radiotherapy for prostate cancer: dose-volume effect. Int J Radiat Oncol Biol Phys 2004, 59:1343-1351. 26. Geinitz H, Zimmermann FB, Narkwong L, Kneschaurek P, Wehrmann R, Kuzmany A, Molls M: [Prostatic carcinoma: problems in the interpretation of rectal dose-volume histograms]. Strahlen- ther Onkol 2000, 176:168-172. 27. Boehmer D, Kuczer D, Badakhshi H, Stiefel S, Kuschke W, Wernecke KD, Budach V: Influence of organ at risk definition on rectal dose-volume histograms in patients with prostate cancer undergoing external-beam radiotherapy. Strahlenther Onkol 2006, 182:277-282. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Comparison of rectal volume definition techniques and their influence on rectal toxicity in patients with prostate cancer treated with 3D conformal radiotherapy: a dose-volume analysis

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Springer Journals
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Copyright © 2009 by Onal et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
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10.1186/1748-717X-4-14
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19432953
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Abstract

Background: To evaluate the impact of four different rectum contouring techniques and rectal toxicities in patients with treated with 3D conformal radiotherapy (3DCRT). Methods: Clinical and dosimetric data were evaluated for 94 patients who received a total dose 3DCRT of 70 Gy, and rectal doses were compared in four different rectal contouring techniques: the prostate-containing CT sections (method 1); 1 cm above and below the planning target volume (PTV) (method 2); 110 mm starting from the anal verge (method 3); and from the anal verge to the sigmoid flexure (method 4). The percentage of rectal volume receiving RT doses (30–70 Gy) and minimum, mean rectal doses were assessed. Results: Median age was 69 years. Percentage of rectal volume receiving high doses (≥ 70 Gy) were higher with the techniques that contoured smaller rectal volumes. In methods 2 and 3, the percentage of rectal volume receiving ≥ 70 Gy was significantly higher in patients with than without rectal bleeding (method 2: 30.8% vs. 22.5%, respectively (p = 0.03); method 3: 26.9% vs. 18.1%, respectively (p = 0.006)). Mean rectal dose was significant predictor of rectal bleeding only in method 3 (48.8 Gy in patients with bleeding vs. 44.4 Gy in patients without bleeding; p = 0.02). Conclusion: Different techniques of rectal contouring significantly influence the calculation of radiation doses to the rectum and the prediction of rectal toxicity. Rectal volume receiving higher doses (≥ 70 Gy) and mean rectal doses may significantly predict rectal bleeding for techniques contouring larger rectal volumes, as was in method 3. Background Those findings support the suggestion that enhanced sur- Prostate cancer is a radio-responsive tumor with a well- vival rates may be achievable with an improvement in defined dose-response relationship [1,2]. Higher radio- local control. However, the use of higher RT doses is lim- therapy (RT) doses have been associated with better bio- ited by an increased risk of complications in adjacent nor- chemical control rates and fewer distant relapses [1,3]. mal tissues. In this setting, more sophisticated techniques Page 1 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:14 http://www.ro-journal.com/content/4/1/14 such as three dimensional conformal RT (3DCRT), inten- mens were scored with the Gleason grading system. sity modulated RT (IMRT), and tomotherapy allow more According to our current protocol, all patients were precise treatment planning with better sparing of the nor- treated with 3 months of neoadjuvant total androgen mal tissues [4], which yields higher local control with sig- blockage prior to planned irradiation. Baskent Univer- nificant reduction in both acute and late complications[5] sity's Institutional Review Board approved this study Nevertheless, the use of higher RT doses beyond the con- design. ventional doses has been demonstrated to cause a moder- ate increase in the dose-limiting, late rectal toxicity, Treatment Planning mainly manifested by rectal bleeding [6,7]. As part of treatment planning, all patients underwent a CT scan with 2.5-mm slice thickness. During the scan, The major predictor of rectal bleeding is the volume of the patients were in supine with their feet fixed in a commer- rectum included in the high dose region [8,9], and the cially available knee support device, an emptied rectum, correlation between rectal bleeding rates and the irradi- and comfortably full bladder. Patients were asked to ated rectal volume has been well established [9-12]. Fur- empty their rectum before treatment, no enema or other thermore dose-volume histograms (DVH) served as useful laxatives were used before planning CT and during treat- tools in demonstrating this significant relationship. ment. The CTV was defined as the entire prostate and sem- Despite its extreme importance, no universally accepted inal vesicles. A 1-cm margin was added to the CTV to method has been established for rectal contouring in RT define the planning target volume (PTV). The treatment planning for prostatic carcinomas. The length of rectum volume included an additional 0.7-cm margin for beam contoured has been defined in different ways by different penumbra in all directions, except for the posterior mar- authors. Examples of these definitions include: 1 cm gin, which overlaps the rectum; thus, posteriorly, a 0.5-cm above and below the planning target volume margin was added for reducing rectal toxicity. The iso- (PTV)[13,14], the length of the rectum in prostate-con- center was positioned in the center of the PTV and beams taining tomography sections [15], 110 mm of rectum were shaped with multi-leaf collimators (MLC; Varian starting from anal verge [12,16], or the anal verge to the DHX 3323, Varian Medical Systems, Palo Alto, California, rectosigmoid flexure [10,17-19]. USA). One important drawback of using different rectal defini- The exposed rectum was defined in four different ways for tions and contouring methods is the resultant difficulty in all 94 patients as depicted in Table 1. All target and organ interpreting the outcomes of different studies. Thus, we at risk volumes were defined and contoured by the same planned to compare four different rectal volume defini- physician. Intra-observer variability was also assessed on tion techniques and dependent irradiated percent rectal randomly selected 10 sample patients by a blind repeti- volumes on predicting rectal toxicity in patients with tion of rectum contouring on randomly chosen CT scans. localized prostate cancer treated with 3DCRT, which will The mean intra-observer variability was 0.7 mm in the cra- be a guide for evaluating the rectal toxicity wherein the nial and 0.9 mm in the caudal directions, respectively. rectal contouring technique used. All treatments were planned with a six-field technique Methods using a treatment planning system (Eclipse , Varian Med- Patient Data ical Systems, Palo Alto, California, USA). A total of 70 Gy A total of 118patients with histological proof of prostate (2 Gy/fr, daily, Monday through Friday) was delivered adenocarcinoma was treated with 3D-CRT between Janu- using 18-MV photons. Portal images obtained from the ary 2007 and February 2008 in the Department of Radia- anterior set-up and two lateral fields on the first treatment tion Oncology at Baskent University. We analyzed clinical day and once weekly, or more (if necessary), during the RT and dosimetric data of 94 eligible patients. Eligibility cri- period, were used to confirm field verifications by com- teria were as follows: Eastern Cooperative Oncology paring them with digitally reconstructed radiographs. The Group performance status (PS) of 0 to 2; age between 18 portal images were reviewed by the treating physician. and 70 years; non-prostatectomised; no prior chemother- apy or abdominal irradiation; no distant metastasis; no Table 1: Rectum contouring techniques contraindication for RT. Invariably, all eligible patients Methods Techniques were treated with the same technique and the same doses, and any deviations from either the technique or dose were 1 All prostate-containing CT sections reasons for exclusion from the study. The clinical and 2 1 cm above and below PTV-containing sections dosimetric records of patients with stage T1c-T3 (Ameri- 3 110 mm of rectum starting from the anal verge can Joint Committee on Cancer, 1997 staging system) 4 Anal verge to the sigmoid flexure prostate cancer were used in this analysis. Prostate speci- Page 2 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:14 http://www.ro-journal.com/content/4/1/14 DVH Analysis were compared for both dosimetric assessment and their The dose distribution of each plan for each patient's rec- predictive value on rectal toxicity. The Fisher's exact test tum was established and the doses were re-calculated for was used to compare qualitative variables and the Stu- the different rectal volumes lengths. The DVHs created for dent's t means comparison test was used for continuous each patient and methods were used to perform inter- variables. The median values of these differences were method comparisons. Our analysis included the percent compared using the Wilcoxon signed rank test to evaluate volume of rectum irradiated with certain dose levels (30 if they were significantly different from zero. A p ≤ 0.05 to 70 Gy, in 10 Gy increments) evident on DVHs created (two-sided) was considered significant for all statistical for each method, and their possible predictive role on rec- tests. tal toxicity incidence and severity. All doses represent total doses that have not been corrected for fractionation. Results Total 94 of 118 eligible patients were evaluated. 26 Toxicity Score patients were excluded from the study, because, 16 Side effects manifested within 90 days from the initiation patients were treated after radical prostatectomy, 6 of RT were considered "acute", and "late" those manifest patients were treated with pelvic box technique because of thereafter. Rectal toxicities were graded according to the lymph node metastasis, and 2 patients did not finish the Radiation Therapy Oncology Group (RTOG) toxicity sheduled treatment (1 with myocardial infarction, 1 with scores [20]. The rectal toxicity grades are: grade 1 = minor no reason). The patient and disease characteristics are symptoms requiring no treatment; grade 2 = symptoms summarized in Table 2. All 94 patients were eligible for that respond to simple management; grade 3 = distressing toxicity analysis and no patient was lost to follow-up; the symptoms affecting lifestyle and necessitating hospital median follow-up interval was 13.1 months (range: 3– admission; grade 4 = symptoms necessitating a major sur- 21.6 months). The treatment protocol was well tolerated gical procedure (laparatomy, colostomy, long stay in hos- in general with no report of grade 4 or 5 acute or late tox- pital); and grade 5 = death. Grades 1 and 2 rectal bleeding icity. Sixteen patients (17%) completed the treatment is defined as incidental or intermittent bleeding requiring without any significant complications. Rectal toxicities of no treatment or responding to simple outpatient manage- grade 1 to 3 were reported in 34 (36%), 36 (38%), and 8 ment, respectively; grade 3 rectal bleeding is defined as (9%) patients, respectively. Rectal bleeding was reported bleeding that requires a blood transfusion or laser cauter- in 13 (14%) patients, and were graded as grade 2 in 12 ization. (13%), and grade 3 in the remaining 1 (1%). This latter th patient was presented at the 9 month after 3DCRT and During the RT course, all eligible patients were evaluated fared well following two courses of laser cauterization. on the same day of the week for toxicity scoring, unless a patient required more frequent visits. In the medical The median prostate and seminal vesicle volumes were 38 3 3 3 records, the type of toxicity and its grade, the time of cm (range: 18–111.7 cm ) and 13 cm (range: 4.8–28.8 occurrence, as well as the prescribed medications and cm ), respectively. The median prostate, seminal vesicle, doses were systematically reported. and PTV doses were 69.7 Gy (range: 68.5 – 71.3 Gy), 69.8 Follow-up Table 2: Patient characteristics. The length of follow-up was calculated from the first date of 3DCRT. According to the medical records, follow-up Patients visits included a thorough physical examination, serum total and free prostate specific antigen (PSA), and testo- Age (years) Median 69 sterone levels, complete blood count and serum biochem- Range 48–82 istry, and pelvic MRI every 6 months. At each visit, Pretreatment PSA n (%) detailed genitourinary and gastrointestinal system toxici- ≤ 10 ng/mL 37 (39) ties were assessed. The patients were first seen 6 weeks > 10 ng/mL 57 (61) after the completion of RT and every 3 months or more Gleason score n (%) frequently, if necessary, thereafter. 6 55 (59) 7 30 (32) 83 (3) Statistical Analysis 96 (6) The dosimetric variables considered were rectal volume, Stage n (%) maximum and mean dose to the rectal volume (Dmax T1 12 (13) and Dmean, respectively), and volumes (percentage and T2 63 (67) absolute) of rectum receiving 30 Gy, 40 Gy, 50 Gy, 60 Gy, T3 19 (20) and 70 Gy. For each patient and each technique, DVHs Page 3 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:14 http://www.ro-journal.com/content/4/1/14 Gy (range: 68.4 – 72.0 Gy), and 70.0 Gy (range: 68.7 – umes those received ≥ 70 Gy were 30.8% and 22.5% for 71.5 Gy), respectively. patients with and without rectal bleeding (p = 0.03), respectively. Similarly in method 3, the percentage of rec- Table 3 shows the median rectum volumes using the dif- tal volume that received ≥ 70 Gy was 26.9% and 18.1% in ferent contouring techniques. As expected, compared to patients with and without bleeding (p = 0.006). The mean methods 1 and 2, relatively larger rectum volumes were rectal dose was found to be a significant predictor of rectal contoured in methods 3 and 4. Table 4 shows the compar- bleeding only in method 3; mean rectal doses were 48.8 ison of rectum minimum, maximum and mean doses and Gy and 44.4 Gy for patients with and without bleeding (p percentage of rectal volumes receiving different doses = 0.02). No significant correlation was found for low or based on these different techniques. The mean rectal moderate dose levels. doses and percentage of rectal volumes receiving different dose levels were higher with contouring techniques that Discussion resulted in small rectal volumes (method 1) than with In this study, four different rectum contouring techniques contouring techniques that resulted in average and large were assessed, and the impact of the contouring tech- rectal volumes (method 3). Thus, for example, the mean niques on DVH and acute rectal toxicity and rectal bleed- rectum dose and V70 were higher in method 1 (57.5 Gy ing was evaluated. We clearly demonstrated that mean and 32.9%, respectively) than in method 3 (49.6 Gy and rectal dose and rectal volume receiving a high dose (≥ 70 24.3%, respectively). Gy) are the most important predictive factors for acute rec- tal toxicity and rectal bleeding, and varies according to rec- The comparison of rectal minimum and mean doses, V30, tal contpuring techniques. This significance was assessed V40, V50, V60 and V70 Gy revealed significantly higher in this study with different rectum contouring techniques, doses for method 1 compared to the other methods; the and especially the method 3 revealed a significant correla- lowest mean rectal doses and percentage of rectal volumes tion. at different dose levels were obtained with the technique used in method 3. The minimum and mean rectal doses The primary aim of 3D-CRT in prostate carcinoma is to significantly differed in each method. Similarly, statisti- maximize the therapeutic ratio to deliver an effective dose cally significant differences were established for the per- to the tumor while maintaining an acceptable dose to the centage of rectum volumes receiving 30 Gy, 40 Gy, 50 Gy, neighboring normal tissues. In this manner, better control 60 Gy, and 70 Gy, respectively. of the local tumor and reduction of distant metastatic rates can be achieved by escalating the dose beyond that Acute rectal toxicity was closely associated with the mean of conventional doses without additional toxicities rectum doses and V30 Gy, V40 Gy, V50 Gy, V60 Gy and [9,21,22]. However, toxicities such as late rectal bleeding, V70 Gy points for all contouring techniques. As shown in which is one of the dose-limiting complications, may pre- Table 5 mean rectal doses and V70 Gy were significantly vent escalation of the dose and therefore adversely affect higher in patients with Grade 2 or more rectal toxicity treatment outcomes. The volume of the rectum included compared to patients with or without Grade 1 rectal tox- in the high dose region is the major determinant for pre- icity. The mean rectal dose in patients with Grade 2 or dicting late rectal bleeding. In recent years a number of more rectal toxicity was lowest in method 3 (52.4 Gy) and studies evaluated the relationship between rectal toxicity highest in method 1(61.0 Gy). Likewise V70 Gy values and rectal irradiation, and for this purpose rectal DVHs, were higher in methods 1 and 2 (42.3% and 37.3%) com- dose wall histograms (DWHs), and dose surface histo- pared to methods 3 and 4 (32.5% and 33.4%), respec- grams (DSHs) have been used. However, the definitions tively. of the affected rectum varied widely among the research- ers [10,12-14,16-19,23], and no universally accepted, When rectal bleeding was evaluated Wilcoxon test conclusive result has been obtained with respect to revealed that, in method 2, the percentage of rectal vol- whether DVH, DSH, or DWH is the best predictor of rectal complications, including late rectal bleeding. Nor has such a result been obtained to determine which length of Table 3: The Median Rectum Volumes the contoured rectum provides the best predictor of com- Methods Volume in cm (min-max) plications. In this current study, we compared mean rectal doses and percentage of rectal volumes receiving particu- Rectum lar doses (30–70 Gy) via DVHs in most commonly used 1 43.6 (22.0–147.3) four rectal contouring techniques to an effort to deter- 2 54.7 (29.8–161.4) mine the best contouring technique for prediction of rec- 3 63.0 (36.5–175.3) tal toxicity. 4 60.5 (30.5–176.2) Page 4 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:14 http://www.ro-journal.com/content/4/1/14 Table 4: Median Dose-Volume Histogram and Dose-Wall Histogram data for the patients treated with 3DCRT. Method 1 Method 2 Method 3 Method 4 p Min dose (Gy) 8.2 3.2 1.5 1.9 0.01 Mean dose (Gy) 57.5 54.0 49.6 51.1 <0.001 Max dose (Gy) 75.1 75.1 75.1 75.1 NS V30 Gy (%) 86.7 84.5 80.6 82.1 <0.001 V40 Gy (%) 78.1 73.3 68.6 70.7 <0.001 V50 Gy (%) 70.9 64.2 55.3 59.8 <0.001 V60 Gy (%) 55.6 48.4 41.7 45.1 <0.001 V70 Gy (%) 32.9 27.9 24.3 26.5 <0.001 The use of different rectal contouring techniques with dif- regardless of contouring techniques (Table 5). Also a sig- ferent rectal lengths and volumes yield various radiation nificant correlation was found between rectal bleeding doses, which may result in a variety of toxicity probabili- and rectal volume receiving ≥ 70 Gy for rectum contoured ties. This issue has been addressed by various authors. in methods 2 and 3. One of the most important predictors of acute rectal tox- icity and rectal bleeding is the rectal volume receiving a The mean rectal dose is another dosimetric factor that pre- high dose (60–80 Gy) [19,24,25]. Koper et al. found that dicts rectal morbidity. Zapatero et al. demonstrated that the risk of rectal bleeding increased from 10% to 63% the mean rectal dose and V60 Gy were closely correlated when the irradiated rectal volume increased from 25% to with grade 2 or worse rectal bleeding in 107 patients with 100% [17]. In that study, the rectum was contoured from prostate cancer treated with 3DCRT [25]. They found that the anal verge proximally to the sacroiliac joint. Michalski patients with rectal bleeding had a mean rectal dose of 57 et al., in the preliminary report of toxicity from an inter- Gy compared with 46 Gy for those without bleeding (p < group trial, observed that the relative risk of developing 0.0005). The rectum was contoured over 150 mm, from late gastrointestinal system toxicity was two-fold greater if the anus (at the level of the ischial tuberosities) to where the total rectal volume receiving radiation dose exceeded the rectosigmoid flexure could be identified. In the cur- 100 cm ; the rectum was contoured as a solid organ rent study, we found a statistically significant correlation extending from the anus to the rectosigmoid flexure [21]. between rectal bleeding and mean rectal doses only when In a randomized trial, Pollack et al. reported a significant the rectum was contoured over 110 mm starting from the increase in rectal toxicity in patients treated with 78 Gy anus (method 3: 48.8 Gy for patients with rectal bleeding compared to 70 Gy [16]. The DVH calculations were per- and 44.4 Gy for patients without rectal bleeding (p = formed with respect to the rectal volumes within a 11-cm 0.02)). The fact that this correlation was significant only cranio-caudal segment, with no specification as to in method 3 may be due to the fact that this technique whether the rectal contents were included. The authors contours larger rectal volumes than the other techniques demonstrated that the 5-year risk of grade ≥ 2 rectal toxic- that we used. The rectum contoured in the study of Zapa- ity was 37% in patients with > 25% of the rectum receiv- tero et al. was even longer and the rectal volume larger ing ≥ 70 Gy compared to 13% for patients with < 25% of compared to those in method 3 of our study. Thus, mean the rectum receiving ≥ 70 Gy. In addition, all grade 3 com- rectal doses may significantly predict rectal bleeding for plications occurred when V70 exceeded 30% of the rectal techniques contouring larger rectal volumes. volume [9]. In this current study, we clearly demonstrated that all grade ≥ 2 acute rectal toxicities were seen in In one of the first studies that evaluated the rectal contour- patients with > 30% of the rectum receiving ≥ 70 Gy ing problem, Geinitz et al. concluded that a uniform def- inition of the rectal volume should be established to Table 5: Mean rectal doses and percentage of rectal volume achieve equivalent DVH results [26]. Boehmer et al. com- receiving 70 Gy (V70 Gy) values according to acute rectal pared two different rectal contouring techniques: one toxicity grade groups. technique included the rectum bounded by two CT slices above and below the PTV; the other technique included Mean Rectal Dose (Gy) V70 Gy (%) the rectum from the anal verge to the sigmoid colon [27]. Grade Grade p Grade Grade p Furthermore, the posterior half of the rectum was con- 0–1 ≥ 2 0–1 ≥ 2 toured for both volumes. The first technique resulted in Method 1 53,4 61,0 < 0.001 27,2 42,3 < 0.001 significantly higher minimum and mean rectal doses than Method 2 49,8 58,4 < 0.001 23,0 37,3 < 0.001 did the second technique. The authors concluded that dif- Method 3 44,5 52,4 < 0.001 19,8 32,5 < 0.001 ferent ways of rectal contouring significantly influence cal- Method 4 46,1 54,7 < 0.001 20,7 33,4 < 0.001 culated doses to the rectum. In another study, Liu et al. Page 5 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:14 http://www.ro-journal.com/content/4/1/14 compared 6 different ways of contouring the rectum in 10 touring of the target volume and organs at risk; ET and MY patients with prostate cancer treated with a four-field box- collected the samples; AY gave advise on the work and technique with a total dose of 70 Gy. They concluded that helped in the interpretation of the data; EE and SS made absolute rectal wall volume, in addition to percent rectal the treatment planning; CO wrote the paper together with volume, should be used in analyzing late rectal toxicity ET. [24]. Acknowledgements This study was accepted as oral presentation at 7th Congress of Balkan Our study also demonstrates that the rectal DVHs vary Union of Oncology from 15 to 19 October 2008. considerably with different rectum delineation tech- niques. The rectum contoured in all prostate-containing References CT sections (method 1) had the largest percentage of rec- 1. Hanks GE, Hanlon AL, Epstein B, Horwitz EM: Dose response in tum receiving a specific radiation dose, since less rectum prostate cancer with 8–12 years' follow-up. Int J Radiat Oncol volume was contoured. Any contouring techniques that Biol Phys 2002, 54:427-435. 2. Zelefsky MJ, Yamada Y, Fuks Z, Zhang Z, Hunt M, Cahlon O, Park J, use a longer length of the rectum will result in a smaller Shippy A: Long-term results of conformal radiotherapy for percentage of the contoured rectum receiving the radia- prostate cancer: impact of dose escalation on biochemical tumor control and distant metastases-free survival out- tion dose. Thus, the technique that contoured a 110-mm comes. Int J Radiat Oncol Biol Phys 2008, 71:1028-1033. rectal segment from the anal verge (method 3) resulted in 3. Nutting CM, Corbishley CM, Sanchez-Nieto B, Cosgrove VP, Webb lower radiation doses than the techniques that contoured S, Dearnaley DP: Potential improvements in the therapeutic ratio of prostate cancer irradiation: dose escalation of path- shorter segments and smaller rectal volumes. This is due ologically identified tumour nodules using intensity modu- to the fact that the absolute volume of rectum receiving a lated radiotherapy. Br J Radiol 2002, 75:151-161. 4. O'Donnell HE, Finnegan K, Eliades H, Oliveros S, Plowman PN: Re- specific dose remains constant while the percentage of rec- defining rectal volume and DVH for analysis of rectal mor- tal volume receiving a specific dose becomes reduced if bidity risk after radiotherapy for early prostate cancer. Br J the total volume contoured is larger. Therefore, with dif- Radiol 2008, 81:327-332. 5. 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Huang EH, Pollack A, Levy L, Starkschall G, Dong L, Rosen I, Kuban DA: Late rectal toxicity: dose-volume effects of conformal Competing interests radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2002, 54:1314-1321. We have no personal or financial conflict of interest and 13. Beckendorf V, Guerif S, Le Prise E, Cosset JM, Lefloch O, Chauvet B, have not entered into any agreement that could interfere Salem N, Chapet O, Bourdin S, Bachaud JM, Maingon P, Lagrange JL, with our access to the data on the research, or upon our Malissard L, Simon JM, Pommier P, Hay MH, Dubray B, Luporsi E, Bey P: The GETUG 70 Gy vs. 80 Gy randomized trial for localized ability to analyze the data independently, to prepare man- prostate cancer: feasibility and acute toxicity. Int J Radiat Oncol uscripts, and to publish them. Biol Phys 2004, 60:1056-1065. 14. 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Boehmer D, Kuczer D, Badakhshi H, Stiefel S, Kuschke W, Wernecke KD, Budach V: Influence of organ at risk definition on rectal dose-volume histograms in patients with prostate cancer undergoing external-beam radiotherapy. Strahlenther Onkol 2006, 182:277-282. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes)

Journal

Radiation Oncology – Springer Journals

Published: May 11, 2009

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