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Intensity modulated radiation therapy (IMRT): differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma

Intensity modulated radiation therapy (IMRT): differences in target volumes and improvement in... Background: A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT), to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT) in standard, preoperative treatment for rectal cancer. Methods: Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1) or node-positive (N = 9), and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters. Results: IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy : 56.8% IMRT versus 75.4% 3DCRT; p = 0.005), pelvic bones (V : 47.0% IMRT 3DCRT; p = 0.005), bladder (V 40Gy 40Gy versus 56.9% 3DCRT; p = 0.005), and femoral heads (V : 3.4% IMRT versus 9.1% 3DCRT; p = 0.005), with an 40Gy improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V : 138-cc IMRT versus 157-cc 3DCRT; p = 0.005). We found that the IMRT treatment 15Gy volumes were typically larger than that covered by classic bony landmark-derived fields, without incurring penalty with respect to adjacent organs-at-risk. Conclusions: For rectal carcinoma, IMRT, compared to 3DCRT, yielded plans superior with respect to target coverage, homogeneity, and conformality, while lowering dose to adjacent organs-at-risk. This is achieved despite treating larger volumes, raising the possibility of a clinically-relevant improvement in the therapeutic ratio through the use of IMRT with a belly-board apparatus. * Correspondence: prajdas@mdanderson.org Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA Full list of author information is available at the end of the article © 2011 Mok et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mok et al. Radiation Oncology 2011, 6:63 Page 2 of 9 http://www.ro-journal.com/content/6/1/63 reduction in small bowel mean dose using IMRT, with Background evidence of sparing at high- and low- dose levels on a Although surgery is necessary to achieve long-term cure case-by-case basis [8]. In one of the largest series to for locally-advanced rectal cancer, randomized data has date, Arbea and colleagues evaluated plans generated demonstrated the role for adjuvant therapy in this dis- from 15 patients, and found using IMRT a significant ease. The use of adjuvant radiation has been shown to reduction of dose to small bowel in the range of 40-Gy significantly reduce the rate of local failure [1], with and higher; relationships at the intermediate- and low- further improvement achieved with its concurrent dose levels were not explicitly reported [17]. Further- administration with chemotherapy [2,3]. Moreover, more, the use of preoperative IMRT with concurrent Sauer and colleagues, demonstrated that preoperative capecitabine and oxaliplatin is currently under investiga- chemoradiation was superior with respect to the rates of tion in the recently completed phase II protocol, RTOG local recurrence and sphincter preservation compared to 0822 [18]. postoperative therapy [4]. The recently published Therefore, the aim of our study is to further elucidate NSABP R-03 trial demonstrated a significant improve- the potential role for IMRT in the management of ment in 5-year disease-free survival with preoperative locally-advanced carcinoma of the rectum with respect therapy, and a trend toward improved overall survival at to minimizing dose to relevant normal tissue structures 5-years [5]. including the bladder, bones, and bowel, through direct The safe, effective, and tolerable administration of pre- dosimetric comparisons with 3DCRT techniques. operative chemoradiation in rectal cancer is not without challenge, owing in part to the irradiation of a large Methods volume at risk for microscopic disease spread, with Patients potential toxicity to nearby bowel, bladder, and bones. Ten patients recently treated preoperatively for adenocar- Indeed, acute grade 3 or higher gastrointestinal toxicity cinoma of the rectum at the University of Texas M.D. in the form of severe diarrhea was reported to be 12% Anderson Cancer Center were identified. These patients by Sauer and colleagues [4], with modern series report- were representative of the breadth of disease typically ing rates as high as 29%[6]. Additionally, a strong dose- encountered at this institution for preoperative chemora- volume relationship between the amount small bowel diotherapy. Six patients were male, and four were female. receiving intermediate- and low-doses of radiation and All ten patients had clinical T3 disease. One patient was the rates of severe diarrhea has been demonstrated, par- clinically node-negative, while nine were clinically node- ticularly at the 15-Gy dose level [7-10]. Higher rates of acute severe toxicity may potentially lead to breaks in positive. No patient had evidence of distant metastasis. treatment or mitigate compliance, which may confer All patients received concurrent fluoropyrimidine-based chemotherapy, typically with capecitabine. untoward consequences with respect to local control or survival [11]. 3-field belly board plans Techniques have been utilized with the aim to reduce All patients were simulated and received treatment in the volume of small bowel irradiated, such as the use of the prone position using a carbon-fiber belly board prone positioning with a belly-board apparatus to apparatus (CIVCO Medical Systems, #125012) to achieve bowel displacement away from the field [12]. achieve displacement of abdominal contents, which is Additionally, there has been interest in the application the current standard practice at our institution. Com- of highly conformal treatment approaches, such as puted tomography (CT) simulation was used in all intensity-modulated radiation therapy (IMRT). Whole- patients. No specific bladder filling instructions were pelvis IMRT has been applied to gynecologic malig- given to patients. No bowel contrast agent was used at nancy, with less toxicity than traditional 3D conformal the time of simulation. The plans used clinically [hence- radiation therapy (3DCRT)[13]. In anal cancer, IMRT forth: 3-field belly board (3FBB)] consisted of a primary has been compared to 3DCRT, showing similar target treatment to a prescribed dose of 45-Gy using a 3-field coverage with reduced dose to the genitals, femoral approach (PA and opposed laterals with wedges), typi- heads, small bowel, and iliac crest [14,15]. In compari- cally without the use of any field-in-field optimization, son, the data for IMRT in rectal cancer are relatively followed by a localized boost for an additional 5.4-Gy sparse. Guerrero Urbano and colleagues compared using opposed lateral fields, using exclusively 18-MV IMRT with 3DCRT in five patients, and found small photons and 1.8-Gy daily fractions. The intended tar- bowel sparing with IMRT only at the 40-Gy level and geted tissues included the gross tumor and nodal dis- higher [16]. Tho and colleagues selected eight patients with the greatest volumes of small bowel irradiated from ease, which were contoured based on the CT simulation theircohortofpatients,andobservedanoverall scan, mesorectum, and the internal iliac and presacral Mok et al. Radiation Oncology 2011, 6:63 Page 3 of 9 http://www.ro-journal.com/content/6/1/63 lymph nodes. Classic anatomical field borders were Radiotherapy planning employed, with the superior field border at L5/S1, and All plans were generated using the Pinnacle version inferior border at the level of the ischial tuberosities or 8.0 m treatment planning system (Philips Healthcare), 3-cm below the caudal-most extent of the tumor. For using MLC-equipped megavoltage linear accelerator the PA field, the lateral field borders were placed 2-cm delivery. For the 3DCRT and IMRT plans, the original CT simulation datasets from each patient were restored, beyond the pelvic inlet. For the lateral fields, the ante- and contoured as delineated above. For the 3DCRT rior border was 3-cm anterior to the sacral promontory, plans, the field borders were modified from the 3FBB and the posterior border was placed sufficient to expose plans with the goal of covering greater than 95% of the a 1-cm margin on the posterior sacral bony contour. Multileaf collimator (MLC) blocking was utilized to PTV volume with the prescription dose, which was pre- block normal tissues outside of the intended targeted scribed to the isocenter or a calculation point, and tissues. For the purposes of this study, given a lack of renormalized based on PTV coverage. Additional field- consensus with regard to delineation of boost volumes in-fields were utilized in all cases for homogeneity con- for rectal cancer [19], only the 45-Gy primary fields trol, to limit hotspots to 107% of the prescription dose, were evaluated. particularly to anterior, bowel-containing regions. 18-MV photons were used for all 3DCRT plans. Target volumes and dose prescription for 3DCRT and IMRT treatment plans were generated with respect to IMRT planning delivery using only 6-MV photons via linear accelerators An IMRT plan as well as a 3DCRT plan designed to equipped with Millennium 120 MLC (Varian Medical cover the PTV (henceforth: 3DCRT) were generated for Systems). Several beam arrangements were tested, with each patient from the initial CT simulation scan data. optimal results achieved using a 7-beam arrangement All cases were contoured by a single physician, and sub- with the following gantry angles: 0°, 40°, 70°, 95°, 265°, sequently reviewed by an attending physician. Delinea- 290°, and 320°. The collimator was set to 90°, with a tion of the clinical target volume (CTV) included the total of 70 control points allocated to all beams. Direct gross tumor and involved lymph nodes, mesorectum, machine parameter optimization (DMPO) was used, and at the discretion of the optimization algorithm, fields presacral and internal iliac lymph node regions, with were split for all beam angles. In terms of general plan- appropriate margin, as described in the RTOG consen- ning strategy, highest priority was given to PTV cover- sus contouring atlas for anorectal cancer [19]. CTV to age, then to minimizing dose to small bowel. Of planning target volume (PTV) expansions of 7-mm were intermediate priority were reducing dose to the pelvic applied. bones, bladder, and normal tissues outside the con- As noted above, the total prescription dose used in this study was limited to 45-Gy in 1.8-Gy daily fractions, toured regions; no specific optimization for sigmoid/ without further boost. colon volume was performed, but instead a general anterior abdominal contents avoidance structure was Organs at risk (OAR) used. Lowest effort was applied to minimizing dose to The relevant OAR volumes for this study were the blad- the femoral head/neck. Collapsed-cone (CC) convolu- der, femoral heads/necks, pelvic bones, small bowel, sig- tion methods were employed for final dose calculations. moid/colon, and normal tissues. The bladder was The final IMRT plans were independently reviewed and contoured according to the CT simulation scan. The deemed clinically acceptable by both a gastrointestinal femoral heads/necks contours consisted of the bilateral clinical physicist and radiation oncologist. femoral heads and necks to the level of the lesser tro- chanter. The pelvic bones contours were defined as the Plan evaluation and statistical tools exterior of the bony table from top of the iliac crests to Evaluated volumes included the PTV and relevant nor- the ischial tuberosities. Differentiation of small bowel mal tissue volumes. The PTV, bladder, pelvic bones, from sigmoid and colon was aided through correlation femoral heads/necks, and small bowel were reported as with the diagnostic, contrast-enhanced CT study closest whole volumes. The sigmoid/colon and normal tissue in time to the date of simulation. The small bowel and were reported exclusive of any overlapping/encompassed sigmoid/colon volumes consisted of individual loops of PTV. bowel, contoured up to 2-cm above the superior-most Dosimetric parameters were calculated using tabular cumulative dose volume histogram (DVH) data, set to a PTV slice. The normal tissues contours were defined by bin size of 1-cGy, with median values reported. By con- the external contour, extending to 2-cm above and vention, D = dose received by X% of the volume of below the superior- and inferior-most PTV slices, X% interest, and V = percent volume of interest respectively. XGy Mok et al. Radiation Oncology 2011, 6:63 Page 4 of 9 http://www.ro-journal.com/content/6/1/63 receiving at least a dose of X Gy. Maximum dose was Dose to organs at risk and normal tissues expressed as D , minimum dose as D , mean dose as With respect to mean dose, IMRT compared to 3FBB 1% 99% D , and maximum point dose as D . The homoge- showed little difference for the bladder, femoral heads, mean max neity index (HI) and conformality index (CI) were calcu- sigmoid, and small bowel. However, compared to lated for the 3DCRT and IMRT plans. HI was expressed 3DCRT, IMRT resulted in significantly lower mean dose to the bladder (p = 0.007), sigmoid (p = 0.005), small as (D -D ) / prescription dose. CI was expressed as 5% 95% bowel (p = 0.005), and to the femoral heads (p = 0.03). the ratio of the absolute volume receiving the prescrip- Mean dose to the pelvic bones was significantly lower tion dose to the volume of the target, V /V . 45Gy PTV with IMRT compared with either 3FBB (p = 0.04) or Plan average cumulative DVH values were calculated by exporting tabular DVH data set to a bin size of 3DCRT (p = 0.005). 10-cGy, and were plotted. For the small bowel, a curve With respect to high dose, IMRT significantly based on the absolute volume irradiated was also gener- improved the V to the femoral heads (p = 0.01) and 40Gy ated. Integral dose to all tissues (including PTV) was pelvic bones (p = 0.005) compared to 3FBB, and to the calculated from the differential DVH data set to 10-cGy bladder (p = 0.005), femoral heads (p = 0.005), and pel- bin size. vic bones (p = 0.005) in comparison to 3DCRT. For the For statistical analysis, each patient’sIMRTplanwas dose to sigmoid/colon, IMRT was comparable to 3FBB compared in a pairwise manner with both the 3FBB and at all dose levels evaluated, but was significantly lower 3DCRT plans, respectively. Non-parametric statistical compared to 3DCRT (p = 0.005). analyses were performed using the paired, two-tailed Volumetric evaluation of total small bowel was per- Wilcoxon signed-rank test, with p-value < 0.05 taken to formed at dose levels ranging from 5- to 45-Gy. When be significant. IMRT was compared to 3FBB, the V was signifi- 15Gy cantly reduced with IMRT (p = 0.03), but similar at Results other doses. IMRT compared to 3DCRT showed signifi- Dose to target volumes cant reductions in the volumes of small bowel irradiated When comparing the 3FBB treatment volumes to the at levels ranging from 15- to 45-Gy (p < 0.01). With contoured volumes based on RTOG consensus guide- respect to V , the magnitude of the difference in 15Gy lines, it was evident that the contoured PTV encom- median volumes was modest (138-cc IMRT versus 157- cc 3DCRT; p = 0.005) when evaluating the ten patients passed a typically larger volume than that treated in the as a whole. However, the most profound bowel sparing 3FBB plans. This was most pronounced superiorly, but was evident in the subset of patients with the largest was also seen in the extent of the PTV anterior to the volume of small bowel in proximity to the treatment sacral promontory, and occasionally in the inferior extent of the field. Indeed, dosimetric comparisons field. For example, in the 6 patients with the highest between 3FBB and IMRT plans, as shown in Table 1, volume of small bowel (range: 209 - 537-cc), the volume revealed that the percentage of the PTV receiving the of bowel receiving 15-Gy was reduced from a median of prescription dose was significantly lower for the 3FBB 231-cc in the 3DCRT plans to 185-cc with IMRT. Con- plans than with IMRT (V : median 3FBB 87.2% ver- versely, in the remaining four patients, only a slight 45Gy sus IMRT 99.5%; p = 0.005). Therefore, a 3DCRT plan absolute reduction was evident (median V : 13-cc 15Gy was generated in each case using techniques described IMRT versus 22-cc 3DCRT). in the methods to adequately cover the PTV. This was Normal tissues outside the target were evaluated, and quite effective, as the 3DCRT V was increased to a IMRT plans had a significantly higher mean dose (p = 45Gy median of 98.4%, though still statistically inferior com- 0.02) and V (p = 0.01) to V (p < 0.02) in com- 10Gy 30Gy pared with IMRT (p = 0.02). Mean doses were similar parison to the 3FBB plans. However, at the highest between the 3DCRT and IMRT plans (p = 0.46). doses, IMRT was significantly lower (V , p = 0.02; 40Gy With respect to target coverage, the minimum dose to V , p < 0.01). IMRT, compared to 3DCRT, had a sig- 45Gy the PTV, D , was higher with IMRT compared to the nificantly lower mean dose (p = 0.007), V (p = 40Gy 99% 3FBB (p = 0.005) and 3DCRT (p = 0.01) plans. Maximum 0.005) and V (p = 0.005), with more modest, but 45Gy dose to the PTV, D , was significantly lower with IMRT significant, differences at V (p = 0.005) and V 1% 10Gy 20Gy in comparison to 3FBB (p = 0.007); results were similar (p = 0.01). between IMRT and 3DCRT (p = 0.35). Both the homoge- Averaged cumulative DVH plots for organs-at-risk and normal tissues are depicted in Figure 1. Representa- neity and conformality indices were significantly better tive axial slices showing isodose distributions for an with IMRT compared to 3DCRT (p = 0.007 and p = 0.005, IMRT and a 3DCRT plan for one patient are shown in respectively). Graphically, these findings are reflected in Figure 2. the averaged cumulative DVH plot (Figure 1A). Mok et al. Radiation Oncology 2011, 6:63 Page 5 of 9 http://www.ro-journal.com/content/6/1/63 Table 1 Dosimetric comparison of IMRT with 3DCRT: median value (range) Volume Parameter IMRT 3FBB 3DCRT PTV D (Gy) 46.6 (46.4 - 46.9) 46.0 (45.6 - 47.0)* 46.6 (46.3 - 48.3) mean 1547 cm V 99.5% (98.7% - 99.8%) 87.2% (80.0% - 93.4%)† 98.4% (97.7% - 99.6%)* 45Gy (1459 - D (Gy) 45.3 (44.8 - 45.8) 35.2 (10.7 - 40.3)† 44.9 (44.2 - 45.2)* 99% 1968 cm)D (Gy) 47.6 (47.2 - 47.9) 48.3 (47.7 - 50.5)† 47.5 (47.1 - 48.2) 1% HI 3.2% (2.5% - 3.6%) N/A 4.2% (3.0% - 5.3%)† CI 1.16 (1.09 - 1.23) N/A 1.35 (1.27 - 1.38)† Bladder D (Gy) 38.6 (31.1 - 42.4) 37.9 (27.5 - 44.2) 41.8 (31.0 - 45.0)† mean 72 cm V 74.7% (40.8% - 90.0%) 72.6% (36.7% -96.6%) 85.8% (47.2% - 100%)† 30Gy (32-652 cm)V 56.8% (26.2% - 76.6%) 58.5% (27.6% - 84.0%) 75.4% (38.0% - 100%)† 40Gy Femoral heads D (Gy) 27.1 (20.8 - 29.6) 24.9 (22.4 - 30.7) 28.5 (21.9 - 31.8)* mean 211 cm V 28.0% (17.8% - 44.2%) 22.6% (12.0% - 33.3%) 31.9% (13.2% - 57.4%) 30Gy (151-393 cm)V 3.4% (1.1% - 7.0%) 6.3% (1.9% - 13.2%)* 9.1% (3.5% - 14.6%)† 40Gy Pelvic bones D (Gy) 34.2 (30.5 - 36.2) 34.7 (31.9 - 36.8)* 36.7 (32.3 - 38.4)† mean 914 cm V 69.8% (55.6% - 76.3%) 66.7% (61.8% - 72.3%) 74.9% (63.4% - 81.0%) 30Gy (725-1338 cm)V 47.0% (35.2% - 52.8%) 53.9% (46.5% - 59.2%)† 56.9% (41.3% - 63.6%)† 40Gy Sigmoid/Colon D (Gy) 18.9 (10.4 - 27.9) 17.5 (9.8 - 23.6) 25.5 (13.7 - 31.1)† mean outside PTV V 41.6% (13.2% - 72.6%) 38.0% (11.5% - 54.0%) 60.6% (24.9% - 75.2%)† 20Gy 162 cm V 17.6% (5.1% - 48.1%) 10.4% (3.0% - 36.9%) 36.9% (10.8% - 63.2%)† 30Gy (23 - 389 cm)V 4.0% (0.7% - 19.2%) 2.4% (0.4% - 30.3%) 18.3% (5.1% - 38.5%)† 40Gy Small bowel D (Gy) 18.6 (11.2 - 34.0) 21.0 (8.6 - 34.2) 25.2 (15.9 - 40.0)† mean 251 cm V (cc) 224 (2.5 - 526) 225 (2.2 - 525) 234 (2.5 - 530) 5Gy (3 - 537 cm)V (cc) 138 (0.1 - 257) 144 (0.4 - 413)* 157 (2.2 - 428)† 15Gy V (cc) 81 (0.0 - 142) 79 (0.0 - 149) 123 (0.5 - 183)† 25Gy V (cc) 45 (0.0 - 111) 50 (0.0 - 118) 76 (0.0 - 156)† 40Gy V (cc) 37 (0.0 - 100) 33 (0.0 - 74) 53 (0.0 - 121)† 45Gy Normal tissues D (Gy) 19.5 (12.0 - 21.6) 17.5 (12.8 - 20.6)* 20.5 (17.4 - 22.4)† mean 3 3 10.3*10 cm V 69.5% (58.0% - 76.9%) 64.9% (53.3% - 75.6%)* 73.8% (62.2% - 80.7%)† 10Gy (7.7*10-V 48.3% (39.5% - 52.7%) 42.0% (32.6% - 52.7%)* 50.5% (40.0% - 58.3%)* 20Gy 3 3 18.9*10 cm)V 20.3% (16.5% - 27.4%) 17.3% (12.6% - 20.2%)* 23.5% (16.8% - 27.8%) 30Gy V 6.7% (4.0% - 9.2%) 8.3% (4.2% - 10.9%)* 11.0% (6.7% - 15.7%)† 40Gy V 2.3% (1.2% - 5.1%) 4.4% (2.1% - 6.0%)† 5.2% (2.8% - 6.4%)† 45Gy Abbreviations: PTV = planning target volume; IMRT = intensity modulated radiation therapy; 3FBB = 3 field belly board; 3DCRT = 3 dimensional conformal radiation therapy; HI = homogeneity index; CI = conformality index; for definitions of dosimetric parameters, refer to text; denotes statistically significant difference with IMRT as comparator, p < 0.05 (*) or p < 0.01 (†); otherwise, not statistically significant. Plan summary characteristics 3DCRT plans targeting the PTV. This was not at the Monitor units were significantly higher with IMRT com- expense of adjacent organs-at-risk, as some measure of pared to either 3FBB (p = 0.005) or 3DCRT (p = 0.005) sparing was evident for all organs-at-risk evaluated: small (Table 2). The overall plan maximum doses were similar bowel, sigmoid, pelvic bones, bladder, and femoral heads between IMRT and 3FBB, but higher with IMRT com- (IMRT versus 3DCRT). In this comparison, IMRT actu- pared to 3DCRT (p = 0.005). Integral dose, calculated ally decreased the overall integral dose to all tissues, and for all tissues including the target volume, was signifi- achieved lower mean doses to normal tissues outside the cantly higher for IMRT compared to 3FBB (p = 0.007), PTV, which was evident especially in the high dose but lower compared to 3DCRT (p = 0.007). range. As expected, IMRT required significantly more monitor units per fraction, compared to 3DCRT. Discussion We found quite interesting the discrepancy between the In this study, we found that the application of IMRT for size of the volumes encompassed by the PTV, which were rectal cancer gave excellent results in comparison to generated according to the RTOG consensus contouring non-IMRT based approaches. With respect to the PTV, atlas [19], and the volumes treated according to classic we found that IMRT plans achieved superior coverage, anatomic landmarks (3FBB), even considering the antici- homogeneity, and conformality in treating the gross dis- pated patient-to-patient anatomical variation. This was ease and at-risk pelvic nodal volume, in comparison to reflected in the significantly lower proportion of the PTV Mok et al. Radiation Oncology 2011, 6:63 Page 6 of 9 http://www.ro-journal.com/content/6/1/63 Figure 1 Averaged cumulative dose-volume histograms. Averaged cumulative dose-volume histograms for (A) PTV, (B) bladder, (C) femoral heads and necks, (D) pelvic bones, (E) sigmoid outside of PTV, (F) small bowel (relative), (G) small bowel (volumetric), and (H) normal tissues outside PTV, for IMRT, 3FBB, and 3DCRT. volume receiving the prescription dose in the 3FBB plans, irradiated had similar mean doses, and the absolute and to a certain extent the significantly lower overall inte- volumes irradiated were similar from the 5- to 45-Gy gral dose, compared to IMRT. We found that despite the levels, except at 15-Gy, where IMRT was statistically significantly larger volume targeted in the IMRT plans, improved, compared to the 3FBB plans. IMRT achieved either similar or improved dose levels to In terms of acute, severe treatment-related toxicity, all organs-at-risk evaluated. For example, the small bowel diarrhea is the most common, and studies have Mok et al. Radiation Oncology 2011, 6:63 Page 7 of 9 http://www.ro-journal.com/content/6/1/63 Figure 2 Representative axial slices. Representative axial slices showing isodose distributions for two planes for an (A), (C) IMRT and (B), (D) 3DCRT plan. demonstrated a strong dose-volume relationship with as other intermediate dose levels, including the V 20Gy small bowel irradiated [7-10]. Baglan and colleagues and V , with respect to severe diarrhea [9,10]. In our 25Gy demonstrated a strong association between the rate of study, we found IMRT achieved significant sparing in small bowel toxicity and the V level; when the V terms of the mean dose to small bowel and absolute 15Gy 15Gy was below 150-cc, low rates of grade 2 or higher toxicity volumes from V to V , whereas no difference was 15Gy 45Gy were observed, while the majority of patients with V seen at the lowest dose level evaluated, V ,compared 15Gy 5Gy over 300-cc had grade 3 or higher toxicity [7]. Subse- to the 3DCRT plans. This sparing at the V level was 15Gy quent studies by Robertson and colleagues have con- most pronounced in the cases with the highest volumes firmed the significance of the V dose level, as well of small bowel within or nearby the PTV. Therefore, we 15Gy would predict a lower rate of severe, acute gastrointest- inal toxicity in these patients treated with IMRT. Table 2 Plan summary comparison of IMRT and 3DCRT Furthermore, reduction in the small bowel V using 45Gy plans: median value (range) IMRT may lead to lower rates of late gastrointestinal Parameter IMRT 3FBB 3DCRT toxicity [20]. Again, in the comparison between IMRT MU/fraction 786 (730 - 950) 238 (224 - 272)† 242 (232 - 276)† and classic bony landmark-derived 3FBB fields, despite a D (Gy) 48.8 (48.4 - 49.4) 48.8 (48.1 - 51.0) 48.2 (47.8 - 49.2)† max more extensivevolumetreated with IMRT,wewould Integral dose 2.74 (2.39 - 4.03) 2.56 (2.15 - 3.60)† 2.86 (2.49 - 4.12)† predict similar, or based on the V ,possibly 15Gy 3 -5 (Gy*cm *10 ) improved rates of severe, acute gastrointestinal toxicity Abbreviations: MU = monitor units; IMRT = intensity modulated radiation with IMRT compared to 3FBB. therapy; 3FBB = 3 field belly board; 3DCRT = 3 dimensional conformal In the context of other planning studies comparing radiation therapy;denotes statistically significant difference with IMRT as comparator, p < 0.05 (*) or p < 0.01 (†); otherwise, not statistically significant. IMRT with 3DCRT, we feel overall our results are Mok et al. Radiation Oncology 2011, 6:63 Page 8 of 9 http://www.ro-journal.com/content/6/1/63 superior and additive. Prior studies have demonstrated a the use of IMRT does not automatically confer normal reduction in small bowel mean dose [8], or improve- tissue sparing, as an excessively voluminous target ment at the high-dose extreme [16,17], with the use of volume may in fact lead to higher absolute volumes of IMRT. With respect to positioning, while all three stu- normal tissues treated. This reinforces the importance dies employed prone positioning, one achieved immobi- of consensus target delineation to achieve standardiza- lization using a foam cushion [17], whereas two made tion from practice-to-practice. no specific reference to the use of a bowel displacement Due to daily setup uncertainties using the rigid car- bon-fiber belly-board apparatus, for IMRT treatment of device [8,16]. In contrast, using a rigid, carbon-fiber a CTV-to-PTV expansion of 7-mm used in this study, it belly board apparatus, we observed a significant improvement in small bowel dose from 15-Gy through may be worthwhile to consider daily kilovoltage imaging, the 45-Gy level, as well as the mean dose, with IMRT or perhaps modifications such as the incorporation of a compared to 3DCRT plans. Therefore, our study vacuum-cradle device to improve setup reproducibility. demonstrates a further significant interval improvement One potential criticism for intensity modulated treat- in small bowel dose is realized with the use of IMRT in ment approaches is with respect to integral dose, conjunction with the carbon-fiber belly board. An addi- whereby larger volumes of normal tissues are exposed tional strength of our study is that our contoured to lower radiation doses, which may lead to increased volumes conformed to the RTOG consensus guidelines. incidence of second malignancies [21]. In our study, we We chose as a “class-solution” approach to use an found a lower integral dose with IMRT compared to asymmetric, seven-beam arrangement, biased against 3DCRT plans targeting the PTV. However, integral dose anterior-directed beams, thus minimizing beam entry was slightly higher with IMRT than in the classic 3FBB through anterior-lying bowel contents or through the plans. belly-board apparatus. This appeared to take advantage Another potential downside of a static-field intensity of strengths of the 3-field beam arrangement, namely modulated therapy approach is a longer beam-delivery sharp dose falloff in the intermediate- and low-dose time that is required as compared to 3DCRT, with range anteriorly. Indeed, recently-published studies of respect to intrafractional motion. This may be overcome IMRT, using 5- to 9-equispaced beams, have principally using volumetric-modulated arc therapy (VMAT) based demonstrated reduced small bowel mean dose and techniques. V , compared to 3DCRT [8,16,17]. In our study, in 40Gy addition to these findings, we found IMRT capable of Conclusions reducing small bowel volumes receiving potentially toxi- For the adjuvant treatment of rectal carcinoma, IMRT, city-inducing intermediate- and low-dose irradiation, at compared to 3DCRT, yielded plans superior with a statistically-significant level. Concomitantly, IMRT respect to target coverage, homogeneity, and conformal- achieved superior PTV target coverage, homogeneity, ity, while lowering dose to adjacent organs-at-risk. This and conformality, as well as evidence of sparing of all benefit was seen additive to the use of prone-positioning other organs-at-risk evaluated in this study. Again, our on a belly-board apparatus, and with respect to small results support a clear dosimetric advantage for IMRT, bowel toxicity, could potentially be clinically significant. even with the use of prone-positioning on a belly-board apparatus. Author details With respect to the volume of the irradiated target, 1 Department of Radiation Oncology, The University of Texas, M.D. Anderson there are at least two different ways to consider this Cancer Center, Houston, Texas, USA. Department of Medical Dosimetry, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA. issue. In our study, the PTVs, generated with a 7-mm Department of Radiation Physics, The University of Texas, M.D. Anderson expansion, were typically larger than the volume treated Cancer Center, Houston, Texas, USA. using classic 3FBB fields. Given the excellent historical Authors’ contributions results obtained with the classic 3FBB fields, one inter- HM carried out the study conception and design, drafted the manuscript, pretation is that the target volumes, as delineated by the and performed treatment planning. PD carried out the study conception RTOG consensus IMRT contouring atlas for anorectal and design and drafted the manuscript. MBP performed treatment planning. TMB and SB performed physics checks/plan evaluation. Patient accrual and disease, may be more generous than necessary. Alterna- radiation field design were performed by CHC, MED, SK, and PD. CHC tively, as we found that the more comprehensive PTV provided mentorship for this work. All authors read and approved the final target coverage was achieved without increasing dose to manuscript. the organs-at-risk including the small bowel, it is con- Competing interests ceivable that improved efficacy is attainable without The authors declare that they have no competing interests. increasing acute- and long-term toxicities through the Received: 30 November 2010 Accepted: 8 June 2011 use of IMRT. Long-term clinical data would be neces- Published: 8 June 2011 sary to provide evidence for this. As an additional point, Mok et al. Radiation Oncology 2011, 6:63 Page 9 of 9 http://www.ro-journal.com/content/6/1/63 References 18. A Phase II Evaluation of Preoperative Chemoradiotherapy Utilizing 1. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 Intensity Moldulated Radiation Therapy (IMRT) in Combination with patients from 22 randomised trials. Lancet 2001, 358:1291-1304. Capecitabine and Oxaliplatin for Patients with Locally Advanced Rectal 2. Douglass HO Jr, Moertel CG, Mayer RJ, Thomas PR, Lindblad AS, Cancer. [http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx? Mittleman A, Stablein DM, Bruckner HW: Survival after postoperative study=0822]. combination treatment of rectal cancer. N Engl J Med 1986, 19. Myerson RJ, Garofalo MC, El Naqa I, Abrams RA, Apte A, Bosch WR, Das P, 315:1294-1295. Gunderson LL, Hong TS, Kim JJ, et al: Elective clinical target volumes for 3. Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW, conformal therapy in anorectal cancer: a radiation therapy oncology Kubista TP, Poon MA, Meyers WC, Mailliard JA, et al: Effective surgical group consensus panel contouring atlas. Int J Radiat Oncol Biol Phys 2009, adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991, 74:824-830. 324:709-715. 20. Gallagher MJ, Brereton HD, Rostock RA, Zero JM, Zekoski DA, Poyss LF, 4. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Richter MP, Kligerman MM: A prospective study of treatment techniques Martus P, Tschmelitsch J, Hager E, Hess CF, et al: Preoperative versus to minimize the volume of pelvic small bowel with reduction of acute postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004, and late effects associated with pelvic irradiation. Int J Radiat Oncol Biol 351:1731-1740. Phys 1986, 12:1565-1573. 5. Roh MS, Colangelo LH, O’Connell MJ, Yothers G, Deutsch M, Allegra CJ, 21. Hall EJ: Intensity-modulated radiation therapy, protons, and the risk of Kahlenberg MS, Baez-Diaz L, Ursiny CS, Petrelli NJ, Wolmark N: Preoperative second cancers. Int J Radiat Oncol Biol Phys 2006, 65:1-7. multimodality therapy improves disease-free survival in patients with doi:10.1186/1748-717X-6-63 carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009, 27:5124-5130. Cite this article as: Mok et al.: Intensity modulated radiation therapy 6. Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, (IMRT): differences in target volumes and improvement in clinically Pahlman L, Wiig JN, Bystrom P, Bujko K, Glimelius B: Randomized phase III relevant doses to small bowel in rectal carcinoma. Radiation Oncology study comparing preoperative radiotherapy with chemoradiotherapy in 2011 6:63. nonresectable rectal cancer. J Clin Oncol 2008, 26:3687-3694. 7. Baglan KL, Frazier RC, Yan D, Huang RR, Martinez AA, Robertson JM: The dose-volume relationship of acute small bowel toxicity from concurrent 5-FU-based chemotherapy and radiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys 2002, 52:176-183. 8. Tho LM, Glegg M, Paterson J, Yap C, MacLeod A, McCabe M, McDonald AC: Acute small bowel toxicity and preoperative chemoradiotherapy for rectal cancer: investigating dose-volume relationships and role for inverse planning. Int J Radiat Oncol Biol Phys 2006, 66:505-513. 9. Robertson JM, Lockman D, Yan D, Wallace M: The dose-volume relationship of small bowel irradiation and acute grade 3 diarrhea during chemoradiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys 2008, 70:413-418. 10. Robertson JM, Sohn M, Yan D: Predicting grade 3 acute diarrhea during radiation therapy for rectal cancer using a cutoff-dose logistic regression normal tissue complication probability model. Int J Radiat Oncol Biol Phys 77:66-72. 11. Fietkau R, Rodel C, Hohenberger W, Raab R, Hess C, Liersch T, Becker H, Wittekind C, Hutter M, Hager E, et al: Rectal cancer delivery of radiotherapy in adequate time and with adequate dose is influenced by treatment center, treatment schedule, and gender and is prognostic parameter for local control: results of study CAO/ARO/AIO-94. Int J Radiat Oncol Biol Phys 2007, 67:1008-1019. 12. Gunderson LL, Russell AH, Llewellyn HJ, Doppke KP, Tepper JE: Treatment planning for colorectal cancer: radiation and surgical techniques and value of small-bowel films. Int J Radiat Oncol Biol Phys 1985, 11:1379-1393. 13. Mundt AJ, Lujan AE, Rotmensch J, Waggoner SE, Yamada SD, Fleming G, Roeske JC: Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys 2002, 52:1330-1337. 14. Chen YJ, Liu A, Tsai PT, Vora NL, Pezner RD, Schultheiss TE, Wong JY: Organ sparing by conformal avoidance intensity-modulated radiation therapy for anal cancer: dosimetric evaluation of coverage of pelvis and inguinal/femoral nodes. Int J Radiat Oncol Biol Phys 2005, 63:274-281. 15. Menkarios C, Azria D, Laliberte B, Moscardo CL, Gourgou S, Lemanski C, Dubois JB, Ailleres N, Fenoglietto P: Optimal organ-sparing intensity- modulated radiation therapy (IMRT) regimen for the treatment of locally Submit your next manuscript to BioMed Central advanced anal canal carcinoma: a comparison of conventional and IMRT and take full advantage of: plans. Radiat Oncol 2007, 2:41. 16. Guerrero Urbano MT, Henrys AJ, Adams EJ, Norman AR, Bedford JL, • Convenient online submission Harrington KJ, Nutting CM, Dearnaley DP, Tait DM: Intensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces • Thorough peer review volume of bowel treated to high dose levels. Int J Radiat Oncol Biol Phys • No space constraints or color figure charges 2006, 65:907-916. • Immediate publication on acceptance 17. Arbea L, Ramos LI, Martinez-Monge R, Moreno M, Aristu J: Intensity- modulated radiation therapy (IMRT) vs. 3D conformal radiotherapy • Inclusion in PubMed, CAS, Scopus and Google Scholar (3DCRT) in locally advanced rectal cancer (LARC): dosimetric comparison • Research which is freely available for redistribution and clinical implications. Radiat Oncol 5:17. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Intensity modulated radiation therapy (IMRT): differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma

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Springer Journals
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Copyright © 2011 by Mok 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-6-63
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21651775
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Abstract

Background: A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT), to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT) in standard, preoperative treatment for rectal cancer. Methods: Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1) or node-positive (N = 9), and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters. Results: IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy : 56.8% IMRT versus 75.4% 3DCRT; p = 0.005), pelvic bones (V : 47.0% IMRT 3DCRT; p = 0.005), bladder (V 40Gy 40Gy versus 56.9% 3DCRT; p = 0.005), and femoral heads (V : 3.4% IMRT versus 9.1% 3DCRT; p = 0.005), with an 40Gy improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V : 138-cc IMRT versus 157-cc 3DCRT; p = 0.005). We found that the IMRT treatment 15Gy volumes were typically larger than that covered by classic bony landmark-derived fields, without incurring penalty with respect to adjacent organs-at-risk. Conclusions: For rectal carcinoma, IMRT, compared to 3DCRT, yielded plans superior with respect to target coverage, homogeneity, and conformality, while lowering dose to adjacent organs-at-risk. This is achieved despite treating larger volumes, raising the possibility of a clinically-relevant improvement in the therapeutic ratio through the use of IMRT with a belly-board apparatus. * Correspondence: prajdas@mdanderson.org Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA Full list of author information is available at the end of the article © 2011 Mok et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mok et al. Radiation Oncology 2011, 6:63 Page 2 of 9 http://www.ro-journal.com/content/6/1/63 reduction in small bowel mean dose using IMRT, with Background evidence of sparing at high- and low- dose levels on a Although surgery is necessary to achieve long-term cure case-by-case basis [8]. In one of the largest series to for locally-advanced rectal cancer, randomized data has date, Arbea and colleagues evaluated plans generated demonstrated the role for adjuvant therapy in this dis- from 15 patients, and found using IMRT a significant ease. The use of adjuvant radiation has been shown to reduction of dose to small bowel in the range of 40-Gy significantly reduce the rate of local failure [1], with and higher; relationships at the intermediate- and low- further improvement achieved with its concurrent dose levels were not explicitly reported [17]. Further- administration with chemotherapy [2,3]. Moreover, more, the use of preoperative IMRT with concurrent Sauer and colleagues, demonstrated that preoperative capecitabine and oxaliplatin is currently under investiga- chemoradiation was superior with respect to the rates of tion in the recently completed phase II protocol, RTOG local recurrence and sphincter preservation compared to 0822 [18]. postoperative therapy [4]. The recently published Therefore, the aim of our study is to further elucidate NSABP R-03 trial demonstrated a significant improve- the potential role for IMRT in the management of ment in 5-year disease-free survival with preoperative locally-advanced carcinoma of the rectum with respect therapy, and a trend toward improved overall survival at to minimizing dose to relevant normal tissue structures 5-years [5]. including the bladder, bones, and bowel, through direct The safe, effective, and tolerable administration of pre- dosimetric comparisons with 3DCRT techniques. operative chemoradiation in rectal cancer is not without challenge, owing in part to the irradiation of a large Methods volume at risk for microscopic disease spread, with Patients potential toxicity to nearby bowel, bladder, and bones. Ten patients recently treated preoperatively for adenocar- Indeed, acute grade 3 or higher gastrointestinal toxicity cinoma of the rectum at the University of Texas M.D. in the form of severe diarrhea was reported to be 12% Anderson Cancer Center were identified. These patients by Sauer and colleagues [4], with modern series report- were representative of the breadth of disease typically ing rates as high as 29%[6]. Additionally, a strong dose- encountered at this institution for preoperative chemora- volume relationship between the amount small bowel diotherapy. Six patients were male, and four were female. receiving intermediate- and low-doses of radiation and All ten patients had clinical T3 disease. One patient was the rates of severe diarrhea has been demonstrated, par- clinically node-negative, while nine were clinically node- ticularly at the 15-Gy dose level [7-10]. Higher rates of acute severe toxicity may potentially lead to breaks in positive. No patient had evidence of distant metastasis. treatment or mitigate compliance, which may confer All patients received concurrent fluoropyrimidine-based chemotherapy, typically with capecitabine. untoward consequences with respect to local control or survival [11]. 3-field belly board plans Techniques have been utilized with the aim to reduce All patients were simulated and received treatment in the volume of small bowel irradiated, such as the use of the prone position using a carbon-fiber belly board prone positioning with a belly-board apparatus to apparatus (CIVCO Medical Systems, #125012) to achieve bowel displacement away from the field [12]. achieve displacement of abdominal contents, which is Additionally, there has been interest in the application the current standard practice at our institution. Com- of highly conformal treatment approaches, such as puted tomography (CT) simulation was used in all intensity-modulated radiation therapy (IMRT). Whole- patients. No specific bladder filling instructions were pelvis IMRT has been applied to gynecologic malig- given to patients. No bowel contrast agent was used at nancy, with less toxicity than traditional 3D conformal the time of simulation. The plans used clinically [hence- radiation therapy (3DCRT)[13]. In anal cancer, IMRT forth: 3-field belly board (3FBB)] consisted of a primary has been compared to 3DCRT, showing similar target treatment to a prescribed dose of 45-Gy using a 3-field coverage with reduced dose to the genitals, femoral approach (PA and opposed laterals with wedges), typi- heads, small bowel, and iliac crest [14,15]. In compari- cally without the use of any field-in-field optimization, son, the data for IMRT in rectal cancer are relatively followed by a localized boost for an additional 5.4-Gy sparse. Guerrero Urbano and colleagues compared using opposed lateral fields, using exclusively 18-MV IMRT with 3DCRT in five patients, and found small photons and 1.8-Gy daily fractions. The intended tar- bowel sparing with IMRT only at the 40-Gy level and geted tissues included the gross tumor and nodal dis- higher [16]. Tho and colleagues selected eight patients with the greatest volumes of small bowel irradiated from ease, which were contoured based on the CT simulation theircohortofpatients,andobservedanoverall scan, mesorectum, and the internal iliac and presacral Mok et al. Radiation Oncology 2011, 6:63 Page 3 of 9 http://www.ro-journal.com/content/6/1/63 lymph nodes. Classic anatomical field borders were Radiotherapy planning employed, with the superior field border at L5/S1, and All plans were generated using the Pinnacle version inferior border at the level of the ischial tuberosities or 8.0 m treatment planning system (Philips Healthcare), 3-cm below the caudal-most extent of the tumor. For using MLC-equipped megavoltage linear accelerator the PA field, the lateral field borders were placed 2-cm delivery. For the 3DCRT and IMRT plans, the original CT simulation datasets from each patient were restored, beyond the pelvic inlet. For the lateral fields, the ante- and contoured as delineated above. For the 3DCRT rior border was 3-cm anterior to the sacral promontory, plans, the field borders were modified from the 3FBB and the posterior border was placed sufficient to expose plans with the goal of covering greater than 95% of the a 1-cm margin on the posterior sacral bony contour. Multileaf collimator (MLC) blocking was utilized to PTV volume with the prescription dose, which was pre- block normal tissues outside of the intended targeted scribed to the isocenter or a calculation point, and tissues. For the purposes of this study, given a lack of renormalized based on PTV coverage. Additional field- consensus with regard to delineation of boost volumes in-fields were utilized in all cases for homogeneity con- for rectal cancer [19], only the 45-Gy primary fields trol, to limit hotspots to 107% of the prescription dose, were evaluated. particularly to anterior, bowel-containing regions. 18-MV photons were used for all 3DCRT plans. Target volumes and dose prescription for 3DCRT and IMRT treatment plans were generated with respect to IMRT planning delivery using only 6-MV photons via linear accelerators An IMRT plan as well as a 3DCRT plan designed to equipped with Millennium 120 MLC (Varian Medical cover the PTV (henceforth: 3DCRT) were generated for Systems). Several beam arrangements were tested, with each patient from the initial CT simulation scan data. optimal results achieved using a 7-beam arrangement All cases were contoured by a single physician, and sub- with the following gantry angles: 0°, 40°, 70°, 95°, 265°, sequently reviewed by an attending physician. Delinea- 290°, and 320°. The collimator was set to 90°, with a tion of the clinical target volume (CTV) included the total of 70 control points allocated to all beams. Direct gross tumor and involved lymph nodes, mesorectum, machine parameter optimization (DMPO) was used, and at the discretion of the optimization algorithm, fields presacral and internal iliac lymph node regions, with were split for all beam angles. In terms of general plan- appropriate margin, as described in the RTOG consen- ning strategy, highest priority was given to PTV cover- sus contouring atlas for anorectal cancer [19]. CTV to age, then to minimizing dose to small bowel. Of planning target volume (PTV) expansions of 7-mm were intermediate priority were reducing dose to the pelvic applied. bones, bladder, and normal tissues outside the con- As noted above, the total prescription dose used in this study was limited to 45-Gy in 1.8-Gy daily fractions, toured regions; no specific optimization for sigmoid/ without further boost. colon volume was performed, but instead a general anterior abdominal contents avoidance structure was Organs at risk (OAR) used. Lowest effort was applied to minimizing dose to The relevant OAR volumes for this study were the blad- the femoral head/neck. Collapsed-cone (CC) convolu- der, femoral heads/necks, pelvic bones, small bowel, sig- tion methods were employed for final dose calculations. moid/colon, and normal tissues. The bladder was The final IMRT plans were independently reviewed and contoured according to the CT simulation scan. The deemed clinically acceptable by both a gastrointestinal femoral heads/necks contours consisted of the bilateral clinical physicist and radiation oncologist. femoral heads and necks to the level of the lesser tro- chanter. The pelvic bones contours were defined as the Plan evaluation and statistical tools exterior of the bony table from top of the iliac crests to Evaluated volumes included the PTV and relevant nor- the ischial tuberosities. Differentiation of small bowel mal tissue volumes. The PTV, bladder, pelvic bones, from sigmoid and colon was aided through correlation femoral heads/necks, and small bowel were reported as with the diagnostic, contrast-enhanced CT study closest whole volumes. The sigmoid/colon and normal tissue in time to the date of simulation. The small bowel and were reported exclusive of any overlapping/encompassed sigmoid/colon volumes consisted of individual loops of PTV. bowel, contoured up to 2-cm above the superior-most Dosimetric parameters were calculated using tabular cumulative dose volume histogram (DVH) data, set to a PTV slice. The normal tissues contours were defined by bin size of 1-cGy, with median values reported. By con- the external contour, extending to 2-cm above and vention, D = dose received by X% of the volume of below the superior- and inferior-most PTV slices, X% interest, and V = percent volume of interest respectively. XGy Mok et al. Radiation Oncology 2011, 6:63 Page 4 of 9 http://www.ro-journal.com/content/6/1/63 receiving at least a dose of X Gy. Maximum dose was Dose to organs at risk and normal tissues expressed as D , minimum dose as D , mean dose as With respect to mean dose, IMRT compared to 3FBB 1% 99% D , and maximum point dose as D . The homoge- showed little difference for the bladder, femoral heads, mean max neity index (HI) and conformality index (CI) were calcu- sigmoid, and small bowel. However, compared to lated for the 3DCRT and IMRT plans. HI was expressed 3DCRT, IMRT resulted in significantly lower mean dose to the bladder (p = 0.007), sigmoid (p = 0.005), small as (D -D ) / prescription dose. CI was expressed as 5% 95% bowel (p = 0.005), and to the femoral heads (p = 0.03). the ratio of the absolute volume receiving the prescrip- Mean dose to the pelvic bones was significantly lower tion dose to the volume of the target, V /V . 45Gy PTV with IMRT compared with either 3FBB (p = 0.04) or Plan average cumulative DVH values were calculated by exporting tabular DVH data set to a bin size of 3DCRT (p = 0.005). 10-cGy, and were plotted. For the small bowel, a curve With respect to high dose, IMRT significantly based on the absolute volume irradiated was also gener- improved the V to the femoral heads (p = 0.01) and 40Gy ated. Integral dose to all tissues (including PTV) was pelvic bones (p = 0.005) compared to 3FBB, and to the calculated from the differential DVH data set to 10-cGy bladder (p = 0.005), femoral heads (p = 0.005), and pel- bin size. vic bones (p = 0.005) in comparison to 3DCRT. For the For statistical analysis, each patient’sIMRTplanwas dose to sigmoid/colon, IMRT was comparable to 3FBB compared in a pairwise manner with both the 3FBB and at all dose levels evaluated, but was significantly lower 3DCRT plans, respectively. Non-parametric statistical compared to 3DCRT (p = 0.005). analyses were performed using the paired, two-tailed Volumetric evaluation of total small bowel was per- Wilcoxon signed-rank test, with p-value < 0.05 taken to formed at dose levels ranging from 5- to 45-Gy. When be significant. IMRT was compared to 3FBB, the V was signifi- 15Gy cantly reduced with IMRT (p = 0.03), but similar at Results other doses. IMRT compared to 3DCRT showed signifi- Dose to target volumes cant reductions in the volumes of small bowel irradiated When comparing the 3FBB treatment volumes to the at levels ranging from 15- to 45-Gy (p < 0.01). With contoured volumes based on RTOG consensus guide- respect to V , the magnitude of the difference in 15Gy lines, it was evident that the contoured PTV encom- median volumes was modest (138-cc IMRT versus 157- cc 3DCRT; p = 0.005) when evaluating the ten patients passed a typically larger volume than that treated in the as a whole. However, the most profound bowel sparing 3FBB plans. This was most pronounced superiorly, but was evident in the subset of patients with the largest was also seen in the extent of the PTV anterior to the volume of small bowel in proximity to the treatment sacral promontory, and occasionally in the inferior extent of the field. Indeed, dosimetric comparisons field. For example, in the 6 patients with the highest between 3FBB and IMRT plans, as shown in Table 1, volume of small bowel (range: 209 - 537-cc), the volume revealed that the percentage of the PTV receiving the of bowel receiving 15-Gy was reduced from a median of prescription dose was significantly lower for the 3FBB 231-cc in the 3DCRT plans to 185-cc with IMRT. Con- plans than with IMRT (V : median 3FBB 87.2% ver- versely, in the remaining four patients, only a slight 45Gy sus IMRT 99.5%; p = 0.005). Therefore, a 3DCRT plan absolute reduction was evident (median V : 13-cc 15Gy was generated in each case using techniques described IMRT versus 22-cc 3DCRT). in the methods to adequately cover the PTV. This was Normal tissues outside the target were evaluated, and quite effective, as the 3DCRT V was increased to a IMRT plans had a significantly higher mean dose (p = 45Gy median of 98.4%, though still statistically inferior com- 0.02) and V (p = 0.01) to V (p < 0.02) in com- 10Gy 30Gy pared with IMRT (p = 0.02). Mean doses were similar parison to the 3FBB plans. However, at the highest between the 3DCRT and IMRT plans (p = 0.46). doses, IMRT was significantly lower (V , p = 0.02; 40Gy With respect to target coverage, the minimum dose to V , p < 0.01). IMRT, compared to 3DCRT, had a sig- 45Gy the PTV, D , was higher with IMRT compared to the nificantly lower mean dose (p = 0.007), V (p = 40Gy 99% 3FBB (p = 0.005) and 3DCRT (p = 0.01) plans. Maximum 0.005) and V (p = 0.005), with more modest, but 45Gy dose to the PTV, D , was significantly lower with IMRT significant, differences at V (p = 0.005) and V 1% 10Gy 20Gy in comparison to 3FBB (p = 0.007); results were similar (p = 0.01). between IMRT and 3DCRT (p = 0.35). Both the homoge- Averaged cumulative DVH plots for organs-at-risk and normal tissues are depicted in Figure 1. Representa- neity and conformality indices were significantly better tive axial slices showing isodose distributions for an with IMRT compared to 3DCRT (p = 0.007 and p = 0.005, IMRT and a 3DCRT plan for one patient are shown in respectively). Graphically, these findings are reflected in Figure 2. the averaged cumulative DVH plot (Figure 1A). Mok et al. Radiation Oncology 2011, 6:63 Page 5 of 9 http://www.ro-journal.com/content/6/1/63 Table 1 Dosimetric comparison of IMRT with 3DCRT: median value (range) Volume Parameter IMRT 3FBB 3DCRT PTV D (Gy) 46.6 (46.4 - 46.9) 46.0 (45.6 - 47.0)* 46.6 (46.3 - 48.3) mean 1547 cm V 99.5% (98.7% - 99.8%) 87.2% (80.0% - 93.4%)† 98.4% (97.7% - 99.6%)* 45Gy (1459 - D (Gy) 45.3 (44.8 - 45.8) 35.2 (10.7 - 40.3)† 44.9 (44.2 - 45.2)* 99% 1968 cm)D (Gy) 47.6 (47.2 - 47.9) 48.3 (47.7 - 50.5)† 47.5 (47.1 - 48.2) 1% HI 3.2% (2.5% - 3.6%) N/A 4.2% (3.0% - 5.3%)† CI 1.16 (1.09 - 1.23) N/A 1.35 (1.27 - 1.38)† Bladder D (Gy) 38.6 (31.1 - 42.4) 37.9 (27.5 - 44.2) 41.8 (31.0 - 45.0)† mean 72 cm V 74.7% (40.8% - 90.0%) 72.6% (36.7% -96.6%) 85.8% (47.2% - 100%)† 30Gy (32-652 cm)V 56.8% (26.2% - 76.6%) 58.5% (27.6% - 84.0%) 75.4% (38.0% - 100%)† 40Gy Femoral heads D (Gy) 27.1 (20.8 - 29.6) 24.9 (22.4 - 30.7) 28.5 (21.9 - 31.8)* mean 211 cm V 28.0% (17.8% - 44.2%) 22.6% (12.0% - 33.3%) 31.9% (13.2% - 57.4%) 30Gy (151-393 cm)V 3.4% (1.1% - 7.0%) 6.3% (1.9% - 13.2%)* 9.1% (3.5% - 14.6%)† 40Gy Pelvic bones D (Gy) 34.2 (30.5 - 36.2) 34.7 (31.9 - 36.8)* 36.7 (32.3 - 38.4)† mean 914 cm V 69.8% (55.6% - 76.3%) 66.7% (61.8% - 72.3%) 74.9% (63.4% - 81.0%) 30Gy (725-1338 cm)V 47.0% (35.2% - 52.8%) 53.9% (46.5% - 59.2%)† 56.9% (41.3% - 63.6%)† 40Gy Sigmoid/Colon D (Gy) 18.9 (10.4 - 27.9) 17.5 (9.8 - 23.6) 25.5 (13.7 - 31.1)† mean outside PTV V 41.6% (13.2% - 72.6%) 38.0% (11.5% - 54.0%) 60.6% (24.9% - 75.2%)† 20Gy 162 cm V 17.6% (5.1% - 48.1%) 10.4% (3.0% - 36.9%) 36.9% (10.8% - 63.2%)† 30Gy (23 - 389 cm)V 4.0% (0.7% - 19.2%) 2.4% (0.4% - 30.3%) 18.3% (5.1% - 38.5%)† 40Gy Small bowel D (Gy) 18.6 (11.2 - 34.0) 21.0 (8.6 - 34.2) 25.2 (15.9 - 40.0)† mean 251 cm V (cc) 224 (2.5 - 526) 225 (2.2 - 525) 234 (2.5 - 530) 5Gy (3 - 537 cm)V (cc) 138 (0.1 - 257) 144 (0.4 - 413)* 157 (2.2 - 428)† 15Gy V (cc) 81 (0.0 - 142) 79 (0.0 - 149) 123 (0.5 - 183)† 25Gy V (cc) 45 (0.0 - 111) 50 (0.0 - 118) 76 (0.0 - 156)† 40Gy V (cc) 37 (0.0 - 100) 33 (0.0 - 74) 53 (0.0 - 121)† 45Gy Normal tissues D (Gy) 19.5 (12.0 - 21.6) 17.5 (12.8 - 20.6)* 20.5 (17.4 - 22.4)† mean 3 3 10.3*10 cm V 69.5% (58.0% - 76.9%) 64.9% (53.3% - 75.6%)* 73.8% (62.2% - 80.7%)† 10Gy (7.7*10-V 48.3% (39.5% - 52.7%) 42.0% (32.6% - 52.7%)* 50.5% (40.0% - 58.3%)* 20Gy 3 3 18.9*10 cm)V 20.3% (16.5% - 27.4%) 17.3% (12.6% - 20.2%)* 23.5% (16.8% - 27.8%) 30Gy V 6.7% (4.0% - 9.2%) 8.3% (4.2% - 10.9%)* 11.0% (6.7% - 15.7%)† 40Gy V 2.3% (1.2% - 5.1%) 4.4% (2.1% - 6.0%)† 5.2% (2.8% - 6.4%)† 45Gy Abbreviations: PTV = planning target volume; IMRT = intensity modulated radiation therapy; 3FBB = 3 field belly board; 3DCRT = 3 dimensional conformal radiation therapy; HI = homogeneity index; CI = conformality index; for definitions of dosimetric parameters, refer to text; denotes statistically significant difference with IMRT as comparator, p < 0.05 (*) or p < 0.01 (†); otherwise, not statistically significant. Plan summary characteristics 3DCRT plans targeting the PTV. This was not at the Monitor units were significantly higher with IMRT com- expense of adjacent organs-at-risk, as some measure of pared to either 3FBB (p = 0.005) or 3DCRT (p = 0.005) sparing was evident for all organs-at-risk evaluated: small (Table 2). The overall plan maximum doses were similar bowel, sigmoid, pelvic bones, bladder, and femoral heads between IMRT and 3FBB, but higher with IMRT com- (IMRT versus 3DCRT). In this comparison, IMRT actu- pared to 3DCRT (p = 0.005). Integral dose, calculated ally decreased the overall integral dose to all tissues, and for all tissues including the target volume, was signifi- achieved lower mean doses to normal tissues outside the cantly higher for IMRT compared to 3FBB (p = 0.007), PTV, which was evident especially in the high dose but lower compared to 3DCRT (p = 0.007). range. As expected, IMRT required significantly more monitor units per fraction, compared to 3DCRT. Discussion We found quite interesting the discrepancy between the In this study, we found that the application of IMRT for size of the volumes encompassed by the PTV, which were rectal cancer gave excellent results in comparison to generated according to the RTOG consensus contouring non-IMRT based approaches. With respect to the PTV, atlas [19], and the volumes treated according to classic we found that IMRT plans achieved superior coverage, anatomic landmarks (3FBB), even considering the antici- homogeneity, and conformality in treating the gross dis- pated patient-to-patient anatomical variation. This was ease and at-risk pelvic nodal volume, in comparison to reflected in the significantly lower proportion of the PTV Mok et al. Radiation Oncology 2011, 6:63 Page 6 of 9 http://www.ro-journal.com/content/6/1/63 Figure 1 Averaged cumulative dose-volume histograms. Averaged cumulative dose-volume histograms for (A) PTV, (B) bladder, (C) femoral heads and necks, (D) pelvic bones, (E) sigmoid outside of PTV, (F) small bowel (relative), (G) small bowel (volumetric), and (H) normal tissues outside PTV, for IMRT, 3FBB, and 3DCRT. volume receiving the prescription dose in the 3FBB plans, irradiated had similar mean doses, and the absolute and to a certain extent the significantly lower overall inte- volumes irradiated were similar from the 5- to 45-Gy gral dose, compared to IMRT. We found that despite the levels, except at 15-Gy, where IMRT was statistically significantly larger volume targeted in the IMRT plans, improved, compared to the 3FBB plans. IMRT achieved either similar or improved dose levels to In terms of acute, severe treatment-related toxicity, all organs-at-risk evaluated. For example, the small bowel diarrhea is the most common, and studies have Mok et al. Radiation Oncology 2011, 6:63 Page 7 of 9 http://www.ro-journal.com/content/6/1/63 Figure 2 Representative axial slices. Representative axial slices showing isodose distributions for two planes for an (A), (C) IMRT and (B), (D) 3DCRT plan. demonstrated a strong dose-volume relationship with as other intermediate dose levels, including the V 20Gy small bowel irradiated [7-10]. Baglan and colleagues and V , with respect to severe diarrhea [9,10]. In our 25Gy demonstrated a strong association between the rate of study, we found IMRT achieved significant sparing in small bowel toxicity and the V level; when the V terms of the mean dose to small bowel and absolute 15Gy 15Gy was below 150-cc, low rates of grade 2 or higher toxicity volumes from V to V , whereas no difference was 15Gy 45Gy were observed, while the majority of patients with V seen at the lowest dose level evaluated, V ,compared 15Gy 5Gy over 300-cc had grade 3 or higher toxicity [7]. Subse- to the 3DCRT plans. This sparing at the V level was 15Gy quent studies by Robertson and colleagues have con- most pronounced in the cases with the highest volumes firmed the significance of the V dose level, as well of small bowel within or nearby the PTV. Therefore, we 15Gy would predict a lower rate of severe, acute gastrointest- inal toxicity in these patients treated with IMRT. Table 2 Plan summary comparison of IMRT and 3DCRT Furthermore, reduction in the small bowel V using 45Gy plans: median value (range) IMRT may lead to lower rates of late gastrointestinal Parameter IMRT 3FBB 3DCRT toxicity [20]. Again, in the comparison between IMRT MU/fraction 786 (730 - 950) 238 (224 - 272)† 242 (232 - 276)† and classic bony landmark-derived 3FBB fields, despite a D (Gy) 48.8 (48.4 - 49.4) 48.8 (48.1 - 51.0) 48.2 (47.8 - 49.2)† max more extensivevolumetreated with IMRT,wewould Integral dose 2.74 (2.39 - 4.03) 2.56 (2.15 - 3.60)† 2.86 (2.49 - 4.12)† predict similar, or based on the V ,possibly 15Gy 3 -5 (Gy*cm *10 ) improved rates of severe, acute gastrointestinal toxicity Abbreviations: MU = monitor units; IMRT = intensity modulated radiation with IMRT compared to 3FBB. therapy; 3FBB = 3 field belly board; 3DCRT = 3 dimensional conformal In the context of other planning studies comparing radiation therapy;denotes statistically significant difference with IMRT as comparator, p < 0.05 (*) or p < 0.01 (†); otherwise, not statistically significant. IMRT with 3DCRT, we feel overall our results are Mok et al. Radiation Oncology 2011, 6:63 Page 8 of 9 http://www.ro-journal.com/content/6/1/63 superior and additive. Prior studies have demonstrated a the use of IMRT does not automatically confer normal reduction in small bowel mean dose [8], or improve- tissue sparing, as an excessively voluminous target ment at the high-dose extreme [16,17], with the use of volume may in fact lead to higher absolute volumes of IMRT. With respect to positioning, while all three stu- normal tissues treated. This reinforces the importance dies employed prone positioning, one achieved immobi- of consensus target delineation to achieve standardiza- lization using a foam cushion [17], whereas two made tion from practice-to-practice. no specific reference to the use of a bowel displacement Due to daily setup uncertainties using the rigid car- bon-fiber belly-board apparatus, for IMRT treatment of device [8,16]. In contrast, using a rigid, carbon-fiber a CTV-to-PTV expansion of 7-mm used in this study, it belly board apparatus, we observed a significant improvement in small bowel dose from 15-Gy through may be worthwhile to consider daily kilovoltage imaging, the 45-Gy level, as well as the mean dose, with IMRT or perhaps modifications such as the incorporation of a compared to 3DCRT plans. Therefore, our study vacuum-cradle device to improve setup reproducibility. demonstrates a further significant interval improvement One potential criticism for intensity modulated treat- in small bowel dose is realized with the use of IMRT in ment approaches is with respect to integral dose, conjunction with the carbon-fiber belly board. An addi- whereby larger volumes of normal tissues are exposed tional strength of our study is that our contoured to lower radiation doses, which may lead to increased volumes conformed to the RTOG consensus guidelines. incidence of second malignancies [21]. In our study, we We chose as a “class-solution” approach to use an found a lower integral dose with IMRT compared to asymmetric, seven-beam arrangement, biased against 3DCRT plans targeting the PTV. However, integral dose anterior-directed beams, thus minimizing beam entry was slightly higher with IMRT than in the classic 3FBB through anterior-lying bowel contents or through the plans. belly-board apparatus. This appeared to take advantage Another potential downside of a static-field intensity of strengths of the 3-field beam arrangement, namely modulated therapy approach is a longer beam-delivery sharp dose falloff in the intermediate- and low-dose time that is required as compared to 3DCRT, with range anteriorly. Indeed, recently-published studies of respect to intrafractional motion. This may be overcome IMRT, using 5- to 9-equispaced beams, have principally using volumetric-modulated arc therapy (VMAT) based demonstrated reduced small bowel mean dose and techniques. V , compared to 3DCRT [8,16,17]. In our study, in 40Gy addition to these findings, we found IMRT capable of Conclusions reducing small bowel volumes receiving potentially toxi- For the adjuvant treatment of rectal carcinoma, IMRT, city-inducing intermediate- and low-dose irradiation, at compared to 3DCRT, yielded plans superior with a statistically-significant level. Concomitantly, IMRT respect to target coverage, homogeneity, and conformal- achieved superior PTV target coverage, homogeneity, ity, while lowering dose to adjacent organs-at-risk. This and conformality, as well as evidence of sparing of all benefit was seen additive to the use of prone-positioning other organs-at-risk evaluated in this study. Again, our on a belly-board apparatus, and with respect to small results support a clear dosimetric advantage for IMRT, bowel toxicity, could potentially be clinically significant. even with the use of prone-positioning on a belly-board apparatus. Author details With respect to the volume of the irradiated target, 1 Department of Radiation Oncology, The University of Texas, M.D. Anderson there are at least two different ways to consider this Cancer Center, Houston, Texas, USA. Department of Medical Dosimetry, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA. issue. In our study, the PTVs, generated with a 7-mm Department of Radiation Physics, The University of Texas, M.D. Anderson expansion, were typically larger than the volume treated Cancer Center, Houston, Texas, USA. using classic 3FBB fields. Given the excellent historical Authors’ contributions results obtained with the classic 3FBB fields, one inter- HM carried out the study conception and design, drafted the manuscript, pretation is that the target volumes, as delineated by the and performed treatment planning. PD carried out the study conception RTOG consensus IMRT contouring atlas for anorectal and design and drafted the manuscript. MBP performed treatment planning. TMB and SB performed physics checks/plan evaluation. Patient accrual and disease, may be more generous than necessary. Alterna- radiation field design were performed by CHC, MED, SK, and PD. CHC tively, as we found that the more comprehensive PTV provided mentorship for this work. All authors read and approved the final target coverage was achieved without increasing dose to manuscript. the organs-at-risk including the small bowel, it is con- Competing interests ceivable that improved efficacy is attainable without The authors declare that they have no competing interests. increasing acute- and long-term toxicities through the Received: 30 November 2010 Accepted: 8 June 2011 use of IMRT. Long-term clinical data would be neces- Published: 8 June 2011 sary to provide evidence for this. As an additional point, Mok et al. Radiation Oncology 2011, 6:63 Page 9 of 9 http://www.ro-journal.com/content/6/1/63 References 18. 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Radiation Oncology – Springer Journals

Published: Jun 8, 2011

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