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Reduced Acute Bowel Toxicity in Patients Treated With Intensity-Modulated Radiotherapy for Rectal Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 5, pp. 1981–1987, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter
doi:10.1016/j.ijrobp.2011.01.051
CLINICAL INVESTIGATION
Gastrointestinal Cancer
REDUCED ACUTE BOWEL TOXICITY IN PATIENTS TREATED WITH INTENSITYMODULATED RADIOTHERAPY FOR RECTAL CANCER JASON M. SAMUELIAN, D.O.,* MATTHEW D. CALLISTER, M.D.,* JONATHAN B. ASHMAN, M.D., PH.D.,* TONIA M. YOUNG-FADOK, M.D.,y MITESH J. BORAD, M.D.,z AND LEONARD L. GUNDERSON, M.D.* *Department of Radiation Oncology and Divisions of yColorectal Surgery and zHematology-Oncology, Mayo Clinic, Scottsdale, AZ Purpose: We have previously shown that intensity-modulated radiotherapy (IMRT) can reduce dose to small bowel, bladder, and bone marrow compared with three-field conventional radiotherapy (CRT) technique in the treatment of rectal cancer. The purpose of this study was to review our experience using IMRT to treat rectal cancer and report patient clinical outcomes. Methods and Materials: A retrospective review was conducted of patients with rectal cancer who were treated at Mayo Clinic Arizona with pelvic radiotherapy (RT). Data regarding patient and tumor characteristics, treatment, acute toxicity according to the Common Terminology Criteria for Adverse Events v 3.0, tumor response, and perioperative morbidity were collected. Results: From 2004 to August 2009, 92 consecutive patients were treated. Sixty-one (66%) patients were treated with CRT, and 31 (34%) patients were treated with IMRT. All but 2 patients received concurrent chemotherapy. There was no significant difference in median dose (50.4 Gy, CRT; 50 Gy, IMRT), preoperative vs. postoperative treatment, type of concurrent chemotherapy, or history of previous pelvic RT between the CRT and IMRT patient groups. Patients who received IMRT had significantly less gastrointestinal (GI) toxicity. Sixty-two percent of patients undergoing CRT experienced $Grade 2 acute GI side effects, compared with 32% among IMRT patients (p = 0.006). The reduction in overall GI toxicity was attributable to fewer symptoms from the lower GI tract. Among CRT patients, $Grade 2 diarrhea and enteritis was experienced among 48% and 30% of patients, respectively, compared with 23% (p = 0.02) and 10% (p = 0.015) among IMRT patients. There was no significant difference in hematologic or genitourinary acute toxicity between groups. In addition, pathologic complete response rates and postoperative morbidity between treatment groups did not differ significantly. Conclusions: In the management of rectal cancer, IMRT is associated with a clinically significant reduction in lower GI toxicity compared with CRT. Further study is needed to evaluate differences in late toxicity and longterm efficacy. Ó 2012 Elsevier Inc. Intensity-modulated radiation therapy, Rectal cancer, Preoperative radiotherapy.
with acute GI toxicity rates (7–9). Compared with traditional techniques, IMRT is able to deliver increased conformality of dose and thus spare normal organ exposure. IMRT has been used in the treatment of other pelvic malignancies such as anal cancer (10), gynecologic cancers (11), and prostate cancer (12) with significant reduction in expected GI toxicity rates compared with conventional techniques. We have previously performed a dosimetric analysis comparing IMRT with conventional radiotherapy (CRT) among patients with rectal cancer (13). IMRT plans were associated with a 19% decrease in the mean dose delivered to small bowel and a 16% reduction in the V30 and V45 compared with CRT planning. In addition, IMRT enabled significant dose reduction to the bladder, bone marrow, and femoral
INTRODUCTION Adjuvant or neoadjuvant pelvic radiotherapy (RT) with concurrent chemotherapy is standard therapy for patients with $T3 or node-positive rectal cancer (1). Three- or four-field techniques have almost universally been used in clinical trials that use RT (2, 3). Gastrointestinal (GI) toxicities are the most clinically significant side effects associated with pelvic RT for this disease. Acute $Grade 3 GI toxicity is reported in 36–44% of patients undergoing RT with concurrent 5-fluorouracil (5-FU) in prospective clinical trials (2, 4, 5,). There are fewer data regarding late bowel complications, but those may be as high as 9–18 % with long-term follow-up (3, 6). The volume of bowel exposed to doses as low as 15 Gy during pelvic RT has been found to strongly correlate
Conflict of interest: none. Received Aug 30, 2010, and in revised form Jan 12, 2011. Accepted for publication Jan 26, 2011.
Reprint requests to: Matthew D. Callister, M.D., 13400 E. Shea Blvd., Scottsdale, AZ 85259. Tel: (480) 301-8120; Fax: (480) 3017687; E-mail: [email protected] Presented at the 2010 Gastrointestinal Cancers Symposium, January 22-24, 2010 Orlando, Fl. 1981
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Fig. 1. Axial (a) and sagittal (b) dosimetry in a 51-year-old woman with a cT3N1 midrectal cancer undergoing preoperative chemoradiotherapy. She was treated with a seven-field coplanar intensity-modulated radiotherapy plan of 45 Gy to the clinical target volume and 50 Gy to thegross tumor volume (target volumes not shown) using daily image guidance.
heads. Other dosimetric studies of IMRT for rectal cancer have reported similar findings with regard to bowel sparing (14–18). On the basis of the apparent benefits of IMRT in rectal cancer patients, we implemented the use of IMRT with rectal cancer patients treated at our department. We conducted this retrospective study to report the outcomes in such patients and compare them with a similar cohort of patients treated with CRT. METHODS AND MATERIALS Patient selection The medical records of all patients undergoing pelvic RT for the treatment of adenocarcinoma of the rectum at the Mayo Clinic Arizona between January 2004 and August 2009 were retrospec-
tively reviewed with approval of the Mayo Clinic Institutional Review Board. Ninety-two consecutive patients were identified. All patients were included, regardless of type of concurrent chemotherapy administered, stage, treatment intent, or previous pelvic RT. Patients whose disease was considered incurable but for whom the intent of therapy was pelvic control were included (5 patients with unresectable metastases and 5 patients with unresectable pelvic disease). Data regarding patient and tumor characteristics, treatment, acute toxicity, and tumor response were collected.
Pretreatment evaluation Before treatment, the patients’ conditions were evaluated by routine medical history and physical examination, endoscopy, endoscopic ultrasound, abdominopelvic computed tomography, and/or pelvic magnetic resonance imaging. Indications for pelvic RT included clinical or pathologic transmural penetration of tumor,
Clinical toxicity of IMRT for rectal cancer d J. M. SAMUELIAN et al.
node involvement, distal lesions that would require abdominoperineal resection without downstaging, or recurrent disease.
Treatment The treatment techniques generally applied in our department during the time of the study were as follows. All patients underwent computed tomography–based treatment planning using an anal marker. Prone positioning with bladder distension and selective use of a belly board was preferred for patients undergoing CRT (66% prone). Supine positioning with lower body immobilization and daily image guidance was more commonly used for patients undergoing IMRT (88% supine). The gross tumor volume (GTV) was contoured on the treatment planning system (Eclipse, Varian Medical Systems, Palo Alto, CA), taking into consideration all clinical information, including digital rectal examination, endoscopy, and all imaging to identify the primary tumor and enlarged regional lymph nodes, with generous coverage to the adjacent presacral space. The clinical target volume (CTV) included a minimum of 2 cm of normal rectum beyond the GTV in addition to the entire mesorectum and the internal iliac, presacral, and lower common iliac lymph nodes up to the sacral promontory and inferiorly at least to the anal–rectal junction. A second CTV (instead of a GTV) was used for postoperative patients to identify the original tumor bed. The external iliac nodes were not intentionally included except for T4 tumors with anterior pelvic extension. Normal structures identified included the proximal femora and bladder. The small bowel was not contoured as individual loops, rather as an avoidance region (peritoneal cavity inferior to L5/S1). Separate planning target volumes (PTV) were constructed for the GTV and CTV. This margin was generally 1 cm but ranged from 0.5 cm to 1 cm among patients with lower body immobilization and who underwent image-guided RT. Patients undergoing CRT were treated using three- or four-field box techniques with 18-MV photons (or 6-MV photons for posteroanterior fields). The CTV was treated to 45 Gy in 1.8 Gy fractions followed by a 5.4- to 9 Gy boost to the GTV or second CTV for preoperative and postoperative patients, respectively. Coverage of the PTV by at least 95% of the prescribed dose was generally required for both IMRT and CRT plans. The IMRT plans used a 7- to 9-field beam arrangement (usually coplanar) with 6-MV or 18-MV photons (Fig. 1). In addition to target coverage, dose homogeneity was carefully assessed with IMRT plans to minimize any volume receiving more than 5% of the prescribed dose. After target coverage and homogeneity, IMRT optimization parameters were prioritized for dose reduction to the small bowel region, followed by bladder and femora. Limited volumes of small bowel volume were allowed to exceed 45 Gy if adjacent to the boost volume, but not to exceed 50 Gy. In addition to maximum dose, multiple dose–volume parameters were specified for the small bowel volume, ranging from 15 to 40 Gym to reduce mean bowel exposure to as low as achievable. The maximum bladder dose was kept from exceeding 50 Gy, and V40 was kept less than 40% or lower if possible. The proximal femora were constrained from receiving more than 40 Gy. The dose fractionation for IMRT patients was similar to that for CRT patients except that often the GTV boost (to 50 Gy) was delivered concurrently with the 45 Gy to the pelvis. Among patients who had previously received pelvic RT, the prescribed dose (median, 30.6 Gy) was determined by the clinical judgment of the radiation oncologist. In addition to the GTV, treatment fields generously incorporated regional tissues at risk, although the whole pelvis was not included in all patients.
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The implementation of IMRT in our clinical practice began after we performed a dosimetric comparison of IMRT and CRT for rectal cancer (13). The selection of IMRT over CRT was that of the treating oncologist, and the use of IMRT for rectal cancer increased over the period of the study. Preoperative therapy for rectal cancer has been the preferred strategy at our institution among patients for whom neoadjuvant therapy is indicated, with resection 6 to 8 weeks after treatment completion. Concurrent 5-FU given by prolonged venous infusion (250 mg/m2, 5 days a week) or capecitabine (875 mg/m2, twice daily) were the predominant regimens administered with RT.
Toxicity and response assessment The patients’ conditions were evaluated weekly during therapy and before surgical resection (among preoperative patients) by the treating radiation oncologist. A complete blood count was obtained at least every other week. The clinic record was retrospectively reviewed, and data regarding acute toxicity were scored according to the Common Terminology Criteria for Adverse Events v3.0 during therapy and 8 weeks after completion among patients treated postoperatively or until 3 months after surgery among patients treated preoperatively.
Statistical analysis Statistical analysis was performed using JMP8 (Copyright Ó 2010, SAS Institute, Inc.). Student’s t test and Fisher’s exact test were used to test the significance of differences between cohorts. When applicable, all p values reported are two-sided.
RESULTS Patient, tumor, and treatment characteristics Among the 92 patients in this study, 61 (66%) were treated with CRT and 31 (34%) with IMRT. Patient, tumor, and treatment characteristics are detailed in Table 1. No significant differences were noted between the IMRT and CRT cohorts except for a slightly older median age in the CRT group. Among the 22 patients treated for recurrent disease, 8 had previous pelvic RT (5 in the IMRT group, 3 in the CRT group). Among such patients there was no difference in median previous dose (50.2 Gy for IMRT, 45 Gy for CRT, p = 0.16). The indication for pelvic RT in all patients was clinical or pathologic $T3 disease, node involvement, transanal excision, or recurrence after previous surgery with curative intent. Among patients treated with preoperative therapy, there was no difference in the rate of subsequent sphincterpreserving surgery (82% IMRT vs. 84% CRT, p = 0.82). Among the 10 patients with noncurative disease, the median delivered dose was 47.2 Gy. Acute GI toxicity The percentage of acute $Grade 2 GI toxicity by treatment group is shown in Table 2. Significantly less overall GI toxicity was observed among the patients receiving IMRT (32% vs. 62%, p = 0.006). This reduction in overall GI toxicity was attributable to fewer GI symptoms associated with the lower GI tract. Among CRT patients, $Grade 2 diarrhea and enteritis (i.e., abdominal pain; mucus, or bloody stool) was experienced among 48% and 30% of patients, respectively, compared with
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Table 1. Patient, tumor, and treatment characteristics Characteristic Median age, y (range) Sex M F Tumor status* T1–2 T3 T4 Recurrent Nodal status Positive Negative RT sequence Preoperative Postoperative Median RT dose (range) Concurrent chemotherapy 5-FU Capecitabiney None Treatment intent Curative Noncurative
IMRT n = 31 (%)
CRT n = 61 (%)
63 (26–75)
67 (38–86)
20 (65) 11 (35)
35 (57) 26 (43)
4 (13) 13 (42) 4 (13) 10 (32)
5 (8) 37 (61) 7 (11) 12 (20)
13 (42%) 18 (58%)
27 (44%) 34 (56%)
25 (81) 6 (19) 50 Gy (25.2–56)
56 (92) 5 (8) 50.4 Gy (25.2–54)
p 0.007 0.51 0.36
0.83 0.17 0.90 0.56 13 (42) 18 (58) 0 (0)
27 (44) 32 (53) 2 (3)
29 (94) 2 (6)
53 (87) 8 (13)
0.49
Abbreviations: IMRT = intensity-modulated radiotherapy; CRT = conventional radiotherapy; 5-FU = 5-fluorouracil. * Clinical stage (if treated preoperatively) or pathologic stage (if treated with initial surgery). y Five patients in the CRT group received concurrent oxaliplatin and 2 patients also received leucovorin.
23% (p = 0.02) and 10% (p = 0.015) of IMRT patients. Intravenous hydration was required by 10% of CRT patients ($Grade 2 dehydration), compared with no patients undergoing IMRT (p = 0.093). Only 3% of IMRT patients and 10% of CRT patients (p = 0.42) experienced acute Grade 3 GI toxicity, and no patients experienced Grade 4 side effects. The grade distribution of maximum experienced lower GI toxicity (diarrhea, enteritis, and proctitis) was more favorable among the patients treated with IMRT (Fig. 2). Reanalysis of the data with the exclusion of the 8 patients who had previously received pelvic RT revealed no major Table 2. Acute $ Grade 2 gastrointestinal toxicities Toxicity Nausea Vomiting Diarrhea Enteritis Proctitis Dehydration Any GI toxicity
IMRT n = 31 (%)
CRT n = 61 (%)
0 (0) 0 (0) 7 (23) 2 (6) 3 (10) 0 (0) 10 (32)
5 (8) 1 (2) 29 (48) 18 (30) 11 (18) 6 (10) 38 (62)
Fig. 2. Distribution of lower gastrointestinal toxicity in rectal cancer patients treated with conventional radiotherapy (CRT) and intensity-modulated radiotherapy (IMRT).
difference in acute GI toxicity; 67% of CRT patients experienced $Grade 2 GI toxicity, compared with 33% of IMRT patients (p = 0.004). Similarly, exclusion of the patients whose treatment was considered noncurative did not affect this endpoint; 60% of CRT patients experienced $Grade 2 GI toxicity, compared with 31% of IMRT patients (p = 0.011). Five patients in the CRT group received concurrent oxaliplatin, but their exclusion from analysis did not change the study findings; $Grade 2 GI toxicity was experienced by 61% of CRT patients vs. 32% of IMRT patients (p = 0.011). Non-GI toxicity Grade 2 or greater acute non-GI toxicity by treatment group is shown in Table 3. No significant differences were identified. Non-GI Grade 3 toxicity was experienced by only 6 patients; 4 patients experienced Grade 3 hematologic toxicity (3 CRT, 1 IMRT), and 2 patients developed Grade 3 skin toxicity (1 CRT, 1 IMRT). There was no Grade 4 toxicity. Between the IMRT and CRT groups, patients requiring RT treatment breaks (6.5% vs. 16.4%, p = 0.33) or early termination of therapy (9.7% vs. 6.6%, p = 0.68) did not differ significantly. Pathologic response Fifty-six patients underwent preoperative chemoradiotherapy for newly diagnosed rectal cancer. A complete pathologic Table 3. Acute $ Grade 2 nongastrointestinal toxicities Toxicity
p 0.16 1.0 0.02 0.015 0.37 0.093 0.006
Abbreviations: IMRT = intensity-modulated radiotherapy; CRT = conventional radiotherapy; GI = gastrointestinal.
Hematologic WBC ANC Hemoglobin Platelets Any hematologic Any urinary Skin
IMRT n = 31 (%)
CRT n = 61 (%)
3 (10) 0 (0) 13 (42) 0 (0) 14 (45) 5 (16) 3 (10)
13 (21) 4 (7) 16 (26) 2 (3) 27 (44) 13 (21) 2 (3)
p 0.25 0.30 0.13 0.55 0.93 0.78 0.33
Abbreviations: IMRT = intensity-modulated radiotherapy; CRT = conventional radiotherapy; WBC = white blood cells; ANC = Absolute neutrophil count.
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response (pCR) was achieved in 19% of IMRT patients (3 of 16) and 28% (11 of 40) of CRT patients (p = 0.73). Postoperative morbidity Among patients treated with preoperative therapy who had not received previous pelvic RT, any postoperative morbidity requiring intervention (e.g., wound infections or dehiscence, high ileostomy output requiring hydration, urinary retention) were common in both groups; 47% of IMRT patients (9 of 19) and 43% of CRT patients (17 or 40) experienced such events (p = 0.78). However, postoperative complications within the pelvis (i.e., pelvic abscess/ infections or reconstructed rectum) were experienced by only 5.3% of IMRT patients (1 with necrosis/dehiscence of transanal excision site) and 15.0% of CRT patients (3 with presacral infection/abscess, 2 with necrosis/dehiscence of transanal excision site, and 1 with rectovaginal fistula) (p = 0.41). DISCUSSION In this retrospective comparison, we observed a significant reduction in GI toxicity among patients treated with IMRT compared with CRT. There were almost 50% fewer $Grade 2 GI side effects among patients treated with IMRT, primarily attributed to reduction in lower GI symptoms rather than upper GI toxicity. These findings are consistent with the improved small bowel sparing achievable with IMRT compared with older techniques. In addition to our previous study (13), multiple comparative dosimetric studies between IMRT and conventional techniques for rectal cancer have been reported (14–17), all showing a significant reduction in bowel exposure with IMRT. Furthermore, other institutional series of the clinical outcomes of IMRT in rectal cancer have reported encouraging GI toxicity rates and tumor response (19–21). To our knowledge, however, our study herein reported is the only clinical comparison to date of patient outcomes between IMRT and CRT. The clinical findings of this study verify our previous dosimetric analysis showing reduction in bowel exposure with IMRT (13). This dose reduction was seen not only with the V45 but also in the mean dose to the small bowel. Acute GI toxicity has been shown to strongly correlate with the volume of small bowel exposed to dose levels as low as 15 Gy rather than merely the volume receiving the maximal tolerated dose (i.e., V45) (7–9, 22). Thus, we assume that the clinical improvement in acute bowel toxicity here observed with IMRT was a function of dose reduction in the 15 to 40 Gy dose range in addition to the reduction in V45. The difference in GI toxicity rates between treatment groups was mainly seen in Grade 2 toxicity rather than more severe toxicity. Nevertheless, the significance of Grade 2 toxicity on patient function and quality of life should not be underrated. Grade 2 lower GI symptoms (according to the Common Terminology Criteria for Adverse Events v.3) include diarrhea of up to six stools per day, temporary intra-
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venous hydration, rectal irritation requiring medical treatment, abdominal pain and cramping, or bloody stools. Acknowledging the limitations of comparison, the GI toxicity rate among patients treated with IMRT in our series seems favorable when contrasted with historical benchmarks from trials where similar RT doses and chemotherapy were used. Grade 2 or 3 diarrhea was experienced by only 23% and 3% of our IMRT patients, respectively. By contrast, Sauer et al. (3) reported Grade 3 diarrhea in 12–18% of patients treated in a randomized trial of preoperative and postoperative chemoradiotherapy. Similarly, 36% of patients in the preoperative arm treated in the National Surgical Adjuvant Breast and Bowel Project(NSABP)R-03 experienced $Grade 3 diarrhea (2). Bosset et al. (5) reported $Grade 2 diarrhea in 38% of patients treated with preoperative chemoradiotherapy. To enhance patient setup reproducibility, most patients receiving IMRT in our series were treated in the supine position. However, prone positioning (with or without abdominal compression or a belly board) has been associated with reduction in pelvic small bowel volumes in multiple studies (23, 24), including patients treated with pelvic IMRT (25, 26). It is unclear whether the dosimetric advantages of IMRT are of independent or overlapping benefit to the advantages of prone positioning in reducing bowel exposure. At least one study comparing GI toxicity according to prone and supine positioning among patients treated with IMRT has shown no difference (27). The question is certainly appropriate for further study. It may be that the relative benefits of bladder distension, prone positioning, and belly board use, and IMRT vary by individual anatomy and circumstance. We did not detect any significant differences in acute nonGI toxicity between treatment groups. Regardless, dermatologic and urinary side effects were infrequent in both groups. Grade 2 hematologic toxicity was common in both groups (44–45%), but higher-grade events occurred in only 4% of the study patients. Among patients with gynecologic cancer, IMRT has been shown to reduce bone marrow exposure and associated hematologic suppression for patients undergoing chemoradiotherapy (28, 29). Concurrent chemotherapy (e.g., cisplatin) used for gynecologic cancer is associated with more severe hematologic suppression than standard drugs (e.g., 5-FU) given during RT for rectal cancer. Thus, we purposely elected not to attempt marrow sparing with IMRT for rectal cancer, under the assumption that such efforts could compete with bowel sparing. If more aggressive chemotherapy regimens are used in the future with RT for rectal cancer, there may be a rationale for reducing marrow exposure. Intensity-modulated radiotherapy for rectal cancer is associated with greater inhomogeneity of dose than is CRT (13, 18). Some have suggested that the dosimetric hot spots associated with IMRT could increase the risk of postoperative complications in the posterior part of the pelvis from inflammation or abscess formation (30). We observed no such increase in complications among patients treated with IMRT.
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Although not a substitute for long-term locoregional control, treatment efficacy with IMRT is supported by the pCR rate among patients who received neoadjuvant therapy. Among the 56 patients in this study who were treated preoperatively, the difference in pCR rates by treatment was not statistically different (19% pCR in IMRT patients vs. 28% in CRT patients, p = 0.73). Furthermore, the pCR rate of both groups compare favorably to published rates of 8–15% from randomized trials using similar doses of preoperative RT with 5-FU–based chemotherapy (2, 3, 31, 32). The results of our study support the efficacy of IMRT, but further follow-up will provide more definitive comparison. The usual limitations of retrospective studies apply to our series. IMRT was applied not in a prospective controlled manner but rather according to the discretion of the treating oncologist. There was no way to blind chart reviewers to the type of treatment delivered. Younger median age (by 4 years) favored the IMRT group, but we believe that this difference would not significantly affect toxicity rates. Whether the increased conformality of IMRT reduces late pelvic complications will require further patient numbers and follow-up. Late bowel complications from CRT (e.g., obstruction or chronic diarrhea) have primarily been associated with small bowel exposure within the high-dose region of pelvic fields (i.e., 45–50 Gy) (6, 33, 34). It is unclear whether the use of IMRT to reduce moderate dose levels of 15–40 Gy to bowel will also reduce late effects. Despite the above limitations, we believe that the findings of this study are important and suggest that IMRT substantially reduces the acute toxicity of pelvic RT for rectal cancer
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patients. Further investigation is warranted. Future study may include refinement in delivery with new IMRT platforms, optimal use of image guidance, and better accounting for rectal motion and distension (35, 36). In addition to reducing toxicity, IMRT may enable radiation dose escalation to the primary tumor or chemotherapy intensification (37). Caution must be taken, however, when this technology is implemented in the routine treatment of rectal cancer patients. Thorough review of published contouring guidelines (30, 38) is critical to ensuring complete targeting of the tissues at risk of harboring subclinical disease (e.g., the entire mesorectum and presacral space). In addition, care must be taken to ensure adequate margins for lesions involving the anterior mid- or upper rectum, given that significant rectal movement can occur as a result of rectal distension or bladder filling (39). Conversely, margins to account for patient or organ movement must be thoughtfully rather than just generously devised, inasmuch as small increases in PTV margins within the pelvis can substantially reduce the dosimetric advantages of IMRT (40). In summary, the implementation of IMRT for rectal cancer in our practice was associated with a clinically significant decrease in acute GI toxicity compared with traditional techniques. These clinical results confirm the findings of dosimetric studies that show the potential for IMRT to reduce bowel exposure compared with CRT. Long-term follow-up will provide more data regarding the influence of IMRT on late toxicity rates and pelvic control. Further investigation and optimization of this modality in the management of rectal cancer is warranted.
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therapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2008;70:1431–1437. Brixey CJ, Roeske JC, Lujan AE, et al. Impact of intensitymodulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys 2002;54:1388–1396. Myerson R, Drzymala R. Technical aspects of image-based treatment planning of rectal carcinoma. Semin Radiat Oncol 2003;13:433–440. Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: Preliminary results—EORTC 22921. J Clin Oncol 2005;23:5620–5627. Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203. J Clin Oncol 2006;24:4620–4625. Gallagher MJ, Brereton HD, Rostock RA, et al. A prospective study of treatment techniques to minimize the volume of pelvic small bowel with reduction of acute and late effects associated with pelvic irradiation. Int J Radiat Oncol Biol Phys 1986;12: 1565–1573. Letschert JG, Lebesque JV, Aleman BM, et al. The volume effect in radiation-related late small bowel complications: Results of a clinical study of the EORTC Radiotherapy Cooperative Group in patients treated for rectal carcinoma. Radiother Oncol 1994;32:116–123. Tournel K, De Ridder M, Engels B, et al. Assessment of intrafractional movement and internal motion in radiotherapy of rectal cancer using megavoltage computed tomography. Int J Radiat Oncol Biol Phys 2008;71:934–939. Robertson JM, Campbell JP, Yan D. Generic planning target margin for rectal cancer treatment setup variation. Int J Radiat Oncol Biol Phys 2009;74:1470–1475. Gerard JP, Chapet O, Nemoz C, et al. Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: The Lyon R0-04 phase II trial. J Clin Oncol 2003;21:1119–1124. Roels S, Duthoy W, Haustermans K, et al. Definition and delineation of the clinical target volume for rectal cancer. Int J Radiat Oncol Biol Phys 2006;65:1129–1142. Nuyttens JJ, Robertson JM, Yan D, et al. The variability of the clinical target volume for rectal cancer due to internal organ motion during adjuvant treatment. Int J Radiat Oncol Biol Phys 2002;53:497–503. Ahamad A, D’Souza W, Salehpour M, et al. Intensity-modulated radiation therapy after hysterectomy: Comparison with conventional treatment and sensitivity of the normal-tissuesparing effect to margin size. Int J Radiat Oncol Biol Phys 2005;62:1117–1124.
doi:10.1016/j.ijrobp.2011.01.051
CLINICAL INVESTIGATION
Gastrointestinal Cancer
REDUCED ACUTE BOWEL TOXICITY IN PATIENTS TREATED WITH INTENSITYMODULATED RADIOTHERAPY FOR RECTAL CANCER JASON M. SAMUELIAN, D.O.,* MATTHEW D. CALLISTER, M.D.,* JONATHAN B. ASHMAN, M.D., PH.D.,* TONIA M. YOUNG-FADOK, M.D.,y MITESH J. BORAD, M.D.,z AND LEONARD L. GUNDERSON, M.D.* *Department of Radiation Oncology and Divisions of yColorectal Surgery and zHematology-Oncology, Mayo Clinic, Scottsdale, AZ Purpose: We have previously shown that intensity-modulated radiotherapy (IMRT) can reduce dose to small bowel, bladder, and bone marrow compared with three-field conventional radiotherapy (CRT) technique in the treatment of rectal cancer. The purpose of this study was to review our experience using IMRT to treat rectal cancer and report patient clinical outcomes. Methods and Materials: A retrospective review was conducted of patients with rectal cancer who were treated at Mayo Clinic Arizona with pelvic radiotherapy (RT). Data regarding patient and tumor characteristics, treatment, acute toxicity according to the Common Terminology Criteria for Adverse Events v 3.0, tumor response, and perioperative morbidity were collected. Results: From 2004 to August 2009, 92 consecutive patients were treated. Sixty-one (66%) patients were treated with CRT, and 31 (34%) patients were treated with IMRT. All but 2 patients received concurrent chemotherapy. There was no significant difference in median dose (50.4 Gy, CRT; 50 Gy, IMRT), preoperative vs. postoperative treatment, type of concurrent chemotherapy, or history of previous pelvic RT between the CRT and IMRT patient groups. Patients who received IMRT had significantly less gastrointestinal (GI) toxicity. Sixty-two percent of patients undergoing CRT experienced $Grade 2 acute GI side effects, compared with 32% among IMRT patients (p = 0.006). The reduction in overall GI toxicity was attributable to fewer symptoms from the lower GI tract. Among CRT patients, $Grade 2 diarrhea and enteritis was experienced among 48% and 30% of patients, respectively, compared with 23% (p = 0.02) and 10% (p = 0.015) among IMRT patients. There was no significant difference in hematologic or genitourinary acute toxicity between groups. In addition, pathologic complete response rates and postoperative morbidity between treatment groups did not differ significantly. Conclusions: In the management of rectal cancer, IMRT is associated with a clinically significant reduction in lower GI toxicity compared with CRT. Further study is needed to evaluate differences in late toxicity and longterm efficacy. Ó 2012 Elsevier Inc. Intensity-modulated radiation therapy, Rectal cancer, Preoperative radiotherapy.
with acute GI toxicity rates (7–9). Compared with traditional techniques, IMRT is able to deliver increased conformality of dose and thus spare normal organ exposure. IMRT has been used in the treatment of other pelvic malignancies such as anal cancer (10), gynecologic cancers (11), and prostate cancer (12) with significant reduction in expected GI toxicity rates compared with conventional techniques. We have previously performed a dosimetric analysis comparing IMRT with conventional radiotherapy (CRT) among patients with rectal cancer (13). IMRT plans were associated with a 19% decrease in the mean dose delivered to small bowel and a 16% reduction in the V30 and V45 compared with CRT planning. In addition, IMRT enabled significant dose reduction to the bladder, bone marrow, and femoral
INTRODUCTION Adjuvant or neoadjuvant pelvic radiotherapy (RT) with concurrent chemotherapy is standard therapy for patients with $T3 or node-positive rectal cancer (1). Three- or four-field techniques have almost universally been used in clinical trials that use RT (2, 3). Gastrointestinal (GI) toxicities are the most clinically significant side effects associated with pelvic RT for this disease. Acute $Grade 3 GI toxicity is reported in 36–44% of patients undergoing RT with concurrent 5-fluorouracil (5-FU) in prospective clinical trials (2, 4, 5,). There are fewer data regarding late bowel complications, but those may be as high as 9–18 % with long-term follow-up (3, 6). The volume of bowel exposed to doses as low as 15 Gy during pelvic RT has been found to strongly correlate
Conflict of interest: none. Received Aug 30, 2010, and in revised form Jan 12, 2011. Accepted for publication Jan 26, 2011.
Reprint requests to: Matthew D. Callister, M.D., 13400 E. Shea Blvd., Scottsdale, AZ 85259. Tel: (480) 301-8120; Fax: (480) 3017687; E-mail: [email protected] Presented at the 2010 Gastrointestinal Cancers Symposium, January 22-24, 2010 Orlando, Fl. 1981
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Fig. 1. Axial (a) and sagittal (b) dosimetry in a 51-year-old woman with a cT3N1 midrectal cancer undergoing preoperative chemoradiotherapy. She was treated with a seven-field coplanar intensity-modulated radiotherapy plan of 45 Gy to the clinical target volume and 50 Gy to thegross tumor volume (target volumes not shown) using daily image guidance.
heads. Other dosimetric studies of IMRT for rectal cancer have reported similar findings with regard to bowel sparing (14–18). On the basis of the apparent benefits of IMRT in rectal cancer patients, we implemented the use of IMRT with rectal cancer patients treated at our department. We conducted this retrospective study to report the outcomes in such patients and compare them with a similar cohort of patients treated with CRT. METHODS AND MATERIALS Patient selection The medical records of all patients undergoing pelvic RT for the treatment of adenocarcinoma of the rectum at the Mayo Clinic Arizona between January 2004 and August 2009 were retrospec-
tively reviewed with approval of the Mayo Clinic Institutional Review Board. Ninety-two consecutive patients were identified. All patients were included, regardless of type of concurrent chemotherapy administered, stage, treatment intent, or previous pelvic RT. Patients whose disease was considered incurable but for whom the intent of therapy was pelvic control were included (5 patients with unresectable metastases and 5 patients with unresectable pelvic disease). Data regarding patient and tumor characteristics, treatment, acute toxicity, and tumor response were collected.
Pretreatment evaluation Before treatment, the patients’ conditions were evaluated by routine medical history and physical examination, endoscopy, endoscopic ultrasound, abdominopelvic computed tomography, and/or pelvic magnetic resonance imaging. Indications for pelvic RT included clinical or pathologic transmural penetration of tumor,
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node involvement, distal lesions that would require abdominoperineal resection without downstaging, or recurrent disease.
Treatment The treatment techniques generally applied in our department during the time of the study were as follows. All patients underwent computed tomography–based treatment planning using an anal marker. Prone positioning with bladder distension and selective use of a belly board was preferred for patients undergoing CRT (66% prone). Supine positioning with lower body immobilization and daily image guidance was more commonly used for patients undergoing IMRT (88% supine). The gross tumor volume (GTV) was contoured on the treatment planning system (Eclipse, Varian Medical Systems, Palo Alto, CA), taking into consideration all clinical information, including digital rectal examination, endoscopy, and all imaging to identify the primary tumor and enlarged regional lymph nodes, with generous coverage to the adjacent presacral space. The clinical target volume (CTV) included a minimum of 2 cm of normal rectum beyond the GTV in addition to the entire mesorectum and the internal iliac, presacral, and lower common iliac lymph nodes up to the sacral promontory and inferiorly at least to the anal–rectal junction. A second CTV (instead of a GTV) was used for postoperative patients to identify the original tumor bed. The external iliac nodes were not intentionally included except for T4 tumors with anterior pelvic extension. Normal structures identified included the proximal femora and bladder. The small bowel was not contoured as individual loops, rather as an avoidance region (peritoneal cavity inferior to L5/S1). Separate planning target volumes (PTV) were constructed for the GTV and CTV. This margin was generally 1 cm but ranged from 0.5 cm to 1 cm among patients with lower body immobilization and who underwent image-guided RT. Patients undergoing CRT were treated using three- or four-field box techniques with 18-MV photons (or 6-MV photons for posteroanterior fields). The CTV was treated to 45 Gy in 1.8 Gy fractions followed by a 5.4- to 9 Gy boost to the GTV or second CTV for preoperative and postoperative patients, respectively. Coverage of the PTV by at least 95% of the prescribed dose was generally required for both IMRT and CRT plans. The IMRT plans used a 7- to 9-field beam arrangement (usually coplanar) with 6-MV or 18-MV photons (Fig. 1). In addition to target coverage, dose homogeneity was carefully assessed with IMRT plans to minimize any volume receiving more than 5% of the prescribed dose. After target coverage and homogeneity, IMRT optimization parameters were prioritized for dose reduction to the small bowel region, followed by bladder and femora. Limited volumes of small bowel volume were allowed to exceed 45 Gy if adjacent to the boost volume, but not to exceed 50 Gy. In addition to maximum dose, multiple dose–volume parameters were specified for the small bowel volume, ranging from 15 to 40 Gym to reduce mean bowel exposure to as low as achievable. The maximum bladder dose was kept from exceeding 50 Gy, and V40 was kept less than 40% or lower if possible. The proximal femora were constrained from receiving more than 40 Gy. The dose fractionation for IMRT patients was similar to that for CRT patients except that often the GTV boost (to 50 Gy) was delivered concurrently with the 45 Gy to the pelvis. Among patients who had previously received pelvic RT, the prescribed dose (median, 30.6 Gy) was determined by the clinical judgment of the radiation oncologist. In addition to the GTV, treatment fields generously incorporated regional tissues at risk, although the whole pelvis was not included in all patients.
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The implementation of IMRT in our clinical practice began after we performed a dosimetric comparison of IMRT and CRT for rectal cancer (13). The selection of IMRT over CRT was that of the treating oncologist, and the use of IMRT for rectal cancer increased over the period of the study. Preoperative therapy for rectal cancer has been the preferred strategy at our institution among patients for whom neoadjuvant therapy is indicated, with resection 6 to 8 weeks after treatment completion. Concurrent 5-FU given by prolonged venous infusion (250 mg/m2, 5 days a week) or capecitabine (875 mg/m2, twice daily) were the predominant regimens administered with RT.
Toxicity and response assessment The patients’ conditions were evaluated weekly during therapy and before surgical resection (among preoperative patients) by the treating radiation oncologist. A complete blood count was obtained at least every other week. The clinic record was retrospectively reviewed, and data regarding acute toxicity were scored according to the Common Terminology Criteria for Adverse Events v3.0 during therapy and 8 weeks after completion among patients treated postoperatively or until 3 months after surgery among patients treated preoperatively.
Statistical analysis Statistical analysis was performed using JMP8 (Copyright Ó 2010, SAS Institute, Inc.). Student’s t test and Fisher’s exact test were used to test the significance of differences between cohorts. When applicable, all p values reported are two-sided.
RESULTS Patient, tumor, and treatment characteristics Among the 92 patients in this study, 61 (66%) were treated with CRT and 31 (34%) with IMRT. Patient, tumor, and treatment characteristics are detailed in Table 1. No significant differences were noted between the IMRT and CRT cohorts except for a slightly older median age in the CRT group. Among the 22 patients treated for recurrent disease, 8 had previous pelvic RT (5 in the IMRT group, 3 in the CRT group). Among such patients there was no difference in median previous dose (50.2 Gy for IMRT, 45 Gy for CRT, p = 0.16). The indication for pelvic RT in all patients was clinical or pathologic $T3 disease, node involvement, transanal excision, or recurrence after previous surgery with curative intent. Among patients treated with preoperative therapy, there was no difference in the rate of subsequent sphincterpreserving surgery (82% IMRT vs. 84% CRT, p = 0.82). Among the 10 patients with noncurative disease, the median delivered dose was 47.2 Gy. Acute GI toxicity The percentage of acute $Grade 2 GI toxicity by treatment group is shown in Table 2. Significantly less overall GI toxicity was observed among the patients receiving IMRT (32% vs. 62%, p = 0.006). This reduction in overall GI toxicity was attributable to fewer GI symptoms associated with the lower GI tract. Among CRT patients, $Grade 2 diarrhea and enteritis (i.e., abdominal pain; mucus, or bloody stool) was experienced among 48% and 30% of patients, respectively, compared with
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Table 1. Patient, tumor, and treatment characteristics Characteristic Median age, y (range) Sex M F Tumor status* T1–2 T3 T4 Recurrent Nodal status Positive Negative RT sequence Preoperative Postoperative Median RT dose (range) Concurrent chemotherapy 5-FU Capecitabiney None Treatment intent Curative Noncurative
IMRT n = 31 (%)
CRT n = 61 (%)
63 (26–75)
67 (38–86)
20 (65) 11 (35)
35 (57) 26 (43)
4 (13) 13 (42) 4 (13) 10 (32)
5 (8) 37 (61) 7 (11) 12 (20)
13 (42%) 18 (58%)
27 (44%) 34 (56%)
25 (81) 6 (19) 50 Gy (25.2–56)
56 (92) 5 (8) 50.4 Gy (25.2–54)
p 0.007 0.51 0.36
0.83 0.17 0.90 0.56 13 (42) 18 (58) 0 (0)
27 (44) 32 (53) 2 (3)
29 (94) 2 (6)
53 (87) 8 (13)
0.49
Abbreviations: IMRT = intensity-modulated radiotherapy; CRT = conventional radiotherapy; 5-FU = 5-fluorouracil. * Clinical stage (if treated preoperatively) or pathologic stage (if treated with initial surgery). y Five patients in the CRT group received concurrent oxaliplatin and 2 patients also received leucovorin.
23% (p = 0.02) and 10% (p = 0.015) of IMRT patients. Intravenous hydration was required by 10% of CRT patients ($Grade 2 dehydration), compared with no patients undergoing IMRT (p = 0.093). Only 3% of IMRT patients and 10% of CRT patients (p = 0.42) experienced acute Grade 3 GI toxicity, and no patients experienced Grade 4 side effects. The grade distribution of maximum experienced lower GI toxicity (diarrhea, enteritis, and proctitis) was more favorable among the patients treated with IMRT (Fig. 2). Reanalysis of the data with the exclusion of the 8 patients who had previously received pelvic RT revealed no major Table 2. Acute $ Grade 2 gastrointestinal toxicities Toxicity Nausea Vomiting Diarrhea Enteritis Proctitis Dehydration Any GI toxicity
IMRT n = 31 (%)
CRT n = 61 (%)
0 (0) 0 (0) 7 (23) 2 (6) 3 (10) 0 (0) 10 (32)
5 (8) 1 (2) 29 (48) 18 (30) 11 (18) 6 (10) 38 (62)
Fig. 2. Distribution of lower gastrointestinal toxicity in rectal cancer patients treated with conventional radiotherapy (CRT) and intensity-modulated radiotherapy (IMRT).
difference in acute GI toxicity; 67% of CRT patients experienced $Grade 2 GI toxicity, compared with 33% of IMRT patients (p = 0.004). Similarly, exclusion of the patients whose treatment was considered noncurative did not affect this endpoint; 60% of CRT patients experienced $Grade 2 GI toxicity, compared with 31% of IMRT patients (p = 0.011). Five patients in the CRT group received concurrent oxaliplatin, but their exclusion from analysis did not change the study findings; $Grade 2 GI toxicity was experienced by 61% of CRT patients vs. 32% of IMRT patients (p = 0.011). Non-GI toxicity Grade 2 or greater acute non-GI toxicity by treatment group is shown in Table 3. No significant differences were identified. Non-GI Grade 3 toxicity was experienced by only 6 patients; 4 patients experienced Grade 3 hematologic toxicity (3 CRT, 1 IMRT), and 2 patients developed Grade 3 skin toxicity (1 CRT, 1 IMRT). There was no Grade 4 toxicity. Between the IMRT and CRT groups, patients requiring RT treatment breaks (6.5% vs. 16.4%, p = 0.33) or early termination of therapy (9.7% vs. 6.6%, p = 0.68) did not differ significantly. Pathologic response Fifty-six patients underwent preoperative chemoradiotherapy for newly diagnosed rectal cancer. A complete pathologic Table 3. Acute $ Grade 2 nongastrointestinal toxicities Toxicity
p 0.16 1.0 0.02 0.015 0.37 0.093 0.006
Abbreviations: IMRT = intensity-modulated radiotherapy; CRT = conventional radiotherapy; GI = gastrointestinal.
Hematologic WBC ANC Hemoglobin Platelets Any hematologic Any urinary Skin
IMRT n = 31 (%)
CRT n = 61 (%)
3 (10) 0 (0) 13 (42) 0 (0) 14 (45) 5 (16) 3 (10)
13 (21) 4 (7) 16 (26) 2 (3) 27 (44) 13 (21) 2 (3)
p 0.25 0.30 0.13 0.55 0.93 0.78 0.33
Abbreviations: IMRT = intensity-modulated radiotherapy; CRT = conventional radiotherapy; WBC = white blood cells; ANC = Absolute neutrophil count.
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response (pCR) was achieved in 19% of IMRT patients (3 of 16) and 28% (11 of 40) of CRT patients (p = 0.73). Postoperative morbidity Among patients treated with preoperative therapy who had not received previous pelvic RT, any postoperative morbidity requiring intervention (e.g., wound infections or dehiscence, high ileostomy output requiring hydration, urinary retention) were common in both groups; 47% of IMRT patients (9 of 19) and 43% of CRT patients (17 or 40) experienced such events (p = 0.78). However, postoperative complications within the pelvis (i.e., pelvic abscess/ infections or reconstructed rectum) were experienced by only 5.3% of IMRT patients (1 with necrosis/dehiscence of transanal excision site) and 15.0% of CRT patients (3 with presacral infection/abscess, 2 with necrosis/dehiscence of transanal excision site, and 1 with rectovaginal fistula) (p = 0.41). DISCUSSION In this retrospective comparison, we observed a significant reduction in GI toxicity among patients treated with IMRT compared with CRT. There were almost 50% fewer $Grade 2 GI side effects among patients treated with IMRT, primarily attributed to reduction in lower GI symptoms rather than upper GI toxicity. These findings are consistent with the improved small bowel sparing achievable with IMRT compared with older techniques. In addition to our previous study (13), multiple comparative dosimetric studies between IMRT and conventional techniques for rectal cancer have been reported (14–17), all showing a significant reduction in bowel exposure with IMRT. Furthermore, other institutional series of the clinical outcomes of IMRT in rectal cancer have reported encouraging GI toxicity rates and tumor response (19–21). To our knowledge, however, our study herein reported is the only clinical comparison to date of patient outcomes between IMRT and CRT. The clinical findings of this study verify our previous dosimetric analysis showing reduction in bowel exposure with IMRT (13). This dose reduction was seen not only with the V45 but also in the mean dose to the small bowel. Acute GI toxicity has been shown to strongly correlate with the volume of small bowel exposed to dose levels as low as 15 Gy rather than merely the volume receiving the maximal tolerated dose (i.e., V45) (7–9, 22). Thus, we assume that the clinical improvement in acute bowel toxicity here observed with IMRT was a function of dose reduction in the 15 to 40 Gy dose range in addition to the reduction in V45. The difference in GI toxicity rates between treatment groups was mainly seen in Grade 2 toxicity rather than more severe toxicity. Nevertheless, the significance of Grade 2 toxicity on patient function and quality of life should not be underrated. Grade 2 lower GI symptoms (according to the Common Terminology Criteria for Adverse Events v.3) include diarrhea of up to six stools per day, temporary intra-
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venous hydration, rectal irritation requiring medical treatment, abdominal pain and cramping, or bloody stools. Acknowledging the limitations of comparison, the GI toxicity rate among patients treated with IMRT in our series seems favorable when contrasted with historical benchmarks from trials where similar RT doses and chemotherapy were used. Grade 2 or 3 diarrhea was experienced by only 23% and 3% of our IMRT patients, respectively. By contrast, Sauer et al. (3) reported Grade 3 diarrhea in 12–18% of patients treated in a randomized trial of preoperative and postoperative chemoradiotherapy. Similarly, 36% of patients in the preoperative arm treated in the National Surgical Adjuvant Breast and Bowel Project(NSABP)R-03 experienced $Grade 3 diarrhea (2). Bosset et al. (5) reported $Grade 2 diarrhea in 38% of patients treated with preoperative chemoradiotherapy. To enhance patient setup reproducibility, most patients receiving IMRT in our series were treated in the supine position. However, prone positioning (with or without abdominal compression or a belly board) has been associated with reduction in pelvic small bowel volumes in multiple studies (23, 24), including patients treated with pelvic IMRT (25, 26). It is unclear whether the dosimetric advantages of IMRT are of independent or overlapping benefit to the advantages of prone positioning in reducing bowel exposure. At least one study comparing GI toxicity according to prone and supine positioning among patients treated with IMRT has shown no difference (27). The question is certainly appropriate for further study. It may be that the relative benefits of bladder distension, prone positioning, and belly board use, and IMRT vary by individual anatomy and circumstance. We did not detect any significant differences in acute nonGI toxicity between treatment groups. Regardless, dermatologic and urinary side effects were infrequent in both groups. Grade 2 hematologic toxicity was common in both groups (44–45%), but higher-grade events occurred in only 4% of the study patients. Among patients with gynecologic cancer, IMRT has been shown to reduce bone marrow exposure and associated hematologic suppression for patients undergoing chemoradiotherapy (28, 29). Concurrent chemotherapy (e.g., cisplatin) used for gynecologic cancer is associated with more severe hematologic suppression than standard drugs (e.g., 5-FU) given during RT for rectal cancer. Thus, we purposely elected not to attempt marrow sparing with IMRT for rectal cancer, under the assumption that such efforts could compete with bowel sparing. If more aggressive chemotherapy regimens are used in the future with RT for rectal cancer, there may be a rationale for reducing marrow exposure. Intensity-modulated radiotherapy for rectal cancer is associated with greater inhomogeneity of dose than is CRT (13, 18). Some have suggested that the dosimetric hot spots associated with IMRT could increase the risk of postoperative complications in the posterior part of the pelvis from inflammation or abscess formation (30). We observed no such increase in complications among patients treated with IMRT.
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Although not a substitute for long-term locoregional control, treatment efficacy with IMRT is supported by the pCR rate among patients who received neoadjuvant therapy. Among the 56 patients in this study who were treated preoperatively, the difference in pCR rates by treatment was not statistically different (19% pCR in IMRT patients vs. 28% in CRT patients, p = 0.73). Furthermore, the pCR rate of both groups compare favorably to published rates of 8–15% from randomized trials using similar doses of preoperative RT with 5-FU–based chemotherapy (2, 3, 31, 32). The results of our study support the efficacy of IMRT, but further follow-up will provide more definitive comparison. The usual limitations of retrospective studies apply to our series. IMRT was applied not in a prospective controlled manner but rather according to the discretion of the treating oncologist. There was no way to blind chart reviewers to the type of treatment delivered. Younger median age (by 4 years) favored the IMRT group, but we believe that this difference would not significantly affect toxicity rates. Whether the increased conformality of IMRT reduces late pelvic complications will require further patient numbers and follow-up. Late bowel complications from CRT (e.g., obstruction or chronic diarrhea) have primarily been associated with small bowel exposure within the high-dose region of pelvic fields (i.e., 45–50 Gy) (6, 33, 34). It is unclear whether the use of IMRT to reduce moderate dose levels of 15–40 Gy to bowel will also reduce late effects. Despite the above limitations, we believe that the findings of this study are important and suggest that IMRT substantially reduces the acute toxicity of pelvic RT for rectal cancer
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patients. Further investigation is warranted. Future study may include refinement in delivery with new IMRT platforms, optimal use of image guidance, and better accounting for rectal motion and distension (35, 36). In addition to reducing toxicity, IMRT may enable radiation dose escalation to the primary tumor or chemotherapy intensification (37). Caution must be taken, however, when this technology is implemented in the routine treatment of rectal cancer patients. Thorough review of published contouring guidelines (30, 38) is critical to ensuring complete targeting of the tissues at risk of harboring subclinical disease (e.g., the entire mesorectum and presacral space). In addition, care must be taken to ensure adequate margins for lesions involving the anterior mid- or upper rectum, given that significant rectal movement can occur as a result of rectal distension or bladder filling (39). Conversely, margins to account for patient or organ movement must be thoughtfully rather than just generously devised, inasmuch as small increases in PTV margins within the pelvis can substantially reduce the dosimetric advantages of IMRT (40). In summary, the implementation of IMRT for rectal cancer in our practice was associated with a clinically significant decrease in acute GI toxicity compared with traditional techniques. These clinical results confirm the findings of dosimetric studies that show the potential for IMRT to reduce bowel exposure compared with CRT. Long-term follow-up will provide more data regarding the influence of IMRT on late toxicity rates and pelvic control. Further investigation and optimization of this modality in the management of rectal cancer is warranted.
REFERENCES 1. Wolmark N, Wieand HS, Hyams DM, et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 2000;92:388–396. 2. Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009;27:5124–5130. 3. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–1740. 4. Smalley SR, Benedetti JK, Williamson SK, et al. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 2006;24:3542–3547. 5. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355:1114–1123. 6. Mak AC, Rich TA, Schultheiss TE, et al. Late complications of postoperative radiation therapy for cancer of the rectum and rectosigmoid. Int J Radiat Oncol Biol Phys 1994;28:597–603. 7. Robertson JM, Lockman D, Yan D, et al. 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. 8. Baglan KL, Frazier RC, Yan D, et al. The dose-volume relationship of acute small bowel toxicity from concurrent 5-FU-
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