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Preoperative Chemoradiation Therapy Shows Improved Clinical Benefit in Patients with Rectal Cancer
Research inBrief Preoperative Chemoradiation Therapy Shows Improved Clinical Benefit in Patients with Rectal Cancer Rationale • The combination of postoperative radiation therapy (RT) and 5-fluorouracil (5-FU)–based adjuvant chemotherapy has been shown to be effective in reducing the risk of local recurrence of rectal cancer after surgery.1-3 In a Gastrointestinal Tumor Study Group trial, the recurrence rate for patients treated with adjuvant chemotherapy was significantly reduced compared with the group treated with surgery alone (33% vs. 55%).3 These results prompted the use of chemo-radiation therapy as the standard postoperative strategy for patients with stage II/III rectal cancer in 1990.4 • Recent studies have suggested that preoperative RT may potentially be more effective in reducing local recurrence rates compared with postoperative chemoradiation therapy.5 Preoperative radiation has resulted in an improvement in survival trends of patients with rectal cancer compared with surgery.6,7 This effect was not expected from a local treatment aimed at reducing pelvic recurrence after a surgical procedure. • In operable tumors, the results of the Swedish Rectal Cancer Trial have shown reduced local recurrence rates and improved overall survival with a short course of preoperative RT compared with conventional surgery alone.6 In addition, significant reduction in the risk of recurrences with short-term preoperative RT was also recently demonstrated by the Dutch Colorectal Prepared by: G. Kesava Reddy, PhD Reviewed by: Eric Nadler, MD, Vinay K. Jain, MD
Figure 1: Trial Design Comparing Radiation Therapy Before Versus After Total Mesorectal Excision Surgery9 5-FU 1000 mg/m2 per day (120-hour continuous infusion) 5-FU 500 mg/m2 per day (5-day infusion)
Arm 1
R A Surgery N D O Weeks 0 2 4 M I Z RT 50.4 Gy E
RT 50.4 Gy RT Boost
6
8
10
12
14
16
18
20
22
24
Surgery
Arm 2
For both treatment arms, 5-FU 1000 mg/m2 was administered daily in 120-hour intravenous infusions for 2 cycles every 5 weeks. Afterward, the 5-FU dosage was decreased to 500 mg/m2 given for 5 consecutive days every 4 weeks as an intravenous bolus for 4 cycles.
Cancer Group.8 Several phase III trials have recently demonstrated that the addition of chemotherapy to these other modalities may confer additional benefit. These trials suggest that preoperative chemoradiation therapy is effective against local recurrences as well as improvements in overall survival and sphincter preservation in patients with rectal cancer. The findings of these studies are summarized herein.
Preoperative Versus Postoperative Chemoradiation Therapy for Locally Advanced Rectal Cancer In a phase III trial, eligible patients with stage T3/4 or node-positive disease were randomized to receive preoperative or postoperative chemoradiation therapy.9 Patients in the postoperative treatment arm underwent immediate surgery (mesorectal excision) followed by adjuvant chemoradiation therapy after
recovery (within 4 weeks of the surgery). Radiation therapy consisted of a total of 50.4 Gy delivered in 28 fractions (1.8 Gy each) 5 times weekly. An additional boost was given to the tumor bed at 5.4 Gy for 3 days. During the first and fifth weeks of RT, patients were administered concurrent chemo-ptherapy consisting of 5-FU (1000 mg/m2 daily) as a 120-hour continuous intravenous infusion. Four more cycles of bolus 5-FU (500 mg/m2 daily) were administered for 5 consecutive days every 4 weeks after completion of the chemoradiation therapy (Figure 1).9 Patients in the preoperative chemotherapy arm received a preoperative course of chemoradiation therapy delivered at the same dose and schedule as the concurrent chemoradiation therapy cycles in the postoperative arm, excluding the 5.4-Gy small-volume boost. Surgery was performed 4-6 weeks after completion of preoperative concurrent chemoradiation therapy. Four weeks after surgery, the additional
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Table 2: Clinical Outcome for Preoperative Versus Postoperative Chemoradiation Therapy in Rectal Cancer9
Table 1: Patient and Tumor Characteristics9 Characteristic
Preoperative CRT (n = 405)
Postoperative CRT (n = 394)
Median Age (Years)
62
62
Sex Male
286
262
Female
119
132
Clinical Tumor Stage (%)
Preoperative CRT (%)
Postoperative CRT (%)
P Value
5-Year Overall Survival
76
74
0.80
5-Year Disease-Free Survival
68
65
0.32
5-Year Local Recurrence Rate
6
13
0.006
5-Year Incidence of Distant Metastasis
36
38
0.84
Sphincter Preservation Rate
39
19
0.004
Outcome
T1/2
5
5
Pathologic Complete Response
8
0
T3
68
66
Positive Stage III Lymph Nodes
25
40
T4
6
3
Unknown
21
26
Nodal Involvement (%) Negative
41
39
Positive
54
51
Unknown
5
10
Abbreviation: CRT = chemoradiation therapy
4 cycles of bolus 5-FU (500 mg/m2 daily) were administered for 5 consecutive days every 4 weeks. The trial enrolled a total of 823 patients, and 799 were randomized to the preoperative (n = 405) and postoperative (n = 394) treatment arms. The tumor characteristics of the eligible patients were well balanced by randomization of the group (Table 1).9 The rate of pathologic complete response was 8% in the preoperative arm, compared with zero in the postoperative arm. Only 25% of the patients had positive lymph nodes of TNM stage 3 in the preoperative treatment group, compared with 40% in the postoperative treatment group (Table 2).9 Before randomization, surgeons made a determination whether they thought the patient would be a candidate for sphincter-sparing surgery. Among 194 patients who were believed to be destined for abdominoperineal excision, the sphincter preservation rate increased significantly in the preoperative therapy arm compared with the postoperative therapy arm (39% vs. 19%; P = 0.004; Table 2). The 5-year disease-free survival rates were 68% for patients who
< 0.001
Abbreviation: CRT = chemoradiation therapy
received preoperative chemoradiation therapy and 65% in the group that was treated postoperatively. Five-year overall survival rates were 76% and 74% in the preoperative and postoperative chemotherapy arms, respectively (Table 3).9 Although there were no significant differences in disease-free or overall survival between the 2 treatment strategies, the cumulative incidence of local relapse at 5 years was significantly reduced in the patients who received preoperative chemoradiation therapy compared with the patients in the postoperative therapy group (6% vs. 13%; P = 0.006). Yet, the development of distant metastases was similar in both groups at 5 years (36% vs. 38%; P = 0.84; Table 3). The major acute toxicity was grade 3 diarrhea, which was significantly less common in patients treated with preoperative chemoradiation therapy compared with the postoperative therapy arm (12% vs. 18%; P = 0.04). Overall, grade 3/4 acute adverse events were significantly less frequent in the preoperative chemoradiation therapy group compared with the postoperative chemoradiation therapy group (27% vs. 40%; P = 0.001). Similarly, the chronic toxicities were significantly less common in the preoperative therapy arm compared with the postoperative therapy arm (14% vs. 24%; P = 0.01). This disparity resulted from a higher incidence of chronic anastomosis (ie, structures at anastomotic site) in the postoperative
164 • Clinical Colorectal Cancer September 2005
chemoradiation therapy group (12% vs. 4%; P = 0.003). The incidence of chronic gastrointestinal and bladder toxicities was similar for both treatment groups.
Phase III Study of Preoperative ShortTerm Radiation Therapy Versus Preoperative Conventionally Fractionated Chemoradiation A phase III study evaluated a total of 316 patients with T3/4 resectable rectal adenocarcinoma, of whom 312 eligible patients were randomized to receive preoperative conventionally fractionated chemoradiation (n = 157) or preoperative short-term RT (n = 155).10 Patients in the conventionally fractionated chemoradiation arm were treated with chemoradiation with a total dose of 50.4 Gy given at 1.8 Gy per fraction. They received treatment for 5.5 weeks concomitantly with 2 courses of bolus 5-FU/leucovorin (LV; LV 20 mg/m2 per day followed 10-20 minutes later by 5-FU 325 mg/m2 per day on 5 consecutive days) and underwent surgery at 4-6 weeks after completion of their preoperative therapy. Patients in the short-term RT arm were treated with 5 fractions of 5 Gy short-term RT and underwent surgery within 7 days. The median intervals between the beginning of irradiation and surgery were 78 days (range, 14-218 days) for
Table 3: Grade 3/4 Adverse Events with Preoperative Versus Postoperative Chemoradiation Therapy in Patients with Rectal Cancer9 Preoperative CRT (%)
Postoperative CRT (%)
P Value
Diarrhea
12
18
0.04
Any grade 3/4 toxicity
27
40
0.001
Gastrointestinal
9
15
0.07
Any grade 3/4 toxicity
14
24
0.01
Adverse Event Acute
Chronic
Abbreviation: CRT = chemoradiation therapy
patients treated with conventionally fractionated chemoradiation and 8 days (range, 5-80 days) for patients receiving short-term RT. Conventionally fractionated RT was better at cytoreduction, with a complete clinical response rate of 13% (18 of 139 patients), compared with 2% (3 of 155) among patients receiving short-term irradiation before surgery (P < 0.001). However, the sphincter preservation rate did not differ between the 2 treatment groups (58% for the conventionally fractionated chemoradiation arm vs. 61% for patients in the short-term RT arm; P = 0.57). Similarly, no differences were seen in sphincter preservation rates in any of the subgroups based on factors such as type of surgery intended before randomization or whether the tumor was ≤ 6 cm from the anal verge.
Ongoing Trials Trials are currently under way to optimize preoperative therapy in patients with carcinoma of the rectum. Previously, Rodel and colleagues reported results of a phase I/II trial using an intensified neoadjuvant chemoradiation therapy program in which RT is delivered over a period of 5 weeks with 2 cycles of XELOX (capecitabine/oxaliplatin).11 The
results of this trial demonstrated that 19% of the patients had a complete pathologic response with XELOX and RT. This group is now conducting a randomized trial to compare neoadjuvant intensified RT combined with XELOX versus the 5FU/LV neoadjuvant regimen evaluated in the trial discussed previously. Additionally, 2 other trials, the European Organization for Research and the Treatment of Cancer 22921 study and the Preoperative Radiotherapy and/or Adjuvant Chemotherapy Combined with TME Surgery in Operable Rectal Cancer study, are assessing the role of preoperative chemotherapy in the management of locally advanced rectal cancer.
Clinical Relevance Preoperative chemoradiation therapy results in higher rates of sphincter preservation and locoregional control compared with postoperative therapy in patients with surgically resected rectal cancer. Furthermore, rates of acute and chronic toxicities were reduced significantly by the delivery of chemoradiation therapy in the neoadjuvant setting. Although preoperative chemoradiation therapy may now be considered a standard of
care, its role in the improvement of sphincter preservation rates still appears to be less clear. In particular, the Polish phase III trial recently demonstrated that preoperative chemoradiation therapy has no additional benefit in sphincter preservation compared with preoperative RT in patients with rectal cancer.10 However, the Polish phase III study was relatively small and has short-term follow-up to realize the benefits from the addition of chemotherapy to preoperative RT.
References 1. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 1988; 80:21-29. 2. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for highrisk rectal carcinoma. N Engl J Med 1991; 324:709-715. 3. Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med 1985; 312:1465-1472. 4. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990; 264:1444-1450. 5. Enker WE. Total mesorectal excision--the new golden standard of surgery for rectal cancer. Ann Med 1997; 29:127-133. 6. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 1997; 336:980-987. 7. Marsh PJ, James RD, Schofield PF. Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective, randomized trial. Dis Colon Rectum 1994; 37:1205-1214. 8. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345:638-646. 9. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiation therapy for rectal cancer. N Engl J Med 2004; 351:1731-1740. 10. Bujko K, Nowacki MP, NasierowskaGuttmejer A, et al. Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother Oncol 2004; 72:15-24. 11. Rodel C, Grabenbauer GG, Papadopoulos T, et al. Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 2003; 21:3098-3104.
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Figure 1: Trial Design Comparing Radiation Therapy Before Versus After Total Mesorectal Excision Surgery9 5-FU 1000 mg/m2 per day (120-hour continuous infusion) 5-FU 500 mg/m2 per day (5-day infusion)
Arm 1
R A Surgery N D O Weeks 0 2 4 M I Z RT 50.4 Gy E
RT 50.4 Gy RT Boost
6
8
10
12
14
16
18
20
22
24
Surgery
Arm 2
For both treatment arms, 5-FU 1000 mg/m2 was administered daily in 120-hour intravenous infusions for 2 cycles every 5 weeks. Afterward, the 5-FU dosage was decreased to 500 mg/m2 given for 5 consecutive days every 4 weeks as an intravenous bolus for 4 cycles.
Cancer Group.8 Several phase III trials have recently demonstrated that the addition of chemotherapy to these other modalities may confer additional benefit. These trials suggest that preoperative chemoradiation therapy is effective against local recurrences as well as improvements in overall survival and sphincter preservation in patients with rectal cancer. The findings of these studies are summarized herein.
Preoperative Versus Postoperative Chemoradiation Therapy for Locally Advanced Rectal Cancer In a phase III trial, eligible patients with stage T3/4 or node-positive disease were randomized to receive preoperative or postoperative chemoradiation therapy.9 Patients in the postoperative treatment arm underwent immediate surgery (mesorectal excision) followed by adjuvant chemoradiation therapy after
recovery (within 4 weeks of the surgery). Radiation therapy consisted of a total of 50.4 Gy delivered in 28 fractions (1.8 Gy each) 5 times weekly. An additional boost was given to the tumor bed at 5.4 Gy for 3 days. During the first and fifth weeks of RT, patients were administered concurrent chemo-ptherapy consisting of 5-FU (1000 mg/m2 daily) as a 120-hour continuous intravenous infusion. Four more cycles of bolus 5-FU (500 mg/m2 daily) were administered for 5 consecutive days every 4 weeks after completion of the chemoradiation therapy (Figure 1).9 Patients in the preoperative chemotherapy arm received a preoperative course of chemoradiation therapy delivered at the same dose and schedule as the concurrent chemoradiation therapy cycles in the postoperative arm, excluding the 5.4-Gy small-volume boost. Surgery was performed 4-6 weeks after completion of preoperative concurrent chemoradiation therapy. Four weeks after surgery, the additional
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Colorectal Cancer September 2005
• 163
Table 2: Clinical Outcome for Preoperative Versus Postoperative Chemoradiation Therapy in Rectal Cancer9
Table 1: Patient and Tumor Characteristics9 Characteristic
Preoperative CRT (n = 405)
Postoperative CRT (n = 394)
Median Age (Years)
62
62
Sex Male
286
262
Female
119
132
Clinical Tumor Stage (%)
Preoperative CRT (%)
Postoperative CRT (%)
P Value
5-Year Overall Survival
76
74
0.80
5-Year Disease-Free Survival
68
65
0.32
5-Year Local Recurrence Rate
6
13
0.006
5-Year Incidence of Distant Metastasis
36
38
0.84
Sphincter Preservation Rate
39
19
0.004
Outcome
T1/2
5
5
Pathologic Complete Response
8
0
T3
68
66
Positive Stage III Lymph Nodes
25
40
T4
6
3
Unknown
21
26
Nodal Involvement (%) Negative
41
39
Positive
54
51
Unknown
5
10
Abbreviation: CRT = chemoradiation therapy
4 cycles of bolus 5-FU (500 mg/m2 daily) were administered for 5 consecutive days every 4 weeks. The trial enrolled a total of 823 patients, and 799 were randomized to the preoperative (n = 405) and postoperative (n = 394) treatment arms. The tumor characteristics of the eligible patients were well balanced by randomization of the group (Table 1).9 The rate of pathologic complete response was 8% in the preoperative arm, compared with zero in the postoperative arm. Only 25% of the patients had positive lymph nodes of TNM stage 3 in the preoperative treatment group, compared with 40% in the postoperative treatment group (Table 2).9 Before randomization, surgeons made a determination whether they thought the patient would be a candidate for sphincter-sparing surgery. Among 194 patients who were believed to be destined for abdominoperineal excision, the sphincter preservation rate increased significantly in the preoperative therapy arm compared with the postoperative therapy arm (39% vs. 19%; P = 0.004; Table 2). The 5-year disease-free survival rates were 68% for patients who
< 0.001
Abbreviation: CRT = chemoradiation therapy
received preoperative chemoradiation therapy and 65% in the group that was treated postoperatively. Five-year overall survival rates were 76% and 74% in the preoperative and postoperative chemotherapy arms, respectively (Table 3).9 Although there were no significant differences in disease-free or overall survival between the 2 treatment strategies, the cumulative incidence of local relapse at 5 years was significantly reduced in the patients who received preoperative chemoradiation therapy compared with the patients in the postoperative therapy group (6% vs. 13%; P = 0.006). Yet, the development of distant metastases was similar in both groups at 5 years (36% vs. 38%; P = 0.84; Table 3). The major acute toxicity was grade 3 diarrhea, which was significantly less common in patients treated with preoperative chemoradiation therapy compared with the postoperative therapy arm (12% vs. 18%; P = 0.04). Overall, grade 3/4 acute adverse events were significantly less frequent in the preoperative chemoradiation therapy group compared with the postoperative chemoradiation therapy group (27% vs. 40%; P = 0.001). Similarly, the chronic toxicities were significantly less common in the preoperative therapy arm compared with the postoperative therapy arm (14% vs. 24%; P = 0.01). This disparity resulted from a higher incidence of chronic anastomosis (ie, structures at anastomotic site) in the postoperative
164 • Clinical Colorectal Cancer September 2005
chemoradiation therapy group (12% vs. 4%; P = 0.003). The incidence of chronic gastrointestinal and bladder toxicities was similar for both treatment groups.
Phase III Study of Preoperative ShortTerm Radiation Therapy Versus Preoperative Conventionally Fractionated Chemoradiation A phase III study evaluated a total of 316 patients with T3/4 resectable rectal adenocarcinoma, of whom 312 eligible patients were randomized to receive preoperative conventionally fractionated chemoradiation (n = 157) or preoperative short-term RT (n = 155).10 Patients in the conventionally fractionated chemoradiation arm were treated with chemoradiation with a total dose of 50.4 Gy given at 1.8 Gy per fraction. They received treatment for 5.5 weeks concomitantly with 2 courses of bolus 5-FU/leucovorin (LV; LV 20 mg/m2 per day followed 10-20 minutes later by 5-FU 325 mg/m2 per day on 5 consecutive days) and underwent surgery at 4-6 weeks after completion of their preoperative therapy. Patients in the short-term RT arm were treated with 5 fractions of 5 Gy short-term RT and underwent surgery within 7 days. The median intervals between the beginning of irradiation and surgery were 78 days (range, 14-218 days) for
Table 3: Grade 3/4 Adverse Events with Preoperative Versus Postoperative Chemoradiation Therapy in Patients with Rectal Cancer9 Preoperative CRT (%)
Postoperative CRT (%)
P Value
Diarrhea
12
18
0.04
Any grade 3/4 toxicity
27
40
0.001
Gastrointestinal
9
15
0.07
Any grade 3/4 toxicity
14
24
0.01
Adverse Event Acute
Chronic
Abbreviation: CRT = chemoradiation therapy
patients treated with conventionally fractionated chemoradiation and 8 days (range, 5-80 days) for patients receiving short-term RT. Conventionally fractionated RT was better at cytoreduction, with a complete clinical response rate of 13% (18 of 139 patients), compared with 2% (3 of 155) among patients receiving short-term irradiation before surgery (P < 0.001). However, the sphincter preservation rate did not differ between the 2 treatment groups (58% for the conventionally fractionated chemoradiation arm vs. 61% for patients in the short-term RT arm; P = 0.57). Similarly, no differences were seen in sphincter preservation rates in any of the subgroups based on factors such as type of surgery intended before randomization or whether the tumor was ≤ 6 cm from the anal verge.
Ongoing Trials Trials are currently under way to optimize preoperative therapy in patients with carcinoma of the rectum. Previously, Rodel and colleagues reported results of a phase I/II trial using an intensified neoadjuvant chemoradiation therapy program in which RT is delivered over a period of 5 weeks with 2 cycles of XELOX (capecitabine/oxaliplatin).11 The
results of this trial demonstrated that 19% of the patients had a complete pathologic response with XELOX and RT. This group is now conducting a randomized trial to compare neoadjuvant intensified RT combined with XELOX versus the 5FU/LV neoadjuvant regimen evaluated in the trial discussed previously. Additionally, 2 other trials, the European Organization for Research and the Treatment of Cancer 22921 study and the Preoperative Radiotherapy and/or Adjuvant Chemotherapy Combined with TME Surgery in Operable Rectal Cancer study, are assessing the role of preoperative chemotherapy in the management of locally advanced rectal cancer.
Clinical Relevance Preoperative chemoradiation therapy results in higher rates of sphincter preservation and locoregional control compared with postoperative therapy in patients with surgically resected rectal cancer. Furthermore, rates of acute and chronic toxicities were reduced significantly by the delivery of chemoradiation therapy in the neoadjuvant setting. Although preoperative chemoradiation therapy may now be considered a standard of
care, its role in the improvement of sphincter preservation rates still appears to be less clear. In particular, the Polish phase III trial recently demonstrated that preoperative chemoradiation therapy has no additional benefit in sphincter preservation compared with preoperative RT in patients with rectal cancer.10 However, the Polish phase III study was relatively small and has short-term follow-up to realize the benefits from the addition of chemotherapy to preoperative RT.
References 1. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 1988; 80:21-29. 2. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for highrisk rectal carcinoma. N Engl J Med 1991; 324:709-715. 3. Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med 1985; 312:1465-1472. 4. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990; 264:1444-1450. 5. Enker WE. Total mesorectal excision--the new golden standard of surgery for rectal cancer. Ann Med 1997; 29:127-133. 6. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 1997; 336:980-987. 7. Marsh PJ, James RD, Schofield PF. Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective, randomized trial. Dis Colon Rectum 1994; 37:1205-1214. 8. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345:638-646. 9. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiation therapy for rectal cancer. N Engl J Med 2004; 351:1731-1740. 10. Bujko K, Nowacki MP, NasierowskaGuttmejer A, et al. Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother Oncol 2004; 72:15-24. 11. Rodel C, Grabenbauer GG, Papadopoulos T, et al. Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 2003; 21:3098-3104.
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