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American Journal of Clinical Oncology:
doi: 10.1097/COC.0b013e318201a3da
Original Articles: Gastrointestinal

Postoperative Low Pelvic Radiotherapy and Chemotherapy for Stage II and III Rectal Cancer

Hsu, Hsuan Chih MD*,†; Chen, Hong Hwa MD; Chang, Chia Lo MD; Fang, Fu Min MD, PhD*,§; Wang, Chong Jong MD*; Chen, Hui Chun MD*; Huang, Yu Jie MD*; Wang, Chang Yu MD*; Wang, Yu Ming MD*; Huang, Eng Yen MD*,§

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Author Information

Departments of *Radiation Oncology

Colorectal Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung

School of Medicine

§School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan

The authors declare no conflicts of interest.

Reprints: Eng Yen Huang, MD, Department of Radiation Oncology, Chang Gung Memorial Hospital, 123, Ta-Pei Rd., Niao Sung Hsian, Kaohsiung, Taiwan. e-mail: huangengyen@gmail.com.

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Abstract

Objectives: To evaluate whether postoperative low pelvic radiotherapy (RT) combined with chemotherapy is an appropriate treatment for stage II and III rectal cancer.

Methods: Between November 1997 and May 2006, 104 patients with stage II and III rectal cancer underwent surgery as the primary treatment followed by postoperative RT combined with chemotherapy in our institute and were reviewed retrospectively. Sixty-nine patients received low pelvic RT only (upper margin at 1 cm above the low end of the sacroiliac joint; median dose 54 Gy) (low pelvic RT group) and the other 35 patients received whole pelvic RT (upper margin at the mid L5; median dose 43.2 Gy) and subsequently received a boost to the low pelvis (total median dose 54 Gy) (whole pelvic RT group).

Results: The 5-year overall survival rate, local control rate, and distant metastasis-free rate were 72% versus 63%, 86% versus 84%, and 66% versus 62% for low pelvic versus whole pelvic RT group. There were no statistical differences in these 2 groups. Two patients (2.9%) of the low pelvic RT group and 2 patients (5.7%) of the whole pelvic RT group developed upper pelvis relapse, which was out of the low pelvic field. The incidence of Grade 3 to 5 small bowel late complications of the low pelvic RT group was significantly less than that of the whole pelvic RT group (4.3% vs. 20%) (P=0.029).

Conclusions: Low pelvic RT significantly reduces small bowel late complications and does not compromise the overall survival rate, local control rate, and distant metastasis-free rate.

In 1990, the consensus statement by the US National Institutes for Health recommended postoperative chemoradiotherapy as the standard treatment for patients with completely resected stage II and III rectal cancer to improve overall survival (OS) and pelvic control.1–8 However, postoperative radiotherapy (RT) increased the risk of small bowel obstruction after surgery. Baxter et al9 reported that the cumulative risk of small bowel obstruction at 5 years was 20% in those undergoing postoperative irradiation. Reviewing the literature, the optimal irradiation field for rectal cancer was still controversial. Myerson10 suggested that the superior port edge be placed between the sacral promontory and the L4/5 interspace—usually in the mid L5 vertebral body. However, some authors11–13 suggested that the superior margin was in the L5-S1 interspace. The philosophy at our department was that the main role of postoperative RT in rectal cancer was to reduce the local recurrence. Therefore, since January 1999, we have further reduced the irradiation field to the low pelvis (1 cm above the low end of the sacroiliac joint) to reduce small bowel late complications. In this study, we evaluated whether postoperative low pelvic RT is an appropriate treatment to reduce small bowel late complications while not compromising survival in rectal cancer patients.

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MATERIALS AND METHODS

Patient Characteristics

Between November 1997 and May 2006, 104 patients with histologically confirmed adenocarcinoma of the rectum underwent radical resection as the primary treatment with curative intent, followed by postoperative adjuvant concurrent chemoradiotherapy in our institute, and were reviewed retrospectively. Surgeons were required to use total mesorectal excision and the number of lymph nodes retrieved was similar in every patient. Thirty-four patients underwent a low-anterior resection, 48 patients underwent an abdominal-perineal resection, and a Hartmann procedure was performed in 22 patients. The surgical margins were all histologically negative. There were 61 men and 43 women; their ages ranged from 21 to 77 years, with a median of 57 years (Table 1).

Table 1
Table 1
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Staging

According to the staging system of the American Joint Committee on Cancer 2002 (AJCC)14 for rectal cancer, the distribution of the 104 patients is given as follows: 29 stage II (IIa:18, IIb:11) and 75 stage III (IIIa:3, IIIb:52, IIIc:20) (Table 1).

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Tumor Size and Location

Tumor size was ≤5 cm in 60 patients (57.7%) and >5 cm in 44 patients (42.3%). All patients had tumors that were located less than 10 cm from the anal verge. The positive regional lymph nodes and anastomosis sites were all lying below the low end of the sacroiliac joint.

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RT

All patients were treated in the supine position by a 3-field [1 posteroanterior (PA) and 2 lateral fields] or box (anteroposterior+PA and 2 lateral fields) technique with 10 or 15 MV photons. The daily fraction size was 1.8 to 2 Gy, 5 fractions per week. Of the 104 patients, 69 patients (66%) received low pelvic RT (median dose 54 Gy; range, 39.6-59.4 Gy) and were categorized as the low pelvic RT group. Thirty-five patients (34%) received whole pelvic RT (median 43.2 Gy; range, 36-45 Gy) and subsequently received a boost to the low pelvis up to a total 45 to 64.8 Gy (median dose 54 Gy) and were categorized as the whole pelvic RT group. This was not a randomized trial. Before January 1999, 20 patients received whole pelvic RT; between January 1999 and December 2001, 15 patients received whole pelvic RT, whereas the other 19 patients received low pelvic RT, determined by the responsible attending physician; after December 2001, total 50 patients received low pelvic RT. The superior edge of the radiation portals in the whole pelvic RT group was at the mid L5 vertebral body and in the low pelvic RT group was set at 1 cm above the low end of the sacroiliac joint. The other boundaries in both groups were the same. The lateral edge of the anteroposterior-PA fields was set at 1.5 cm beyond the pelvic wall. The distal port edge was about 5 cm below the best estimate of the preoperative tumor bed and (if an abdominal-perineal resection has been performed) below the perineum. The anterior edge of the lateral fields was usually at the anterior acetabulum, and the posterior border included the sacral canal. External iliac nodes were not included, unless pelvic organs with external iliac drainage were involved by direct extension.

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Chemotherapy

Adjuvant chemotherapy followed 1 of 3 regimens: oral UFUR (300 mg/m2/d×48 wk; regimen I, 14 patients); a monthly schedule [5-fluorouracil 500 mg/m2/d infusion+leucovorin 50 mg intravenous (IV) bolus on days 1 to 5 every 28 d, ×6 cycles; regimen II, 42 patients]; or a weekly schedule (5-fluorouracil 500 mg/m2/d IV bolus+leucovorin 100 mg IV once per week×24 wk; regimen III, 48 patients), determined by the responsible attending physician.

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Follow-up

Patients had follow-up in the Radiation Oncology Department at 1-month to 3-month intervals during the first 2 years and every 4 to 6 months between the second and fifth posttreatment years; after 5 years, the patients were seen every 6 to 12 months. All patients were followed-up for at least 37 months. Computed tomography was performed every 6 months for the first 2 years after treatment, and every 8 to 12 months thereafter. Positron emission tomography or magnetic resonance imaging was not routinely examined. Local recurrence was defined by either histologic proof or an imaging study showing regrowth of tumor or lymph node below mid L5 vertebral body. Any tumor or lymph node above mid L5 vertebral body by pathologic or radiologic evidence was defined as a distant metastasis. Synchronous local and distant failure was defined as an interval between the 2 events < 1 month. The grading of small bowel late complications was recorded by the scoring schema of the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer.15

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Statistics

The balance between patient and tumor characteristics for low pelvic and whole pelvic RT group was evaluated with the χ2/Fisher exact test.16 Retrospectively, we evaluated the OS rate, local control (LC) rate, and distant metastasis-free (DMF) rate using the Kaplan-Meier method.17 Several prognostic factors including sex, age, tumor size, dose to low pelvis, stage, chemotherapy regimen, and RT field were evaluated in univariate analysis. The differences between curves were assessed by using the log-rank test.18 Multivariate analysis of the prognostic factors for treatment results and risk factors for complications made use of the Cox proportional hazard model and logistic regression model, respectively.19

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RESULTS

As shown in Table 1, the low pelvic and whole pelvic RT groups were well-balanced with regard to sex, age, tumor size, dose, stage, and chemotherapy regimen.

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OS Rate

Three and 5-year OS rate for all patients were 81% and 69%, respectively. In the univariate analysis, stage was the only significant prognostic factor in OS. The respective 5-year OS rates were 69% versus 70% for male versus female (P=0.847); 70% versus 68% for age ≤57 versus >57 (P=0.452); 75% versus 62% for tumor size ≤5 versus >5 (P=0.123); 75% versus 69% for dose ≤50.4 versus >50.4 (P=0.455); 84% versus 64% for stage II versus III (P=0.020); 77% versus 67% versus 70% for chemotherapy regimen I versus II versus III (P=0.396); and 72% versus 63% for low pelvic versus whole pelvic RT (P=0.217) (Fig. 1) (Table 2).

Table 2
Table 2
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Figure 1
Figure 1
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Multivariate Analysis

All prognostic factors were tested by a Cox regression analysis. Only stage (II vs. III) [odds ratio (OR) 3.21; 95% confidence interval (CI), 1.13-9.12; P=0.028] was found to significantly influence OS rate (Table 3).

Table 3
Table 3
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LC Rate

Of the 104 patients, 14 patients (13%) had local failures: 9 out of 69 (13%) in the low pelvic RT group versus 5 out of 35 (14%) patients in the whole pelvic RT group. The median time for developing local recurrence was 17.4 months (range, 6.1-42.9 mo). Isolated local recurrences were observed in 2 patients (2%), isolated metastatic disease without local recurrence in 25 patients (24%), and combined local and metastatic disease in 12 patients (12%). The 3-year and 5-year LC rates for all patients were 88% and 85%, respectively. Four patients had relapses in the upper pelvis (between mid L5 and the level of 1 cm above the low end of the sacroiliac joint), which was out of the low pelvic field. Two of the 4 patients were in the whole pelvic RT group (1 had an isolated upper pelvis relapse; the other had synchronous relapses at the upper pelvis and distant metastasis) and the other 2 patients (2.9%) were in the low pelvic RT group (2 patients had synchronous relapses at the upper pelvis and distant metastasis). The data showed that whole pelvic RT could not prevent upper pelvic failures and only 2 patients (2.9%) developed upper pelvic failures in the low pelvic RT group. In the univariate analysis, no prognostic factor was correlated with LC rate. The respective 5-year LC rates were 86% versus 84% for low pelvic versus whole pelvic RT (P=0.702) (Table 2).

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Multivariate Analysis

In addition, no factor was found to influence the LC rate (Table 3).

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DMF Rate

All patients had the 3-year and 5-year DMF of 67% and 65%, respectively. Univariate analysis revealed significant correlation for stage. The respective 5-year DMF rates were 78% versus 60% for stage II versus III (P=0.043), and 66% versus 62% for low pelvic versus whole pelvic RT (P=0.662) (Table 2).

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Multivariate Analysis

Only stage (OR 2.40; 95% CI, 0.99-5.75; P=0.050) was found to marginally influence the DMF rate (Table 3).

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Toxicities

Because the RT field influences the volume of irradiated small bowel, our end point in this study was only to evaluate the small bowel late complications, which are less reversible and therefore much more important than acute complications. The incidence of Grade 3 to 5 small bowel late complications was 11.5% versus 7% for male versus female (P=0.518); 8.9% versus 10.4% for age ≤57 versus >57 (P=0.999); 16.7% versus 8.7% for radiation dose to low pelvis of ≤50.4 Gy versus >50.4 Gy (P=0.324); and 4.3% versus 20% for low pelvic versus whole pelvic RT group (P=0.029) (Table 4). The incidence of Grade 3 to 5 small bowel late complications was significantly less in the low pelvic RT group. By multivariate analysis, treatment field (low pelvic vs. whole pelvic) was still the only factor to predict small bowel late complications (OR 5.5; 95% CI, 1.33-22.82; P=0.019) (Table 4).

Table 4
Table 4
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DISCUSSION

During irradiation, a large amount of small intestine was included in the RT field and received a substantial radiation dose. There is a strong correlation between the development of small bowel complications and volume of the irradiated bowel.20–22 The incidence of small bowel complications could be increased when postoperative RT is combined with chemotherapy.23 The development of complications attenuated the benefit of postoperative RT. Reducing the treatment field was the simplest way to minimize severe small bowel complications. Reviewing the literature, the optimal irradiation field for rectal cancer was still controversial. Conventionally, the superior port edge was placed between the sacral promontory and the L4/5 interspace—usually in the mid L5 vertebral body.10 In 1993, Wiggenraad et al11 reported the results of 147 rectal cancer patients treated with postoperative local RT (upper margin was at the L5-S1 or at least 5 cm above the tumor area). They found that the treatment results were comparable with the published results of locoregional radiation. Only the 1 out-of-field recurrence might have been prevented with locoregional RT. Now, in most series, the superior edge of the radiation portals is at the L5-S1 level.11–13

We hypothesized that the main role of postoperative RT for rectal cancer was only to reduce the local recurrences, based on the following 2 reasons: first, the Medical Research Council III randomized trial demonstrated that postoperative RT for rectal cancer could significantly improve LC but no survival benefit24; and second, postoperative RT combined with chemotherapy produced a significant reduction in local recurrence and improvement in OS.2–8 Therefore, in January 1999, our department began to reduce the treatment fields further, to low pelvis (1 cm above the low end of the sacroiliac joint). In addition, in December 2001, low pelvic RT was applied to all postoperative rectal cancer patients. In our study, although not a randomized trial, we tried to evaluate retrospectively whether postoperative low pelvic RT was an appropriate treatment to reduce small bowel late complications without compromising the results in rectal cancer patients. The respective 5-year OS, LC, and DMF rates were 72% versus 63%, 86% versus 84%, and 66% versus 62% for low pelvic versus whole pelvic RT group in our study. The cumulative local recurrence rate (total local recurrences during the observation time) was 13% for the low pelvic RT group and 14% for the whole pelvic RT group, with no statistical differences between the 2 groups. On reviewing the literature, our treatment results agree with the previous studies, in which the 5-year survival rate was about 55% to 71%3,12,25,26 and cumulative local recurrence rate was 12% to 13%.6,12,25 Regarding local failure sites, 2 patients (2.9%) of the low pelvic RT group and 2 patients (5.7%) of the whole pelvic RT group developed the upper pelvis relapse, which was out of the low pelvic field. The data showed that whole pelvic RT could not prevent upper pelvic failures and only 2 patients (2.9%) developed upper pelvic failures in the low pelvic RT group. Therefore, we found that low pelvic RT does not compromise the treatment results or increase the incidence of upper pelvic failures in rectal cancer patients.

Concerning treatment toxicities, in this study, the incidence of Grade 3 to 5 small bowel late complications of the low pelvic RT group was significantly less than that of the whole pelvic RT group (4.3% vs. 20%) (P=0.029). Using the logistic regression model, treatment field was the only independent factor for predicting small bowel complications (P=0.019). Reducing the treatment field did decrease the incidence of small bowel late complications.

With regard to prognostic factors of postoperative chemoradiotherapy for rectal cancer patients, the AJCC staging system was the only independent prognostic factor for OS and DMF. Radiation field was not correlated with OS, LC, and DMF rates. In 1997, Tveit et al12 also reported that Duke C disease predicted an unfavorable prognosis with respect to survival.

In earlier studies, there were no data about the treatment results and toxicities of postoperative low pelvic RT combined with chemotherapy in rectal cancer patients. In our retrospective study, we considered and validated the feasibility of a new irradiation field. Currently, there are more and more concurrent chemoradiotherapy protocols used in the treatment of rectal cancer; therefore, how to reduce the side effects of radiation therapy is indeed an important issue. In future, by some large randomized trials, we hope that low pelvic irradiation will not only be used in postoperative RT, but will also be applied to preoperative RT.

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REFERENCES

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19. Cox DR. Regression models and life tables. J R Stat Soc. 1972;34:187–220

20. Baglan KL, Frazier RC, Yan D, et al. The dosevolume 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

21. Tho LM, Glegg M, Paterson J, et al. 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

22. 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

23. Thomas PR, Lindblad AS, Stablein DM, et al. Toxicity associated with adjuvant postoperative therapy for adenocarcinoma of the rectum. Cancer. 1986;57:1130–1134

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26. Burmeister BH, Schache D, Burmeister EA, et al. Synchronous postoperative adjuvant chemoradiation therapy for locally advanced carcinoma of the rectum. Int J Colorectal Dis. 2004;19:55–59

Keywords:

rectal cancer; postoperative radiotherapy; low pelvic irradiation

© 2012 Lippincott Williams & Wilkins, Inc.

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