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Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1255-1259 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.0001 Patient Assessment of Bowel Function During and After Pelvic Radiotherapy: Results of a Prospective Phase III North Central Cancer Treatment Group Clinical Trial
From the Mayo Clinic, Rochester, MN; Grand Forks, Ltd, Urbana, IL; the Missouri Valley Cancer Consortium, Omaha, NE; and the Merit Care Hospital Community Clinical Oncology Program, Fargo, ND Address reprint requests to Michael G. Haddock, MD, Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: haddock.michael{at}mayo.edu
Purpose: To evaluate patient assessment of long-term effect of pelvic radiotherapy on bowel function. Patients and Methods: As part of a prospective randomized trial evaluating the impact of sucralfate on bowel function in patients receiving pelvic radiotherapy, patient-assessed bowel function data were collected during radiotherapy and again at 4 weeks and 1 year after completion of radiotherapy. Results: The number of bowel movements per day increased up to week 4 and then slowly decreased. At 1 year, the mean number of bowel movements per day had increased from 1.75 to 2.09 and the median from 1 to 2. All measures of adverse bowel function worsened during radiotherapy. Frequency of bowel movements and symptoms of frequency, nocturnal bowel movements, cramping, and bleeding returned close to baseline values by 1 year. Symptoms of urgency, clustering, and measures of incontinence were all persistent at 1 year. The mean increase in bowel function score at 1 year was 0.74 (range, –5 to 7). Conclusion: Pelvic radiotherapy is associated with a slight increase in bowel movement frequency and decrease in several patient-reported measures of adverse bowel function. Several measures of adverse function persisted at 1 year.
Pelvic radiotherapy is a commonly used component of treatment for patients with various gastrointestinal, gynecologic, or genitourinary malignancies. Prospective studies have identified that bowel toxicity manifested primarily by diarrhea is the most common type of acute toxicity experienced by patients receiving pelvic radiotherapy.1-5 Severe acute gastrointestinal toxicity is relatively uncommon in patients receiving pelvic radiotherapy without chemotherapy, occurring in 2% to 6% of patients.1,2,4-8 Some degree of diarrhea, however, is experienced by 40% to 50% of patients who receive pelvic radiation alone.2,4 The risk of severe bowel toxicity or diarrhea is much higher for patients who receive concomitant chemotherapy, especially fluorouracil (FU) -based chemotherapy, with 53% to 56% of patients experiencing diarrhea2,4 and 10% to 24% experiencing severe or life-threatening diarrhea.1-4,8 Although the addition of pelvic radiotherapy to FU-based chemotherapy has not consistently been found to increase the overall rate of diarrhea over that with chemotherapy alone,9 pelvic radiotherapy with or without chemotherapy may affect other measures of bowel function not commonly assessed in prospective studies, such as cramping, bleeding, nocturnal bowel movements, clustering, inability to distinguish stool from gas, and fecal urgency.10-12 However, relatively little prospective information has been reported about long-term bowel function and time course to resolution of toxicity. In an effort to decrease acute bowel toxicity associated with pelvic radiotherapy, a prospective randomized, double-blind, placebo-controlled trial evaluating prophylactic administration of oral sucralfate was performed by the North Central Cancer Treatment Group. The results of this trial, which did not demonstrate a beneficial effect of sucralfate, have been reported previously.13 As part of this study, bowel function was assessed from the patient's perspective during and after treatment. The acute bowel function results have been reported previously.13 The long-term effect of pelvic radiotherapy on bowel function is the subject of this article.
Patients with pelvic malignancy treated with whole pelvic radiotherapy to a total dose of 45 to 53.5 Gy in 1.7- to 2.1-Gy fractions were eligible for the study. Two, three, or four field techniques were allowed, and treatment of the whole pelvis was required. The superior border of the field was to be between the most inferior aspect of the sacroiliac joints and the top of the fifth lumbar vertebral body. A boost dose to a smaller field was allowed. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0 to 2. Written informed consent and approval by the institutional review board were required, and patients had to enter the study before the second fraction of radiation. Patients were randomly assigned in a double-blind manner to receive either sucralfate (500 mg, three capsules every 6 hours) or placebo (microcrystalline cellulase capsules, three capsules every 6 hours). Treatment with sucralfate or placebo continued until the end of radiotherapy or until grade 3 diarrhea occurred. Randomization was through the operations office of the North Central Cancer Treatment Group. Patients were stratified using a dynamic allocation method that balances the marginal distribution14 according to the following factors: previous rectal surgery (regardless of primary site), total radiation dose, concurrent use of FU, and the primary site of the tumor. Patients with active intraluminal gastrointestinal tumors and those without a functioning rectum were not eligible. None of the eligible patients underwent proctectomy after radiation. The primary end point of the study was frequency and severity of treatment-related diarrhea during radiotherapy. Secondary end points included bleeding, tenesmus, constipation, and abdominal cramping. A toxicity score for these end points was assigned weekly during radiation by the physician. Other aspects of bowel function from the patient's perspective were assessed by use of a questionnaire (Appendix Table A1, online only). The questionnaire was derived from a previous study that evaluated the long-term effects of radiation on bowel function.11 A bowel function score was assigned on the basis of the questionnaire, with 1 point being assigned for each affirmative response. The questionnaire was administered weekly during radiation, for 4 weeks after completion of radiation, and 10 to 12 months after completion of radiation. Fisher's exact tests were used to compare incidence rates at baseline and 12 months. Student t test was used to determine whether the change from baseline to 12 months was significantly different from zero. All tests were two sided, with a type I error rate of .05. The results of the randomized analysis have been reported previously,13 and they did not show any significant difference in the incidence and severity of diarrhea between the sucralfate and placebo arms. For the current analysis, all patients entered on the trial were grouped together. Between April 1996 and May 1997, 128 patients entered the study. The primary site of origin was prostate in 73 patients, gynecologic in 35, rectum in 12, and other in three. Because the study evaluated changes in bowel function over time, patients were grouped for analysis without regard to primary site of origin. Five patients were determined to be ineligible because of the presence of intraluminal gastrointestinal tumors at the time of irradiation. The other 123 patients are the subjects of this analysis.
The average number of stools per day during radiotherapy, after completion of radiotherapy, and at 1 year is shown in Table 1. The average number of stools per day increased up to week 4 and then slowly decreased. The average increase in the number of stools per day at 12 months compared with baseline was 0.43 (range, –5 to 4).
Results of the nine measures of bowel function, other than frequency, derived from the patient questionnaire at baseline and at 12 months are summarized in Table 2. Nocturnal bowel movements peaked at week 4 for 25% of patients and were only slightly above baseline at 1 year. Fecal incontinence was experienced occasionally by only 2% of patients at baseline, but was reported by 20% at 1 year (P < .001). Clustering of bowel movements, defined as the need to have a second bowel movement within 30 minutes after the previous one, increased from 26% at baseline to 50% to 53% in weeks 3 to 6 and then decreased slightly to 39% at 1 year (P = .0005). Despite the frequency of reported incontinence, the use of protective clothing was relatively uncommon, peaking at 10% in week 2 and then decreasing slightly. Problems with gas-stool discrimination peaked at 44% in week 3, with no significant decrease at 1 year (P = .0005). Occasional liquid stools were reported by a maximum of 49% of patients in week 4 and decreased to 28% at 1 year. The most commonly reported symptom of adverse bowel function was urgency, defined as the need to have a bowel movement within 15 minutes after the initial urge to avoid an accident. This symptom was reported relatively commonly by 33% of patients at baseline, peaked at 62% in week 6, and decreased slightly to 53% at 1 year (P < .001). Cramping peaked at 38% in week 4 and had returned to baseline levels at 1 year (P = .60). Among patients who experienced cramping, symptoms were mild in 89% and moderate in 11% at baseline compared with mild in 79% and moderate in 21% at 1 year (P < .001). During radiotherapy, however, cramping was rated as moderate by 33% of patients and severe by 18% in week 3. Bleeding with bowel movements increased over baseline (12%) beginning in week 3 (24%) and returned to baseline by 1 year (16%). However, of the patients who experienced bleeding with bowel movements, 75% reported blood on toilet tissue only and 25% reported blood mixed with or coating bowel movement at baseline. In comparison, at 1 year, 56% of these patients reported blood on toilet tissue only, 17% reported blood mixed with or coating bowel movement, and 28% reported enough blood to turn the water in the toilet bowl red.
The weekly bowel function score during the first 8 weeks and at week 52 is shown in Table 3. The mean increase in the bowel function score at 1 year was 0.74 (range, –5 to 7). The median number of reported symptoms was 1 at baseline, peaked at 3 in weeks 3 to 5, and decreased to 1.5 at 1 year (P < .0001).
Late radiation injury involving the bowel may not be manifested for several months or even years after radiotherapy. The median time to the appearance of symptoms from late intestinal injury has been reported to be 8 to 12 months.15 The most commonly reported late symptoms are frequent bowel movements and urgency.16,17 There is relatively little information from prospective trials about bowel function after pelvic radiotherapy delivered with standard fractionation. Also, data about the evolution of specific gastrointestinal complaints over time as measured from the patient's perspective are sparse. Some of what has been termed late radiation bowel toxicity may in fact be persistent symptoms of acute bowel dysfunction. In a randomized Swedish study evaluating the effect of sucralfate on bowel function in patients treated with more than 60 Gy for prostate or bladder cancer, the following symptoms were reported by 20% or more of patients at 1 year: more than two stools per day, mucus in stool, blood in stool, abdominal cramps, and the use of loperamide.18,19 At 1 year, in the current study, 20% or more of patients reported fecal incontinence, clustering, gas-stool discrimination difficulties, liquid stools, and urgency. Furthermore, although decreased frequency of bowel movements and a reduction in the number of symptoms were observed at 12 months, several measures of adverse bowel function had not returned to baseline levels. Effects of radiotherapy are affected by both the total dose and the dose per fraction used. Moderate-dose hypofractionated radiotherapy has been associated with late bowel dysfunction in several phase III rectal cancer trials. Randomized studies performed in Sweden and the Netherlands evaluated the effects of 25 Gy in 5 fractions delivered preoperatively for rectal cancer. Bowel function was assessed at 18 and 24 months in a subset of 597 patients treated in the Dutch trial. Preoperative radiation was associated significantly with incontinence and anal bleeding. The mean number of bowel movements and mean number of nocturnal bowel movements were not increased.20 In the Swedish study, bowel function was assessed between 63 and 101 months postoperatively in a subset of 171 patients. Radiation was associated significantly with an increase in the median number of bowel movements per week and the frequency of experiencing more than four bowel movements per day, urgency, clustering, and incontinence. Bowel function was rated as poor in 7% of irradiated patients and in none of the nonirradiated patients.10 Less information is available from prospective studies about bowel function after radiotherapy with fraction sizes of 1.8 to 2 Gy. However, the results of this study suggest that although improvement is seen over the course of the first year after radiation, there is some persistence of bowel dysfunction at 1 year after standard fractionated radiotherapy. Furthermore, limited long-term follow-up at 15 to 20 years for a randomized postoperative radiation (50 Gy in 25 fractions) study of Danish patients with rectal cancer has suggested that increased bowel movements, incontinence, urgency, and difficulties with gas-stool discrimination persist long-term in some patients.12 Pelvic radiotherapy is only one of several factors that may affect bowel function. Changes in reservoir capacity leading to decreased compliance and decreased rectal sensitivity volumes occur as a result of surgical resection in patients with rectal cancer. Damage to the internal anal sphincter and pelvic floor musculature may also result from surgery.21 The level of the anastomosis has a major effect on postoperative bowel function.22 Symptoms of incontinence, decreased gas-feces discrimination ability, inability to defer bowel movements more than 15 minutes, and the need to modify diet are reported by 40% to 60% of patients with anastomoses below 5 cm; patients with anastomoses above 10 cm are similar to elderly control patients who have not undergone an operation.22 Surgical factors associated with frequency of bowel movement include use of the descending colon instead of the sigmoid colon for the anastomosis. In addition, increasing age and the use of the descending colon as opposed to the sigmoid colon for anastomosis have been associated with an increased risk of incontinence.23 Observed physiologic changes after colorectal anastomosis include a decrease in anal resting pressure, disappearance of the rectoanal inhibitory reflex, and a decrease in rectal capacity and compliance.23 In this study, patients with active intraluminal gastrointestinal tumors were excluded to minimize the potential confounding effects of subsequent bowel surgery. In addition to surgical factors, the timing of radiotherapy in relation to surgery may affect subsequent bowel function. In the German randomized trial comparing preoperative radiation and chemotherapy with postoperative radiation and chemotherapy in patients with rectal cancer, postoperative radiation was associated with a higher frequency of acute grade 3 diarrhea (18% v 12%; P =.04) and chronic diarrhea and small-bowel obstruction (15% v 9%; P =.07).24 The pathophysiology of bowel disfunction after pelvic radiotherapy is poorly understood. Observations of decreased maximal resting anal canal pressure and decreased physiologic sphincter length have led to the suggestion that dysfunction of the internal anal sphincter may contribute to the frequency and urgency in patients receiving radiation.25 However, anal manometry before and after 45 Gy in 25 fractions as preoperative treatment for rectal cancer has shown no change in mean maximal squeeze pressure, resting pressure, minimal sensory threshold, or rectoanal inhibitory reflex in asymptomatic patients. No long-term abnormalities were noted 14 to 42 months after completion of radiation in asymptomatic patients, suggesting that moderate-dose standard fractionated radiotherapy has minimal effect on anal sphincter function in most patients.26 Evaluation of patients with chronic radiation proctopathy after hypofractionated radiotherapy (50 Gy in 20 fractions for prostate cancer) has shown a decrease in the maximal tolerable rectal volume and compliance. Histopathologic evaluation has shown smooth muscle hypertrophy associated with damage to the myenteric plexus, suggesting the possibility that dysfunction is due to a direct neuropathic effect of radiation within the bowel wall rather than effects on the sphincter mechanism.27 Although radiotherapy is clearly associated with long-term changes in bowel function, these alterations have not been shown clearly to affect the quality of life. A weakness of this study is the lack of information in regard to patient bother. Indeed, symptoms of clustering, gas-stool discrimination difficulty, and urgency were present in more than 20% of patients before the initiation of radiotherapy. In a previous study by the North Central Cancer Treatment Group, quality of life as measured by single-item Spitzer Uniscale28 was found to decrease slightly during pelvic radiotherapy and then return to baseline after completion of treatment.29 Similarly, in the Dutch rectal cancer randomized study evaluating 25 Gy in 5 fractions preoperatively, an increase in fecal incontinence in patients receiving radiation did not produce a decrease in health-related quality of life as measured by the modified Rotterdam Symptom checklist.30 In this study, an increase in occasional fecal incontinence at 1 year was not associated with a commensurate increase in the use of protective clothing, suggesting that the frequency of this occurrence was low. We plan to evaluate measures of patient bother in relation to symptomatology in future investigations. Pelvic radiotherapy is associated with a significant reduction in the likelihood of tumor relapse and tumor-related morbidity in a variety of malignancies. In this clinical trial, pelvic radiotherapy was also associated with a mild increased frequency of bowel movements and mildly increased frequency of several reported measures of adverse bowel function. Bowel movement frequency decreased and bowel function improved at 1 year after treatment, but did not return to normal for the population as a whole.
The authors indicated no potential conflicts of interest.
Conception and design: Jeff A. Sloan, James A. Martenson Provision of study materials or patients: Gamini Soori, Preston D. Steen Collection and assembly of data: Jeff A. Sloan, John W. Bollinger Data analysis and interpretation: Michael G. Haddock, James A. Martenson Manuscript writing: Michael G. Haddock Final approval of manuscript: Michael G. Haddock, Jeff A. Sloan, James A. Martenson
Editing, proofreading, and reference verification for the manuscript were provided by the Section of Scientific Publications, Mayo Clinic.
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service Grants No. CA-25224, CA-37404, CA-35269, CA-35103, CA-35195, CA-63849, CA-37417, CA-63848, CA-35448, CA-35415, CA-35101, CA-35113, CA-52352, and CA-35272 from the National Cancer Institute, US Department of Health and Human Services. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Keys HM, Roberts JA, Brunetto VL, et al: A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 92:744-751, 2004[CrossRef][Medline] 6. 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 80:21-29, 1988 7. Roach M III, DeSilvio M, Lawton C, et al: Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression. J Clin Oncol 21:1904-1911, 2003 8. Thomas PR, Lindblad AS, Stablein DM, et al: Toxicity associated with adjuvant postoperative therapy for adenocarcinoma of the rectum. Cancer 57:1130-1134, 1986[CrossRef][Medline] 9. 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 92:388-396, 2000 10. Dahlberg M, Glimelius B, Graf W, et al: Preoperative irradiation affects functional results after surgery for rectal cancer: Results from a randomized study. Dis Colon Rectum 41:543-549, 1998[CrossRef][Medline] 11. Kollmorgen CF, Meagher AP, Wolff BG, et al: The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 220:676-682, 1994[Medline] 12. Lundby L, Krogh K, Jensen VJ, et al: Long-term anorectal dysfunction after postoperative radiotherapy for rectal cancer. Dis Colon Rectum 48:1343-1349, 2005[CrossRef][Medline] 13. Martenson JA, Bollinger JW, Sloan JA, et al: Sucralfate in the prevention of treatment-induced diarrhea in patients receiving pelvic radiation therapy: A North Central Cancer Treatment Group phase III double-blind placebo-controlled trial. J Clin Oncol 18:1239-1245, 2000 14. Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31:103-115, 1975[CrossRef][Medline] 15. Coia LR, Myerson RJ, Tepper JE: Late effects of radiation therapy on the gastrointestinal tract. Int J Radiat Oncol Biol Phys 31:1213-1236, 1995[CrossRef][Medline] 16. Pilepich MV, Asbell SO, Krall JM, et al: Correlation of radiotherapeutic parameters and treatment related morbidity: Analysis of RTOG Study 77-06. Int J Radiat Oncol Biol Phys 13:1007-1012, 1987[Medline] 17. Pilepich MV, Krall JM, Sause WT, et al: Correlation of radiotherapeutic parameters and treatment related morbidity in carcinoma of the prostate: Analysis of RTOG study 75-06. Int J Radiat Oncol Biol Phys 13:351-357, 1987[Medline] 18. Henriksson R, Franzen L, Littbrand B: Prevention of irradiation-induced bowel discomfort by sucralfate: A double-blind, placebo-controlled study when treating localized pelvic cancer. Am J Med 91:151S–157S, 1991[CrossRef][Medline] 19. Henriksson R, Franzen L, Littbrand B: Effects of sucralfate on acute and late bowel discomfort following radiotherapy of pelvic cancer. J Clin Oncol 10:969-975, 1992[Abstract] 20. Peeters KC, van de Velde CJ, Leer JW, et al: Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: Increased bowel dysfunction in irradiated patients: A Dutch colorectal cancer group study. J Clin Oncol 23:6199-6206, 2005 21. Batignani G, Monaci I, Ficari F, et al: What affects continence after anterior resection of the rectum? Dis Colon Rectum 34:329-335, 1991[CrossRef][Medline] 22. McDonald PJ, Heald RJ: A survey of postoperative function after rectal anastomosis with circular stapling devices. Br J Surg 70:727-729, 1983[CrossRef][Medline] 23. Graf W, Ekstrom K, Glimelius B, et al: A pilot study of factors influencing bowel function after colorectal anastomosis. Dis Colon Rectum 39:744-749, 1996[CrossRef][Medline] 24. Sauer R, Becker H, Hohenberger W, et al: German Rectal Cancer Study Group: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 25. Varma JS, Smith AN, Busuttil A: Function of the anal sphincters after chronic radiation injury. Gut 27:528-533, 1986 26. Birnbaum EH, Myerson RJ, Fry RD, et al: Chronic effects of pelvic radiation therapy on anorectal function. Dis Colon Rectum 37:909-915, 1994[CrossRef][Medline] 27. Varma JS, Smith AN, Busuttil A: Correlation of clinical and manometric abnormalities of rectal function following chronic radiation injury. Br J Surg 72:875-878, 1985[Medline] 28. Spilker B: Quality of life and pharmacoeconomics in clinical trials (ed 2). Philadelphia, Lippencott-Raven, 1996 29. Kozelsky TF, Meyers GE, Sloan JA, et al: Phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy. J Clin Oncol 21:1669-1674, 2003 30. Marijnen CA, van de Velde CJ, Putter H, et al: Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: Report of a multicenter randomized trial. J Clin Oncol 23:1847-1858, 2005 Submitted August 29, 2006; accepted December 20, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
