Prevention and Therapy of Radiation-Induced Bowel Discomfort R. HENRIKSSON, L. FRANZEN & B. LIlTBRAND Dept. of Oncology, University Hospital, Umeh, Sweden
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Henriksson R, Franzkn L, Littbrand B. Prevention and therapy of radiation-induced bowel discomfort. Scand J Gastroenterol 1992;27 Suppl 191:7-11. In a double-blind randomized placebo-controlled study, including 70 patients treated with radiotherapy of localized malignancies in the pelvis, the effects of prophylactic sucralfate in preventing bowel discomfort were evaluated. Radiotherapy was delivered in a conventional manner with high-energy photons in a total dose of 62-66 Gy (target dose, 1.8-2.2 Gy) during 6.5 weeks. Dose granules of sucralfate or placebo were given 2 weeks after irradiation started and continued for 6 weeks. All analyses were performed blindly. The patients in the sucralfate group had significantly less problems with acute (5 weeks) and chronic (66 weeks) bowel discomfort. The consumption of loperamide was also reduced in the sucralfate group, and the weight decrease was less pronounced. No adverse effects were seen. Thus, sucralfate seems to be beneficial in minimizing the problems of bowel discomfort during and after irradiation of malignancies in the pelvis. These results are discussed in relation to other related
observations. Key words: Diarrhoea; late effects; pelvic carcinoma; radiotherapy; sucralfate Roger Henriksson, M . D . , Dept. of Oncology, University Hospital, S-90185 Umed, Sweden
Cancer therapy is generally afflicted with a diversity of side effects. Irradiation is one of the cornerstones in the management of different malignancies. Pelvic radiotherapy is accompanied by intestinal reactions when treating cancer in prostate, urinary bladder, and other malignancies in the pelvis. The adverse effects can be seen as either acute effects during irradiation or as later damage (1-4). Early effects of radiotherapy are seen within 2 weeks’ treatment with conventional fractionation, which corresponds to a delivered dose of 18-22Gy. Acute enteropathy during and after irradiation can be seen in almost all patients after radiation doses of more than 40Gy. Proctitis accounts for 50-75% of radiation-induced damage (5). Diarrhoea is the main symptom. Tine late symptoms after irradiation are usually seen after 1 year; however, they can appear at any time during the lifetime of the patients. The incidence of chronic radiation-induced bowel discomfort after irradiation to the pelvis is approximately 5% (6). A wide spectrum of different disorders is shown by barium enema and endoscopy, such as decreased distensibility, intestinal fixation, and altered mucosal pattern (6-8). Clinical manifestations are diarrhoea with blood, mucus, and tenesmus with pain. The pathogenesis of both acute and late effects have been attributed to radiation sensitivity of the mucosa, since the epithelial cells of the intestine have a short cell cycle time. Secondary, an impaired function with regard to lactose and bile salt absorption has also been associated with pelvic irradiation (2,9-11). Changes in bacterial contamination have also been suggested to be of additive importance in increasing the severity of irradiation-induced enteropathy (6, 11). The internal sphincter is also affected (12). Especially with regard to the long-term effects, the damage
to endothelial cells in the blood vessels and connective tissue results in ischaemia and fibrosis (1,6,10). The therapy to date has been oral or rectal steroids, bile acid-sequestering resins, sulfasalazine, and anti-diarrhoeics, and, recently, antibacterial drugs have also been shown to be of some value with regard to the late effects ( 6 , l l ) . However, symptoms often persist, and hitherto used drugs are associated with a relatively high rate of side-effects, and surgery is sometimes of importance in diminishing a hampered quality of life. It has recently been suggested that sucralfate can be of value in minimizing radiation-induced bowel discomforts (13-16). The present paper describes the results of a double-blind randomized placebo-controlled study in 70 patients treated with radiotherapy for pelvic cancer. Moreover, the results are discussed in relation to other performed studies that also point out the importance of sucralfate in increasing the quality of life during cancer therapy affecting the mucosa of the whole gastrointestinal tract.
PATIENTS AND METHODS This study was prospectively randomized before radiotherapy in a double-blind fashion using placebo and included 70 patients receiving pelvic irradiation with a curative intent. The eligibility requirements included patients with the primary diagnosis of carcinoma of the prostate and urinary bladder with peformance status of 290% Karnofsky scale. Patients with gastrointestinal problems who had undergone intestinal surgery, colostomy, and previous chemotherapy or radiation therapy were not entered in the study. The patients were stratified on the basis of diagnosis. At the
R. Henriksson et al.
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8
Fig. 1 . Radiographic demonstration of a treatment field from anterior-posterior view (A) and lateral view (B).
commencement of the trial all patients were interviewed, the complications relating to medication were discussed, and informed consent was obtained individually for each patient. A complete blood picture, electrolytes, and liver status were obtained at the beginning, after 3 weeks, at the end of treatment, and 17 weeks and 66 weeks after the end of treatment. The general condition was followed throughout the treatment period, and the occurrence of symptoms such as nausea and vomiting were observed. All patients had
regular consultation with a dietician during treatment, with advice regarding the need for a low-fat intake. Irradiation treatment
Radiotherapy was administered with 20.9 MV photons (Microtron Scanditronix) at 100 cm source-skin distance (SSD) and 50 MV photons (Scanditronix, Race-track). The fraction schedule was five fractions per week with daily doses of 1.8-2.2 Gy and total dose of 62-66 Gy (CRE 18.2-18.6);
Irradiation-induced Diarrhoea and Sucralfate
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total treatment time was 6.5 weeks. The mean field size was 14 x 14cm, and the irradiation was given with a four-field box technique (Figs. la, b). Drug administration Dose granules of sucralfate and placebo identical in taste, colour, and consistency were dispensed randomly to each patient 2 weeks after radiotherapy started, with the instruction to ingest one dose package (1 g) dissolved in water six times daily. Patients were instructed to ask for loperamide when they required symptomatic therapy for diarrhoea. Administration of placebo and sucralfate continued for 6 weeks. Evaluation All patients were given a calendar and instructed to record daily medication taken, details of bowel action (frequency, stool consistency, pain, occurrence of blood or mucus), and other medication. Objective patient response was documented. Patients were interviewed by the same physician once every week and at the end of treatment. Two months and 66 weeks after termination of the radiotherapy the patients were interviewed again by the physician. The details of the bowel action registered on the calendar were consecutively converted by the patients and the physician to a diarrhoea score during the period of investigation (Table I). Statistical analysis The statistical analysis and evaluations were performed blindly by an independent statistician without knowing the nature of the treatment arms. The code for test medication was broken when all patients had fulfilled the whole period. Differences between groups for categoric variables were tested with the Pearson chi-square test. Weight decrement was tested with the t test.
RESULTS With the exception of one patient with obstipation in the placebo group, no adverse effects were seen. Three patients in the sucralfate group were excluded, one because of disagreement with the study protocol and two because of alterations in irradiation treatment due to the appearance of other diseases. Apart from these patients the compliance
9
Table 11. Effects of sucralfate o n the bowel habits and loperamide intake as compared with placebo-treated control patients 5 weeks after initiation of radiotherapy ~~~
Variable
Sucralfate ( n = 32)
( n = 34)
Placebo
Diarrhoea score 2 + 3 Daily stools >5 ‘Normal’ consistency Mucus (blood) Loperamide consumption
14 3 29 17(3) 3
27 11 24 19(5) 14
was good. There were no obvious differences in laboratory status between the two treatment arms. The results 5 weeks after starting radiotherapy are shown in Table 11. Significantly fewer patients in the sucralfate group than in the placebo group had a high diarrhoea score, fewer patients had more than five daily stools, and fewer patients had loose stool consistency. Finally, and perhaps most interestingly, the loperamide consumption was significantly lower in the patients receiving sucralfate. Fifty-six of the initially evaluable 66 patients were also evaluable for follow-up 66 weeks after radiotherapy treatment (Table 111). Six patients had died of tumour progression; four were lost to follow-up because of their own decision. Fourteen of 28 evaluable patients in the placebo group and 24 of 28 evaluable patients in the sucralfate group did not present disturbances in the bowel function 66 weeks after radiotherapy. The frequency of defaecation and the diarrhoea score were also seemingly improved; however, a statistical significance was not reached. This was possibly due to the appearance of mainly ‘normal’ consistency of the stools. A small increase in the weight deviation was also evident; that is, the mean weight was more decreased in the control group at 1 year compared with the initial weight difference between the two groups of patients (Table IV). Moreover, blood in the stools was seen by 9 patients in the placebo group and by 4 patients in the sucralfate group; mucus was observed in 16 control patients and in 7 sucralfate patients (Table 111). Eight controls and five patients had abdominal pain that was treated with sucralfate. Furthermore, 9 patients in the placebo group and 4 in the sucralfate group required loperamide owing to more advanced problems with the bowel habits (Table 111).
Table 111. Effects of sucralfate on the bowel habits and loperamide consumption as compared with placebo 66 weeks after irradiation Table I. Diarrhoea score Score
Symptoms
Variable
Sucralfate ( n = 28)
( n = 28)
Placebo
No change in bowel habit (‘normal’) Small increase in frequency and soft tools More pronounced increase in frequency and loose stools Marked increase in frequency and watery stools
Diarrhoea score 2-3 Daily stools >5 ‘Normal’consistency Mucus (blood) Loperamide
4 1 28 7(4) 4
8 4 9 16(9) 9
10
R. Henriksson et al.
Table IV. Effects of sucralfate on body weight loss evaluated 5 weeks after initiation of radiotherapy and 66 weeks after radiotherapy
5 weeks 66 weeks
Sucralfate
Placebo
(kg)
(kg)
1.2 0.1
2.3
1.9
Values denote weight loss in kilograms
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DISCUSSION A critical contribution in the treatment of abdominal malignancies is significant damage to the normal intestine. During treatment of pelvic tumours with external, intracavitary, or combined irradiation the lower colon and rectum usually are included in the treatment volume (1,5,6,8). Furthermore, exposure of the small intestine is also plausible and depends on the position and mobility of the intestine. Consequently, symptoms during and shortly after treatment are usually seen by every patient (1,5,6,8, 15). The most frequent discomfort experienced by the patients consists of diarrhoea and altered bowel habits. Therefore, it is of utmost clinical significance to report that the drug sucralfate (aluminium hydroxide complex of sulphated sucrose) markedly reduced the irradiation-induced diarrhoea and bowel discomfort when treating pelvic carcinoma. This study is, as far as we know, the first double-blind placebo-controlled evaluation that demonstrates that a prophylactic medical treatment can be of value in reducing the bowel discomfort with regard to both acute and late aspects when using irradiation in the treatment of abdominal and pelvic malignancies. The frequency of diarrhoea or the number of defaecation episodes, probably the most objective parameter, showed a clear reduction in the sucralfate group as compared with placebo controls. In addition, significant changes in the stool consistency were also shown, with a more ‘watery’ appearance in the group of patients given the placebo. Furthermore, and most interestingly, only a few patients in the sucralfate group took the anti-diarrhoeic loperamide, whereas almost 50% in the placebo group took loperamide. Loperamide is a calcium-channel blocker as well as an opiate. The effects of opiates-that is, the paralyzing of smooth muscle-may be dangerous owing to the risk of causing large amounts of fluid to be trapped in the intestines, with the attendant dangers of bowel strangulation and miscalculation of fluid losses (17). Obviously, the patients in the sucralfate group in general displayed only minor alterations in bowel habits even at the end of the radiation course. There was no evidence of adverse effects associated with the use of sucralfate. One patient in the control group suffered from obstipation, an effect seen in approximately 2 4 % of the patients when treating with sucralfate for gastric ulcer. It cannot be excluded that the used placebo altered and improved the bowel discomfort in the placebo group and, thus, diminished the differences between the treatment
arms. It must also be emphasized that the dietician consultations with advice on a change in diet and especially a lower fat intake further reduce the discomforts for the patients, and, thus, also probably diminish the possibilities of detecting differences between the placebo and sucralfate groups. The results are, with regard to the acute effects, in accordance with earlier open studies (12-16). Endoscopic evaluation during the period of investigation had, of course, been of some interest, especially when discussing the mechanisms of action. However, we did not find it ethical to perform rectosigmoidoscopic assessment, since we logically assumed that the bowel symptoms were due to an inflammatory reaction caused by the irradiation. Moreover, in our experience an intervention during the acute phase should be avoided because of the risk of irreversible damage to the internal sphincter, as examination of the urinary bladder during the acute phase is not advised owing to the risk of incontinency. In addition, the clinical severity of the disease seems not to correlate with the endoscopic severity (5). Nevertheless, an endoscopic evaluation will be performed at a later stage. The mode of action by which sucralfate exerts its effects can include all the earlier proposed actions: protection of the denoded mucosa from local irritants (18-20), cytoprotection (18), and binding of bile acids (21,22). It is of interest that the effects mediated by sucralfate are not in need of an acidic medium (23). The advantages of using sucralfate are the simple means of administration and especially the low frequency of side-effects despite its extensive use (18,24). In this study we have used granules, which are introduced for use in healing gastric ulcer. From a pharmacokinetic standpoint it would be preferable to have the drug designed in another way, such as slow-release preparation or dragee, for optimal effect in the lower part of the gastrointestinal tract. Moreover, it should also be evaluated whether a decreased intake, such as two doses per day, of sucralfate can be as effective as the six doses per day used in the present study. The economic aspects with low costs of sucralfate use must also be considered. In conclusion, this double-blind placebo-controlled study clearly suggests sucralfate to be promising in preventing radiation-induced bowel discomfort. A reduction in the risk of complications increases the possibility of carrying through planned treatment and avoiding unfavourable interruptions and, thus, curing the patient with cancer in the pelvis by means of radiotherapy. It is obvious that by reducing the radiation-induced bowel symptoms the quality of life during (and following) therapy can be enhanced, and it may be possible to increase the therapeutic ratio by escalating the dose. Recently published studies further support the beneficial effects of sucralfate in reducing the problems of chronic bowel injury following irradiation (25), radiationinduced mucositis (26, 27), and chemotherapy-induced mucositis (28). Finally, there are other beneficial reports of sucralfate on various colorectal disorders, such as solitary
Irradiation-induced Diarrhoea and Sucralfate rectal ulcer (291, postpo~ypectomy bleeding (30), and inflammatory bowel disease (31).
ACKNOWLEDGEMENTS
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This study was supported by grants from The Swedish Society for Cancer Research and The Lions’ Cancer Research Foundation, UmeA, Sweden. T h e skilful assistance of Mikael Arevarn, radiographer, and Hhkan Jonsson, statistician, is acknowledged.
REFERENCES 1, Rubin p, Casarett G. A direction for clinical radiation path& ogy: the tolerance dose. Front Radiat Ther Oncol 1972;6:1-16. 2. Stryker JA, Chung CK, Layser JD. Colestipol hydrochoride prophylaxisof diarrhoea duringpelvic radiotherapy. rnt J Radiat Oncol Biol Phvs 1983:9:185. 3. Chary S, Thotkson DH. A clinical trial evaluating cholestyramine to prevent diarrhea in patients maintained on low fat diets during pelvic radiation therapy. Int J Radiat Oncol Biol Phys 1984;10:1885. 4. Yoonessi M. Romney S. Dayen H. Gastrointestinal tract complications following radiotherapy of uterine cervical cancer: past and present. J Surg Oncol 1981;18:135-42. 5. Gilinsky NH, Burns DG, Barzebat GO. The natural history of radiation-induced proctosigmoiditis: an analysis of 88 patients. Q J Med 1983;205:40-53. 6. Sher ME, Bauer J. Radiation-induced enteropathy. Am J Gastroenterol 1990;85:121-8. 7. Pilepich MV, Krall J, George FW et al. Treatment-related morbidity in phase I11 RTOG studies of extended field irradiation for carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1984;10:1861-7. 8. Hartog FCA, Cohen P, van Haastert M. Late radiation injury of the rectum and sigmoid colon: barium enema findings in 92 patients. Br J Radiol 1989;62:807-12. 9. Anderson H, Bosaeus I, Nystrom C. Bile salt malabsorption in the radiation syndrome. Acta Radiol Oncol 1978;17:312. 10. Kinsella TJ, Bloomer WD. Tolerance of the intestine to radiation therapv. Surg Gynecol Obstet 1980;151:273-84. 11. Danielsson A, Nyhlin H, Persson H, Stendahl U, Stenling R, Suhr 0. Chronic diarrhoea after radiotherapy for gynaecological cancer: occurrence and aetiology. Gut 1991;32:1180-7. 12. Varma JS, Smith AN, Busuttil A. Function of the anal sphincters after chronic radiation injury. Gut 1986;27:528-33.
11
13. Henriksson R , Franzkn L. Littbrand B. Does sucralfate reduce radiation-induced diarrhoea? Acta Radiol Oncol 1987;26:7&7. 14. Henriksson R, Arevarn M, Franztn L, Persson H, Stendahl U. Beneficial effects of sucralfate in radiation induced diarrhoea. An open randomized study in gynaecological cancer patients. Eur J Gynaecol Oncol 1990;11:4. 15. Henriksson R , Franztn L, Littbrand B. Prevention of irradiation induced gastrointestinal tract discomfort by sucralfate. Am J Med 1991;91 SUPPI 2A:151-7. 16. Kochar R, Sharma SC, Gupta BB, Mehta SK. Rectal sucralfate in radiation proctitis. Lancet 1988:400. 17. Field M, Rao MC, Chang EB. Intestinal electrolyte transport and diarrheal disease. N Engl J Med 1989;13:87+83. 18. Hollander D, editor. Proceedings of the 5th international sucralfate research conference. Am J Med 1989;86:1-155. 19. Nagashima R. Mechanism of action of sucralfate. J Clin Gastroenterol 1981;3: 117-23. 20. Tarnawski A. Sucralfate. Is it more than just a barrier? Cytoprotection-future direction in prevention and treatment of gastrointestinal mucosal injury. Curr Conc Gastroenterol 1984; 1:5-8. 21. Tobiasson P, Stenstam M. Effects of sucralfate and cholestyramine on bile acid absorption. Gastroenterology 1985;88:3936. 22. Tanghoj H, Stenstam M, Tobiasson P. Effects of sucralfate and cholestyramine on bile acid absorption [abstract]. Gastroenterology 1985;88:1699. 23. Danesh BJG, Duncan A, Russel RI. Is an acid pH medium required for the protective effect of sucralfate against mucosal injury? Am J Med 1987;83:11-3. 24. Ishimori A. Safety experience with sucralfate in Japan. J Clin Gast roenterol 1981;3:169-72. 25. Kochar R, Patel F, Dhar A et al. Radiation induced proctosigmoiditis. Dig Dis Sci 1991;36:103-7. 26. Barker G, Loftus L, Cuddy P, Parker B. The effects of sucralfate suspension and diphenhydramine syrup plus kaolin-pectin in radiotherapy-induced mucositis. Oral Surg Oral Med Oral Pathol 1991;71:288-93. 27. Scherlacher A, Beaufort-Spontin F. Strahlentherapie von KopfHals-Malignomen: Entziindungsprophylaxe der Schleimhaut durch Sucralfatbehandlung. HNO 1990;38:248. 28. Pfeiffer P. Madsen EL, Hansen 0, May D. Effect of prophylactic sucralfate suspension on stomatitis induced by cancer chemotherapy. Acta Oncol 1990;21:171-3. 29. Batman F, Arslan S, Telatar H. Effect of sucralfate in the treatment of solitary rectal ulcer. Endoscopy 1988;20:128. 30. Bronne MH, Yantis PL. Intracolonic sucralfate suspension for postpolypectomy hemorrhage. Gastrointest Endosc 1986;32: 362-3. 31. Carling L, Kagevi I, Borvall E. Sucralfate enema-ffective in IBD? Endoscopy 1986;18:115.
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Henriksson R, Franzkn L, Littbrand B. Prevention and therapy of radiation-induced bowel discomfort. Scand J Gastroenterol 1992;27 Suppl 191:7-11. In a double-blind randomized placebo-controlled study, including 70 patients treated with radiotherapy of localized malignancies in the pelvis, the effects of prophylactic sucralfate in preventing bowel discomfort were evaluated. Radiotherapy was delivered in a conventional manner with high-energy photons in a total dose of 62-66 Gy (target dose, 1.8-2.2 Gy) during 6.5 weeks. Dose granules of sucralfate or placebo were given 2 weeks after irradiation started and continued for 6 weeks. All analyses were performed blindly. The patients in the sucralfate group had significantly less problems with acute (5 weeks) and chronic (66 weeks) bowel discomfort. The consumption of loperamide was also reduced in the sucralfate group, and the weight decrease was less pronounced. No adverse effects were seen. Thus, sucralfate seems to be beneficial in minimizing the problems of bowel discomfort during and after irradiation of malignancies in the pelvis. These results are discussed in relation to other related
observations. Key words: Diarrhoea; late effects; pelvic carcinoma; radiotherapy; sucralfate Roger Henriksson, M . D . , Dept. of Oncology, University Hospital, S-90185 Umed, Sweden
Cancer therapy is generally afflicted with a diversity of side effects. Irradiation is one of the cornerstones in the management of different malignancies. Pelvic radiotherapy is accompanied by intestinal reactions when treating cancer in prostate, urinary bladder, and other malignancies in the pelvis. The adverse effects can be seen as either acute effects during irradiation or as later damage (1-4). Early effects of radiotherapy are seen within 2 weeks’ treatment with conventional fractionation, which corresponds to a delivered dose of 18-22Gy. Acute enteropathy during and after irradiation can be seen in almost all patients after radiation doses of more than 40Gy. Proctitis accounts for 50-75% of radiation-induced damage (5). Diarrhoea is the main symptom. Tine late symptoms after irradiation are usually seen after 1 year; however, they can appear at any time during the lifetime of the patients. The incidence of chronic radiation-induced bowel discomfort after irradiation to the pelvis is approximately 5% (6). A wide spectrum of different disorders is shown by barium enema and endoscopy, such as decreased distensibility, intestinal fixation, and altered mucosal pattern (6-8). Clinical manifestations are diarrhoea with blood, mucus, and tenesmus with pain. The pathogenesis of both acute and late effects have been attributed to radiation sensitivity of the mucosa, since the epithelial cells of the intestine have a short cell cycle time. Secondary, an impaired function with regard to lactose and bile salt absorption has also been associated with pelvic irradiation (2,9-11). Changes in bacterial contamination have also been suggested to be of additive importance in increasing the severity of irradiation-induced enteropathy (6, 11). The internal sphincter is also affected (12). Especially with regard to the long-term effects, the damage
to endothelial cells in the blood vessels and connective tissue results in ischaemia and fibrosis (1,6,10). The therapy to date has been oral or rectal steroids, bile acid-sequestering resins, sulfasalazine, and anti-diarrhoeics, and, recently, antibacterial drugs have also been shown to be of some value with regard to the late effects ( 6 , l l ) . However, symptoms often persist, and hitherto used drugs are associated with a relatively high rate of side-effects, and surgery is sometimes of importance in diminishing a hampered quality of life. It has recently been suggested that sucralfate can be of value in minimizing radiation-induced bowel discomforts (13-16). The present paper describes the results of a double-blind randomized placebo-controlled study in 70 patients treated with radiotherapy for pelvic cancer. Moreover, the results are discussed in relation to other performed studies that also point out the importance of sucralfate in increasing the quality of life during cancer therapy affecting the mucosa of the whole gastrointestinal tract.
PATIENTS AND METHODS This study was prospectively randomized before radiotherapy in a double-blind fashion using placebo and included 70 patients receiving pelvic irradiation with a curative intent. The eligibility requirements included patients with the primary diagnosis of carcinoma of the prostate and urinary bladder with peformance status of 290% Karnofsky scale. Patients with gastrointestinal problems who had undergone intestinal surgery, colostomy, and previous chemotherapy or radiation therapy were not entered in the study. The patients were stratified on the basis of diagnosis. At the
R. Henriksson et al.
Scand J Gastroenterol Downloaded from informahealthcare.com by McMaster University on 10/27/14 For personal use only.
8
Fig. 1 . Radiographic demonstration of a treatment field from anterior-posterior view (A) and lateral view (B).
commencement of the trial all patients were interviewed, the complications relating to medication were discussed, and informed consent was obtained individually for each patient. A complete blood picture, electrolytes, and liver status were obtained at the beginning, after 3 weeks, at the end of treatment, and 17 weeks and 66 weeks after the end of treatment. The general condition was followed throughout the treatment period, and the occurrence of symptoms such as nausea and vomiting were observed. All patients had
regular consultation with a dietician during treatment, with advice regarding the need for a low-fat intake. Irradiation treatment
Radiotherapy was administered with 20.9 MV photons (Microtron Scanditronix) at 100 cm source-skin distance (SSD) and 50 MV photons (Scanditronix, Race-track). The fraction schedule was five fractions per week with daily doses of 1.8-2.2 Gy and total dose of 62-66 Gy (CRE 18.2-18.6);
Irradiation-induced Diarrhoea and Sucralfate
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total treatment time was 6.5 weeks. The mean field size was 14 x 14cm, and the irradiation was given with a four-field box technique (Figs. la, b). Drug administration Dose granules of sucralfate and placebo identical in taste, colour, and consistency were dispensed randomly to each patient 2 weeks after radiotherapy started, with the instruction to ingest one dose package (1 g) dissolved in water six times daily. Patients were instructed to ask for loperamide when they required symptomatic therapy for diarrhoea. Administration of placebo and sucralfate continued for 6 weeks. Evaluation All patients were given a calendar and instructed to record daily medication taken, details of bowel action (frequency, stool consistency, pain, occurrence of blood or mucus), and other medication. Objective patient response was documented. Patients were interviewed by the same physician once every week and at the end of treatment. Two months and 66 weeks after termination of the radiotherapy the patients were interviewed again by the physician. The details of the bowel action registered on the calendar were consecutively converted by the patients and the physician to a diarrhoea score during the period of investigation (Table I). Statistical analysis The statistical analysis and evaluations were performed blindly by an independent statistician without knowing the nature of the treatment arms. The code for test medication was broken when all patients had fulfilled the whole period. Differences between groups for categoric variables were tested with the Pearson chi-square test. Weight decrement was tested with the t test.
RESULTS With the exception of one patient with obstipation in the placebo group, no adverse effects were seen. Three patients in the sucralfate group were excluded, one because of disagreement with the study protocol and two because of alterations in irradiation treatment due to the appearance of other diseases. Apart from these patients the compliance
9
Table 11. Effects of sucralfate o n the bowel habits and loperamide intake as compared with placebo-treated control patients 5 weeks after initiation of radiotherapy ~~~
Variable
Sucralfate ( n = 32)
( n = 34)
Placebo
Diarrhoea score 2 + 3 Daily stools >5 ‘Normal’ consistency Mucus (blood) Loperamide consumption
14 3 29 17(3) 3
27 11 24 19(5) 14
was good. There were no obvious differences in laboratory status between the two treatment arms. The results 5 weeks after starting radiotherapy are shown in Table 11. Significantly fewer patients in the sucralfate group than in the placebo group had a high diarrhoea score, fewer patients had more than five daily stools, and fewer patients had loose stool consistency. Finally, and perhaps most interestingly, the loperamide consumption was significantly lower in the patients receiving sucralfate. Fifty-six of the initially evaluable 66 patients were also evaluable for follow-up 66 weeks after radiotherapy treatment (Table 111). Six patients had died of tumour progression; four were lost to follow-up because of their own decision. Fourteen of 28 evaluable patients in the placebo group and 24 of 28 evaluable patients in the sucralfate group did not present disturbances in the bowel function 66 weeks after radiotherapy. The frequency of defaecation and the diarrhoea score were also seemingly improved; however, a statistical significance was not reached. This was possibly due to the appearance of mainly ‘normal’ consistency of the stools. A small increase in the weight deviation was also evident; that is, the mean weight was more decreased in the control group at 1 year compared with the initial weight difference between the two groups of patients (Table IV). Moreover, blood in the stools was seen by 9 patients in the placebo group and by 4 patients in the sucralfate group; mucus was observed in 16 control patients and in 7 sucralfate patients (Table 111). Eight controls and five patients had abdominal pain that was treated with sucralfate. Furthermore, 9 patients in the placebo group and 4 in the sucralfate group required loperamide owing to more advanced problems with the bowel habits (Table 111).
Table 111. Effects of sucralfate on the bowel habits and loperamide consumption as compared with placebo 66 weeks after irradiation Table I. Diarrhoea score Score
Symptoms
Variable
Sucralfate ( n = 28)
( n = 28)
Placebo
No change in bowel habit (‘normal’) Small increase in frequency and soft tools More pronounced increase in frequency and loose stools Marked increase in frequency and watery stools
Diarrhoea score 2-3 Daily stools >5 ‘Normal’consistency Mucus (blood) Loperamide
4 1 28 7(4) 4
8 4 9 16(9) 9
10
R. Henriksson et al.
Table IV. Effects of sucralfate on body weight loss evaluated 5 weeks after initiation of radiotherapy and 66 weeks after radiotherapy
5 weeks 66 weeks
Sucralfate
Placebo
(kg)
(kg)
1.2 0.1
2.3
1.9
Values denote weight loss in kilograms
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DISCUSSION A critical contribution in the treatment of abdominal malignancies is significant damage to the normal intestine. During treatment of pelvic tumours with external, intracavitary, or combined irradiation the lower colon and rectum usually are included in the treatment volume (1,5,6,8). Furthermore, exposure of the small intestine is also plausible and depends on the position and mobility of the intestine. Consequently, symptoms during and shortly after treatment are usually seen by every patient (1,5,6,8, 15). The most frequent discomfort experienced by the patients consists of diarrhoea and altered bowel habits. Therefore, it is of utmost clinical significance to report that the drug sucralfate (aluminium hydroxide complex of sulphated sucrose) markedly reduced the irradiation-induced diarrhoea and bowel discomfort when treating pelvic carcinoma. This study is, as far as we know, the first double-blind placebo-controlled evaluation that demonstrates that a prophylactic medical treatment can be of value in reducing the bowel discomfort with regard to both acute and late aspects when using irradiation in the treatment of abdominal and pelvic malignancies. The frequency of diarrhoea or the number of defaecation episodes, probably the most objective parameter, showed a clear reduction in the sucralfate group as compared with placebo controls. In addition, significant changes in the stool consistency were also shown, with a more ‘watery’ appearance in the group of patients given the placebo. Furthermore, and most interestingly, only a few patients in the sucralfate group took the anti-diarrhoeic loperamide, whereas almost 50% in the placebo group took loperamide. Loperamide is a calcium-channel blocker as well as an opiate. The effects of opiates-that is, the paralyzing of smooth muscle-may be dangerous owing to the risk of causing large amounts of fluid to be trapped in the intestines, with the attendant dangers of bowel strangulation and miscalculation of fluid losses (17). Obviously, the patients in the sucralfate group in general displayed only minor alterations in bowel habits even at the end of the radiation course. There was no evidence of adverse effects associated with the use of sucralfate. One patient in the control group suffered from obstipation, an effect seen in approximately 2 4 % of the patients when treating with sucralfate for gastric ulcer. It cannot be excluded that the used placebo altered and improved the bowel discomfort in the placebo group and, thus, diminished the differences between the treatment
arms. It must also be emphasized that the dietician consultations with advice on a change in diet and especially a lower fat intake further reduce the discomforts for the patients, and, thus, also probably diminish the possibilities of detecting differences between the placebo and sucralfate groups. The results are, with regard to the acute effects, in accordance with earlier open studies (12-16). Endoscopic evaluation during the period of investigation had, of course, been of some interest, especially when discussing the mechanisms of action. However, we did not find it ethical to perform rectosigmoidoscopic assessment, since we logically assumed that the bowel symptoms were due to an inflammatory reaction caused by the irradiation. Moreover, in our experience an intervention during the acute phase should be avoided because of the risk of irreversible damage to the internal sphincter, as examination of the urinary bladder during the acute phase is not advised owing to the risk of incontinency. In addition, the clinical severity of the disease seems not to correlate with the endoscopic severity (5). Nevertheless, an endoscopic evaluation will be performed at a later stage. The mode of action by which sucralfate exerts its effects can include all the earlier proposed actions: protection of the denoded mucosa from local irritants (18-20), cytoprotection (18), and binding of bile acids (21,22). It is of interest that the effects mediated by sucralfate are not in need of an acidic medium (23). The advantages of using sucralfate are the simple means of administration and especially the low frequency of side-effects despite its extensive use (18,24). In this study we have used granules, which are introduced for use in healing gastric ulcer. From a pharmacokinetic standpoint it would be preferable to have the drug designed in another way, such as slow-release preparation or dragee, for optimal effect in the lower part of the gastrointestinal tract. Moreover, it should also be evaluated whether a decreased intake, such as two doses per day, of sucralfate can be as effective as the six doses per day used in the present study. The economic aspects with low costs of sucralfate use must also be considered. In conclusion, this double-blind placebo-controlled study clearly suggests sucralfate to be promising in preventing radiation-induced bowel discomfort. A reduction in the risk of complications increases the possibility of carrying through planned treatment and avoiding unfavourable interruptions and, thus, curing the patient with cancer in the pelvis by means of radiotherapy. It is obvious that by reducing the radiation-induced bowel symptoms the quality of life during (and following) therapy can be enhanced, and it may be possible to increase the therapeutic ratio by escalating the dose. Recently published studies further support the beneficial effects of sucralfate in reducing the problems of chronic bowel injury following irradiation (25), radiationinduced mucositis (26, 27), and chemotherapy-induced mucositis (28). Finally, there are other beneficial reports of sucralfate on various colorectal disorders, such as solitary
Irradiation-induced Diarrhoea and Sucralfate rectal ulcer (291, postpo~ypectomy bleeding (30), and inflammatory bowel disease (31).
ACKNOWLEDGEMENTS
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This study was supported by grants from The Swedish Society for Cancer Research and The Lions’ Cancer Research Foundation, UmeA, Sweden. T h e skilful assistance of Mikael Arevarn, radiographer, and Hhkan Jonsson, statistician, is acknowledged.
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