Prevention of Irradiation-Induced Bowel Discomfort by Sucralfate: A Double-Blind, Placebo-Controlled Study When Treating Localized Pelvic Cancer ROGER
HENRIKSSON,
M.D.,
LARS FRANZEN,
M.D.,
Bo
LIT-TBRAND,
Sucralfate, an aluminum hydroxide complex of sulfated sucrose used in the treatment of gastric ulcer, was shown to prevent irradiationinduced diarrhea and bowel discomfort significantly in patients treated for pelvic cancer with external radiotherapy with intent to cure. The double-blind placebo-controlled study included ‘70 patients with carcinoma of the prostate and urinary bladder without distant metastasis (TI-4NolxMo) and performance status of z 90% Karnofsky scale. Radiotherapy was administered in a conventional manner with MeV photons and a four-field technique. The total dose was 62-66 Gy and total treatment time of 6.5 weeks. Dose granules of sucralfate or placebo were dispensed to each patient 2 weeks after radiation started and continued for 6 weeks. All analyses were performed blindly. Seven of 34 evaluable patients in the placebo group and 18 of 32 evaluable patients in the sucralfate group did not present with diarrhea during the observation period. The frequency of defecation and stool consistency were significantly improved by sucralfate. Fourteen patients in the placebo group and only three in the sucralfate group required symptomatic therapy with loperamide. There was no evidence of adverse effects associated with the use of sucralfate. Sucralfate can be of beneficial value in diminishing the bowel discomfort during radiotherapy of pelvic malignancies, and the earlier proposed mechanisms of action (e.g., protection of denuded mucosa, cytoprotective properties, binding bile acids) can also be valid for the current effects of sucralfate.
From the Department of Oncology, University Hospital, Umea, Sweden. This study was supported in part by grants from the Swedish Society Against Cancer and the Lion’s Cancer Research Foundation, Umed, Sweden. Requests for reprints should be addressed to Roger Henriksson, M.D., Department of Oncology, University Hospital S-901 85 Umea, Sweden.
M.D.,
Urned, Sweden
P
atients receiving cancertherapy are generally afflicted with a diversity of adverse effects. Irradiation is a cornerstonein the curative management of different malignanciesin the pelvis. Intestinal reactions are well-known complicationswhen treating cancer of the prostate, urinary bladder, and other malignanciesin the pelvis with radiotherapy, sincevarious parts of small and/or large intestine are in the treatment volume. After approximately 2 weeks of treatment with conventional fractionation, which corresponds to a delivered doseof 18-22 Gy, bowel discomforts such as diarrhea usually develop.Enteropathy during andafter irradiation canbe seenin almost all patients following radiation dosesof 40-80 Gy [l-3]. Proctitis accountsfor more than 75%of radiation injuries in the gut [4,53.The pathogenesishas been attributed to the radiation sensitivity of the epithelial cells in the mucosadue to a short cell cycle time. This is also evident in intestinal malignanciesin which a high cell turnover rate has been shown [6]. The effects have beendescribedboth from morphologicalterations as well as from functional changes.The diarrhea during and directly after irradiation is accompanied by edema in the intestinal wall. The late symptoms following irradiation are usually seen after 1 year; however, these symptoms can appear at any time during the lifetime of the patients [7,8]. Analysis with barium enema and endoscopyrevealed a wide spectrum of different disorders and varied with the localizationi-81.The most frequent adverse effects seenwere decreaseddistensibility in the rectum, and intestinal fixation and altered mucosal pattern in the sigmoid colon. An impaired ileal function with regard to lactose and bile salt absorption has been associatedwith pelvic irradiation [2,9], and fecal content of bile salts was even higher in patients with diarrhea secondary to irradiation comparedwith patients with ulcerative colitis or acute gastroenteritis [9]. The importanceof bile acidsin the developmentof diarrhea has further been stressed in several other studies [lo, 111.Consequently,in these patients fat malabsorptionis common[g-11]. Bacterial contamination can also be an additive factor in increasing
August 8, 1991
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ET AL
TABLE I Patient Characteristics Placebo (n = 35) Prostatic carcinoma TO-T3pN0Mo Prostatic carcinoma T1-T,,pN,h$ Bladder carcinoma T2.T4 NoMo Not evaluable: Vertigo-change in treatment policy Disagreement with the study protocol Two malignancies-change in treatment policy Obstipation-disagreement to continue the study
Sucralfate (n = 35) 19
1’; 3
: ; 1
1
the severity of irradiation-induced enteropathy [ll]. External radiotherapy for prostatic carcinoma with 50 Gy has also been shown to affect the internal anal sphincter, giving rise to an increased frequency of defecation and even incontinence [12]. The desirability of reducing these discomforts for the patient is obvious, and the mainstay of medical therapy has been sulfasalazine and oral or rectal steroids [5,13]. During recent years the main interest has been focused on bile-acid malabsorption [2,3,9]. Bile-acid sequestering resins, such as cholestyramine and colestipol, have been shown to be somewhat effective in preventing acute diarrhea induced by pelvic irradiation. However, these
Figure 1. Radiographic demonstration
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of a treatment field. Left anteroposterior
The American Journal of Medicine
drugs are associated with a high rate of side effects [2,3]. Furthermore, the symptoms often persist, and surgery is sometimes needed. Recently, in an open consecutive study [14], in an open randomized study [Xl, and in some case observations [16], it has been suggested that sucralfate, an aluminum hydroxide complex of sulfated sucrose used in the treatment of gastric ulcer, can be of value in preventing radiation-induced bowel discomfort. With support of these encouraging results, we have performed a double-blind randomized placebo-controlled study evaluating the effects of sucralfate on irradiation-induced bowel discomfort when treating pelvic cancer.
PATIENTSAND METHODS This study was prospectively randomized prior to radiotherapy in a double-blind fashion using placebo. The study included 70 patients receiving pelvic irradiation with a curative intent. The eligibility requirements included patients with the primary diagnosis of carcinoma of the prostate or urinary bladder with performance status of 2 90% Karnofsky scale (Table I). Patients with preexisting gastrointestinal problems who had undergone intestinal surgery, colostomy, and previous chemotherapy or radiation therapy were not entered in
view; Right, lateral view.
Volume 91 (suppl 2A)
SYMPOSIUMON SUCRALFATE/HENRIKSSONET AL
Figure 2. Cross-section of a dose plan demonstrating the four-field technique when treating carcinoma in the prostate. Shadow areas indicate the tumor, especially the target volume. The treatment volume is outlined by the thick line, showing the 90% isodose curve.
the study. The patients were stratified according to diagnosis. At the 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 measured in the beginning, after 3 weeks, at the end of treatment, and during the first 2 months after the end of treatment. The general condition was followed throughout the treatment period, and the occurrence of symptoms such as nausea and vomiting was observed. All patients had regular consultation with a dietitian during the treatment and advice regarding the necessity of a low fat intake. Irradiation Treatment Radiotherapy was administered with 20.9 MeV photons (Microtron, Scanditronix) at 100~cm source-skin distance or 50 MeV photons (Racetrack, Scanditronix, Uppsala, Sweden). The fraction schedule was five fractions per week with daily doses of 1.8-2.2 Gy for a total dose of 62-66 Gy (cumulative radiation effect, 18.5). The total treatment time was 6.5 weeks. The mean field size was 14 x 14 cm, and the irradiation was given with a four-field technique (Figures lA,B and 2). Drug Administration Dose granules of sucralfate (an alkaline aluminum hydroxide of sulfated sucrose) and placebo identical in taste, color, and consistency were dispensed randomly to each patient 2 weeks after radiotherapy started, which corresponds to a radiation dose of 18-22 Gy, 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 diarrhea. Administration of placebo and sucralfate continued for a total of 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 medication other than test drugs. Objective patient response was documented. Patients were interviewed by the same physician once every week and at the end of treatment. Two months after the termination of radiotherapy, all the calendars were collected and patients were interviewed again by the physician. The details of the bowel action from the calendar were consecutively converted by the physician to a diarrhea score during the period of investigation (Table II).
Statistical Analysis The statistical analysis and evaluations were performed blindly by an independent statistician without knowledge of the nature of the treatment arms. The code for test medication was broken when all patients had completed the whole 2-month period TABLE II Diarrhea Score
August 8, 1991
Scale 0 : 3
No change in bowel habit (“normal”) A small increase in frequency and soft stools A more pronounced increase in frequency and loose stools Marked increase in frequency and watery stools
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SYMPOSIUMON SUCRALFATE / HENRIKSSONET AL
good, as the patients kept records of bowel habits and medication on the calendar supplied. None of the patients discontinued the medication and no change in the diet was reported apart from the general advice from the dietitian, especially with regard to low fat intake. All patients received the same information. There were no differences in the laboratory status of patients in the two treatment arms (blood, electrolyte, liver status) during the period of investigation. A small weight decrease was seen in the placebo group compared with the sucralfate group at the end of the irradiation treatment (Table III). Seven of 34 evaluable patients in the placebo group and 18 of 32 evaluable patients in the sucralfate group did not present with diarrhea during the observation period. The frequency of defecation (Figure 3) and the mean diarrhea score were significantly lower during the whole period in the sucralfate group compared with the placebo group (Figure 4). The highest mean diarrhea score was noted from the fourth week of irradiation in the placebo group. The differences, though less pronounced, were still seen, even 2 months after the end of radiotherapy. There was also a significant difference in the stool consistency between the groups, with increased frequency of “loose stools” in the placebo group (Table III). Moreover, 14 patients in the placebo group and only three in the sucralfate group required loperamide due to severe discomfort of diarrhea (Table III). There were no significant differences in the appearance of blood or mucus in the stools or abdominal cramps between the groups (Table III).
TABLE III Statistical Evaluation of the Differences Between Sucralfate Treated Patients and Patients in the Placebo GroupEvaluable Patients Parameter Diarrhea Score 021-3 t 1 Number of stools i I :
Sucralfate (n=32)
Placebo (n=34)
::
23 7 16
13 16
>5
p-Value 0.003
0.04
11 24 10 19
Stool consistency: ;;r$l Mucus Blood Abdominal cramps LoperamIde consumption Weight decrement (kg)
; 1.2
0.04 0.82 0.51 0.45 0.003 0.81
2” ::
e two randomlzeo groups were comparea 5 weeK aner lnmatlon or raalotnerapy. Rerences between groups for categoncal variables were tested with Pearson chi-square test. Weight decrement was tested with t-test
following the end of irradiation. Differences between groups for categorial variables were tested with the Pearson chi-square test. Weight decrease was assessed with the t-test.
RESULTS Three patients in the sucralfate group were excluded early in the study; one because of disagreement with the study design, one because of vertigo that required treatment at another clinic, and one patient due to the discovery of a new malignancy that required a major change in the treatment schedule. One patient in the placebo group with moderate obstipation was excluded due to his own decision. No other adverse effects were seen. Apart from these patients the compliance was
10
Figure 3. Mean number of daily stools during the investigation period. 0-0, group; O-0, sucralfate group. cates start of sucralfate treatment.
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01
placebo Arrow indi-
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SYMPOSIUM ON SUCRALFATE/
Figure 4. Mean diarrhea score according to the score illustrated in Table II during the period of investigation. e-0, placebo group; O-0, sucralfate group. Arrow indicates start of sucralfate treatment.
HENRIKSSON
ET AL
11 o’-
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COMMENTS A critical side effect in the treatment of abdominal malignancies is significant damage to the normal intestine. During treatment of pelvic tumors with external, intracavitary, or combined irradiation, the lower colon and rectum usually are included in the treatment volume [1,5,8]. Furthermore, exposure of the small intestine is also plausible and depends on the position and mobility of the intestine. Consequently, symptoms during and shortly following treatment are seen in virtually every patient [1,5,8,14]. The most frequent discomforts experienced by patients are diarrhea and altered bowel habits. Therefore, it is of significant interest to the clinician to report that the drug sucralfate-aluminum hydroxide complex of sulfated sucrose-markedly reduced irradiation-induced diarrhea and bowel discomfort for patients receiving treatment for pelvic carcinoma. This study is, as far as we know, the first doubleblind placebo-controlled evaluation that demonstrates that a drug such as sucralfate can be of value in reducing bowel discomfort when using irradiation in the treatment of abdominal and pelvic malignancies. The frequency of diarrhea or number of defecation episodes, probably the most objective parameter, displayed a significant reduction in the sucralfate group compared with the placebo controls. In addition, significant changes in the stool consistency with a more “watery” appearance were shown in the group of patients receiving placebo. Furthermore, and most interestingly, the consumption of the antidiarrheicum loperamide was seen in few patients in the sucralfate group, whereas almost 50% in the placebo group used loAugust 8,
I
’
I
”
”
”
8
”
17
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-1
peramide. Loperamide is a calcium antagonist and an opiate. The effects of opiates, i.e., the paralysis of smooth muscle, may be dangerous due 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 radiation course and 2 months after the final radiation treatment. 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 treated with sucralfate for gastric ulcer. It cannot be excluded that the bowel discomfort in the placebo group was altered and improved by the use of placebo, which may thus have diminished the differences between the treatment arms. It has also to be emphasized that the consultations with the dietitian, who advised a change in diet and especially a lower fat intake, further reduced the discomforts for the patients and, thus, probably also diminished the possibilities of detecting differences between the placebo and sucralfate groups. The results are in accordance with earlier open studies [14-161. In contrast to these results, there is a report from an animal model of irradiation-induced proctitis that was unable to describe positive effects of sucralfate [18]. The method used, however, was difficult to evaluate strictly. The mode of action by which sucralfate exerts its effect is not clearly established. Sucralfate is known to be effective in healing gastric ulcer [19-211. Sucralfate acts locally by forming a viscous coagulum 1991 The American Journal of Medicine
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andby forming a protective barrier for the denuded mucosa.Thus, it selectively coats areas of ulceration, providing local protection for raw areasfrom the effectsof acids,enzymes,andother irritants for severalhours after ingestion [22,23].Oneplausible explanation could consequentlybe that sucralfate protects mucosal damage induced by irradiation from the effect of local irritants such as bile acids and foodconstituents.The proposedcytoprotective properties [23] also seem to be an additional and interesting explanationfor the prevention of radiation-induced injury. This cytoprotective effect of mucosalprotection includesa wide diversity of factors suchas mucus and bicarbonatesecretion,gastric microcirculation, proliferative zone stimulation, and protection and binding of epidermal growth factor [20]. Although prostaglandins are suggestedto be involved, irradiation-induceddiarrheais not affectedby prostaglandininhibitors [24]. In addition, the binding capacity of bile acids [25,26]can also be an additive effect in preventing bowel discomfort, especially when small intestine and terminal ileum are thought to be in the treatment volume. Bile-acid sequestering resins have been proposedto be effective in preventing acute diarrhea induced by pelvic irradiation [2,3]. However, in patients receiving radiotherapy, no direct relationship has been shown between severity of diarrhea and degreeof bile acid malabsorption,indicating that other factors also can be the cause [27]. Indeed, it is known that enteric organisms causediarrheain severalways [17], and recently, it hasbeendemonstratedthat irradiation hasinduced alterations in the bacterial contamination of the small intestine [ll]. Endoscopicevaluationduring the period of investigation has, of course,beenof someinterest, especially when discussing the mechanismsof action. However, mainly for ethical considerations,we did not perform recta-sigmoidoscopic assessments, since we presumed logically that the bowel symptoms were due to an inflammatory reaction caused by the irradiation. Moreover, in our experiencean intervention during the acute phase should be avoidedbecauseof the risk of irreversible damage to the internal sphincter, and examination of the urinary bladder during the acute phaseis not preferable due to the risk of its causing incontinence. The advantagesof using sucralfateare its simple meansof administration and especiallythe low frequencyof side effects despiteits extensiveuse [19211.Virtually no sucralfate is absorbedfrom the gastrointestinaltract [22,28].In this study we have usedgranulesthat are introducedfor usein healing gastric ulcer. From a pharmacokineticstandpointit
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may be preferableto have the drug designedin another way (e.g., slow-release preparation or dragee)for optimal effect in the lower part of the gastrointestinal tract. Moreover, whether a decreasedintake (e.g., two dosesper day) of sucralfate canbe aseffective asthe six dosesper day used in the current study remains to be seen. It is obvious that by reducing the irradiationinducedbowel symptoms, the quality of life during (and following) therapy can be enhanced,and it may be possibleto increasethe therapeutic ratio by escalating the dose and hyperlsuper-fractionating it, without alteration in the acute side effects. It hasbeenshown,for example,that colorectalcancer and bladder cancer(grade III) have a short potential doublingtime [6,29],indicating that accelerated radiotherapy could improve the therapeutic results. However, the acute side effects have been shownto hamperthe possibility of achievingan optimal total irradiation dose [30]. Sucralfate could thus be of value in combination with accelerated radiotherapy to counteract its acute side effects, consequentlygiving clinicians the possibility of enhancing the therapeutic ratio. In conclusion, this double-blind placebocontrolled study clearly suggestssucralfate to be promising in preventing radiation-induced bowel discomfort. A reduction in the risk of irradiation complications enhancesthe quality of life during and after treatment, and alsoincreasesthe possibility of carrying through planned treatment and avoiding unfavorableintermissions, and, thus, curing the patient with cancerof the pelvis by radiotherapy. Finally, a larger follow-up is of interest to evaluatethe potential role of sucralfatein preventing chronic disturbancesin bowel habits following radiotherapy. ACKNOWLEDGMENT The skillful technical assistance of Mikael Arevarn, and the statistical evaluations by H&an Jonsson are acknowledged. We also thank Kristina Puzey and Farmos Group AB, Stockholm, Sweden, for supply of drugs and support during the study.
REFERENCES 1. Rubin P, Casarett G. A direction for clinical radiation pathology: the tolerance dose. In Vaeth JM. ed: Frontiers of Radiation Therapy and Oncology. Baltlmore: University Park Press, 1972; 6: l-16. 2. Stryker JA, Chung CK, Layser JD. Colestipol hydrochloride prophylaxis of diarrhea during pelvic radiotherapy. Int J Radiat Oncol Biol Phys 1983; 9: 185-90 3. Chary S, Thomson 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: 1885-90. 4 Yoonessi M, Romney S, Dayem 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, Levin W, Myers HS, Marks IN. The natural history of radiation-induced proctosigmoiditis: an analysis of 88 patients. Q J Med 1983; 52: 40-53.
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SYMPOSIUM 6. Steel GG. Growth kinetics of turnours. Cavendish Press, Oxford: 1977 191. 7. Pilepich MV, Krall J, George FW,et a/. Treatment-related morbrdity in phase Ill RTOG studies of extended-field irradiabon for carcinoma of the prostate. Int J Radiaat Oncol Biol Phys 1984; 10: 1861-7. 8. Hartog Jager FC, Cohen P, van Haastert M. Late radration injury of the rectum and srgmoid colon: banum enema findings rn 92 patients. Br J Radio1 1989; 62: 807-12. 9. Andersson H, Bosaeus I, Nystrdm C. Brie salt malabsorptron rn the radratron syndrome. Acta Radrol Oncol Radiat Phys Biol 1978; 17: 312. 10. Kinsella TJ, Bloomer WD. Tolerance of the intestine to radration therapy. Surg Gynecol Obstet 1980; 151: 273-84. 11. Danrelsson A, Nyhltn H, Persson H, Stendahl U. Stenling R, Suhr 0. Chronrc drarrhea after radrotherapy for gynecologrcal cancer. An investigation of occurrence and etrology. Gut, in press. 12. Varma JS, Smith AN, Busuttil A. Function of the anal sphincters after chronic radiation injury Gut 1986; 27: 528-33. 13. Goldstein F, Khoury J, Thornton JJ. Treatment of chronic radiation enterrtis and colitis with salicylazosulfapyridine and systemic corhcosteroids. Am J Gastroenterol 1976; 65: 201-B. 14. Henriksson R, Franzen L, Littbrand B. Does sucralfate reduce radrabon-induced drarrhea? Acta Radrol Oncol 1987; 26: 76-7. 15. Henriksson R, Arevarn M, Franzen L, Persson H, Stendahl U. Beneficial effects of sucralfate in radiatron induced diarrhea. An open randomized study in gynecological cancer patients. Eur J Gyn Oncol 1990; 11: 299-302. 16. Kochar R, Sharma SC, Gupta BB, Mehta SK. Rectal sucralfate in radration proctitis (Letter). Lancet 1988; 2: 400. 17. Freld M, Rao MC, Chang EB. Intestinal electrolyte transport and diarrhea1 disease. N Engl J Med 1989; 321: 879-83. 18. Northway MG, Scobey MW, Geisinger KR. Radiahon proctitis rn the rat. Sequential changes and effects of anti-inflammatory agents. Cancer 1988; 62: 1962-9.
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19. Hallerback 8, Solhaug JH, Carling L,et al. Recurrent
ulcer after treatment
ET AL with
cimetidine or sucralfate. Stand J Gastroenterol 1987; 22: 791-7. 20. Hollander D, ed. Proceedings of the 5th International Sucralfate Research Conference. Am J Med 1989; 86 (Suppl 6A): 1-153. 21. Martin F, Farley A, Gagnon M, Bensemana D. Companson of the healrng capacrtres of sucralfate and cimetrdrne in the short-term treatment of duodenal ulcer: a double-blrnd randomrzed trial. Gastroenterology 1982; 82: 401-5. 22. Nagashima K. Mechanrsm of actron of sucralfate. J Clan Gastroenterol 1981; 3: 117-23. 23. Tamawski A. Sucralfate. Is it more than lust a barner? Cytoprotecbon-future drrection in prevention and treatment of gastrointestinal mucosal Injury. Curr Concepts Gastroenterol 1984; 1: 5-8. 24. Mennie AT, Dalley VM, Dinneen LC, Collier HO. Treatment of radiatton-Induced gastrorntestrnal distress wrth acetylsalicylate. Lancet 1975; 2: 942-3. 25. Tobiasson P, Stenstam M. Effects of sucralfate and cholestyramine on brie acid absorptron. Gastroenterology 1985; 88: 393-6. 26. Tanghbj H, Stenstam M, Tobiasson P. Effects of sucralfate and cholestyramine on bile acid absorphon (Abstr). Gastroenterology 1985; 88: 1699. 27. Yeoh EK, Lui D, Lee NY. The mechanism of diarrhea resulting from pelvic and abdomrnal radiotherapy; a prospective study using selenium-75 labelled conlugated bile acid and cobalt-58 labelled cyanocobolamin. Br J Radrol 1984; 57: 1131-6. 28. lshimorr A. Safety experience with sucralfate in Japan. J Ckn Gastroenterol 1981; 3 (Suppl 2): 169-73. 29. Trott KR, Kummermehr J. What is known about tumor prolrferation rates to choose between accelerated fractronation or hyperfractronation? Radiother Oncol 1985; 3: 1-9. 30. Saunders MJ, Drsche S, Fowler JF,et al. Radiotherapy with three fractions per day for twelve consecutive days for tumors on the thorax, head and neck. Front Radiat Ther Oncol 1988; 22: 99-104.
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Volume 91 (suppl 2A)
2A-157s
HENRIKSSON,
M.D.,
LARS FRANZEN,
M.D.,
Bo
LIT-TBRAND,
Sucralfate, an aluminum hydroxide complex of sulfated sucrose used in the treatment of gastric ulcer, was shown to prevent irradiationinduced diarrhea and bowel discomfort significantly in patients treated for pelvic cancer with external radiotherapy with intent to cure. The double-blind placebo-controlled study included ‘70 patients with carcinoma of the prostate and urinary bladder without distant metastasis (TI-4NolxMo) and performance status of z 90% Karnofsky scale. Radiotherapy was administered in a conventional manner with MeV photons and a four-field technique. The total dose was 62-66 Gy and total treatment time of 6.5 weeks. Dose granules of sucralfate or placebo were dispensed to each patient 2 weeks after radiation started and continued for 6 weeks. All analyses were performed blindly. Seven of 34 evaluable patients in the placebo group and 18 of 32 evaluable patients in the sucralfate group did not present with diarrhea during the observation period. The frequency of defecation and stool consistency were significantly improved by sucralfate. Fourteen patients in the placebo group and only three in the sucralfate group required symptomatic therapy with loperamide. There was no evidence of adverse effects associated with the use of sucralfate. Sucralfate can be of beneficial value in diminishing the bowel discomfort during radiotherapy of pelvic malignancies, and the earlier proposed mechanisms of action (e.g., protection of denuded mucosa, cytoprotective properties, binding bile acids) can also be valid for the current effects of sucralfate.
From the Department of Oncology, University Hospital, Umea, Sweden. This study was supported in part by grants from the Swedish Society Against Cancer and the Lion’s Cancer Research Foundation, Umed, Sweden. Requests for reprints should be addressed to Roger Henriksson, M.D., Department of Oncology, University Hospital S-901 85 Umea, Sweden.
M.D.,
Urned, Sweden
P
atients receiving cancertherapy are generally afflicted with a diversity of adverse effects. Irradiation is a cornerstonein the curative management of different malignanciesin the pelvis. Intestinal reactions are well-known complicationswhen treating cancer of the prostate, urinary bladder, and other malignanciesin the pelvis with radiotherapy, sincevarious parts of small and/or large intestine are in the treatment volume. After approximately 2 weeks of treatment with conventional fractionation, which corresponds to a delivered doseof 18-22 Gy, bowel discomforts such as diarrhea usually develop.Enteropathy during andafter irradiation canbe seenin almost all patients following radiation dosesof 40-80 Gy [l-3]. Proctitis accountsfor more than 75%of radiation injuries in the gut [4,53.The pathogenesishas been attributed to the radiation sensitivity of the epithelial cells in the mucosadue to a short cell cycle time. This is also evident in intestinal malignanciesin which a high cell turnover rate has been shown [6]. The effects have beendescribedboth from morphologicalterations as well as from functional changes.The diarrhea during and directly after irradiation is accompanied by edema in the intestinal wall. The late symptoms following irradiation are usually seen after 1 year; however, these symptoms can appear at any time during the lifetime of the patients [7,8]. Analysis with barium enema and endoscopyrevealed a wide spectrum of different disorders and varied with the localizationi-81.The most frequent adverse effects seenwere decreaseddistensibility in the rectum, and intestinal fixation and altered mucosal pattern in the sigmoid colon. An impaired ileal function with regard to lactose and bile salt absorption has been associatedwith pelvic irradiation [2,9], and fecal content of bile salts was even higher in patients with diarrhea secondary to irradiation comparedwith patients with ulcerative colitis or acute gastroenteritis [9]. The importanceof bile acidsin the developmentof diarrhea has further been stressed in several other studies [lo, 111.Consequently,in these patients fat malabsorptionis common[g-11]. Bacterial contamination can also be an additive factor in increasing
August 8, 1991
The American Journal of Medicine
Volume 91 (suppl 2A)
2A151S
SYMPOSlUM ON SUCRALFATE I HENRIKSSON
ET AL
TABLE I Patient Characteristics Placebo (n = 35) Prostatic carcinoma TO-T3pN0Mo Prostatic carcinoma T1-T,,pN,h$ Bladder carcinoma T2.T4 NoMo Not evaluable: Vertigo-change in treatment policy Disagreement with the study protocol Two malignancies-change in treatment policy Obstipation-disagreement to continue the study
Sucralfate (n = 35) 19
1’; 3
: ; 1
1
the severity of irradiation-induced enteropathy [ll]. External radiotherapy for prostatic carcinoma with 50 Gy has also been shown to affect the internal anal sphincter, giving rise to an increased frequency of defecation and even incontinence [12]. The desirability of reducing these discomforts for the patient is obvious, and the mainstay of medical therapy has been sulfasalazine and oral or rectal steroids [5,13]. During recent years the main interest has been focused on bile-acid malabsorption [2,3,9]. Bile-acid sequestering resins, such as cholestyramine and colestipol, have been shown to be somewhat effective in preventing acute diarrhea induced by pelvic irradiation. However, these
Figure 1. Radiographic demonstration
2A-152s
August 8, 1991
of a treatment field. Left anteroposterior
The American Journal of Medicine
drugs are associated with a high rate of side effects [2,3]. Furthermore, the symptoms often persist, and surgery is sometimes needed. Recently, in an open consecutive study [14], in an open randomized study [Xl, and in some case observations [16], it has been suggested that sucralfate, an aluminum hydroxide complex of sulfated sucrose used in the treatment of gastric ulcer, can be of value in preventing radiation-induced bowel discomfort. With support of these encouraging results, we have performed a double-blind randomized placebo-controlled study evaluating the effects of sucralfate on irradiation-induced bowel discomfort when treating pelvic cancer.
PATIENTSAND METHODS This study was prospectively randomized prior to radiotherapy in a double-blind fashion using placebo. The study included 70 patients receiving pelvic irradiation with a curative intent. The eligibility requirements included patients with the primary diagnosis of carcinoma of the prostate or urinary bladder with performance status of 2 90% Karnofsky scale (Table I). Patients with preexisting gastrointestinal problems who had undergone intestinal surgery, colostomy, and previous chemotherapy or radiation therapy were not entered in
view; Right, lateral view.
Volume 91 (suppl 2A)
SYMPOSIUMON SUCRALFATE/HENRIKSSONET AL
Figure 2. Cross-section of a dose plan demonstrating the four-field technique when treating carcinoma in the prostate. Shadow areas indicate the tumor, especially the target volume. The treatment volume is outlined by the thick line, showing the 90% isodose curve.
the study. The patients were stratified according to diagnosis. At the 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 measured in the beginning, after 3 weeks, at the end of treatment, and during the first 2 months after the end of treatment. The general condition was followed throughout the treatment period, and the occurrence of symptoms such as nausea and vomiting was observed. All patients had regular consultation with a dietitian during the treatment and advice regarding the necessity of a low fat intake. Irradiation Treatment Radiotherapy was administered with 20.9 MeV photons (Microtron, Scanditronix) at 100~cm source-skin distance or 50 MeV photons (Racetrack, Scanditronix, Uppsala, Sweden). The fraction schedule was five fractions per week with daily doses of 1.8-2.2 Gy for a total dose of 62-66 Gy (cumulative radiation effect, 18.5). The total treatment time was 6.5 weeks. The mean field size was 14 x 14 cm, and the irradiation was given with a four-field technique (Figures lA,B and 2). Drug Administration Dose granules of sucralfate (an alkaline aluminum hydroxide of sulfated sucrose) and placebo identical in taste, color, and consistency were dispensed randomly to each patient 2 weeks after radiotherapy started, which corresponds to a radiation dose of 18-22 Gy, 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 diarrhea. Administration of placebo and sucralfate continued for a total of 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 medication other than test drugs. Objective patient response was documented. Patients were interviewed by the same physician once every week and at the end of treatment. Two months after the termination of radiotherapy, all the calendars were collected and patients were interviewed again by the physician. The details of the bowel action from the calendar were consecutively converted by the physician to a diarrhea score during the period of investigation (Table II).
Statistical Analysis The statistical analysis and evaluations were performed blindly by an independent statistician without knowledge of the nature of the treatment arms. The code for test medication was broken when all patients had completed the whole 2-month period TABLE II Diarrhea Score
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Scale 0 : 3
No change in bowel habit (“normal”) A small increase in frequency and soft stools A more pronounced increase in frequency and loose stools Marked increase in frequency and watery stools
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good, as the patients kept records of bowel habits and medication on the calendar supplied. None of the patients discontinued the medication and no change in the diet was reported apart from the general advice from the dietitian, especially with regard to low fat intake. All patients received the same information. There were no differences in the laboratory status of patients in the two treatment arms (blood, electrolyte, liver status) during the period of investigation. A small weight decrease was seen in the placebo group compared with the sucralfate group at the end of the irradiation treatment (Table III). Seven of 34 evaluable patients in the placebo group and 18 of 32 evaluable patients in the sucralfate group did not present with diarrhea during the observation period. The frequency of defecation (Figure 3) and the mean diarrhea score were significantly lower during the whole period in the sucralfate group compared with the placebo group (Figure 4). The highest mean diarrhea score was noted from the fourth week of irradiation in the placebo group. The differences, though less pronounced, were still seen, even 2 months after the end of radiotherapy. There was also a significant difference in the stool consistency between the groups, with increased frequency of “loose stools” in the placebo group (Table III). Moreover, 14 patients in the placebo group and only three in the sucralfate group required loperamide due to severe discomfort of diarrhea (Table III). There were no significant differences in the appearance of blood or mucus in the stools or abdominal cramps between the groups (Table III).
TABLE III Statistical Evaluation of the Differences Between Sucralfate Treated Patients and Patients in the Placebo GroupEvaluable Patients Parameter Diarrhea Score 021-3 t 1 Number of stools i I :
Sucralfate (n=32)
Placebo (n=34)
::
23 7 16
13 16
>5
p-Value 0.003
0.04
11 24 10 19
Stool consistency: ;;r$l Mucus Blood Abdominal cramps LoperamIde consumption Weight decrement (kg)
; 1.2
0.04 0.82 0.51 0.45 0.003 0.81
2” ::
e two randomlzeo groups were comparea 5 weeK aner lnmatlon or raalotnerapy. Rerences between groups for categoncal variables were tested with Pearson chi-square test. Weight decrement was tested with t-test
following the end of irradiation. Differences between groups for categorial variables were tested with the Pearson chi-square test. Weight decrease was assessed with the t-test.
RESULTS Three patients in the sucralfate group were excluded early in the study; one because of disagreement with the study design, one because of vertigo that required treatment at another clinic, and one patient due to the discovery of a new malignancy that required a major change in the treatment schedule. One patient in the placebo group with moderate obstipation was excluded due to his own decision. No other adverse effects were seen. Apart from these patients the compliance was
10
Figure 3. Mean number of daily stools during the investigation period. 0-0, group; O-0, sucralfate group. cates start of sucralfate treatment.
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Figure 4. Mean diarrhea score according to the score illustrated in Table II during the period of investigation. e-0, placebo group; O-0, sucralfate group. Arrow indicates start of sucralfate treatment.
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COMMENTS A critical side effect in the treatment of abdominal malignancies is significant damage to the normal intestine. During treatment of pelvic tumors with external, intracavitary, or combined irradiation, the lower colon and rectum usually are included in the treatment volume [1,5,8]. Furthermore, exposure of the small intestine is also plausible and depends on the position and mobility of the intestine. Consequently, symptoms during and shortly following treatment are seen in virtually every patient [1,5,8,14]. The most frequent discomforts experienced by patients are diarrhea and altered bowel habits. Therefore, it is of significant interest to the clinician to report that the drug sucralfate-aluminum hydroxide complex of sulfated sucrose-markedly reduced irradiation-induced diarrhea and bowel discomfort for patients receiving treatment for pelvic carcinoma. This study is, as far as we know, the first doubleblind placebo-controlled evaluation that demonstrates that a drug such as sucralfate can be of value in reducing bowel discomfort when using irradiation in the treatment of abdominal and pelvic malignancies. The frequency of diarrhea or number of defecation episodes, probably the most objective parameter, displayed a significant reduction in the sucralfate group compared with the placebo controls. In addition, significant changes in the stool consistency with a more “watery” appearance were shown in the group of patients receiving placebo. Furthermore, and most interestingly, the consumption of the antidiarrheicum loperamide was seen in few patients in the sucralfate group, whereas almost 50% in the placebo group used loAugust 8,
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peramide. Loperamide is a calcium antagonist and an opiate. The effects of opiates, i.e., the paralysis of smooth muscle, may be dangerous due 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 radiation course and 2 months after the final radiation treatment. 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 treated with sucralfate for gastric ulcer. It cannot be excluded that the bowel discomfort in the placebo group was altered and improved by the use of placebo, which may thus have diminished the differences between the treatment arms. It has also to be emphasized that the consultations with the dietitian, who advised a change in diet and especially a lower fat intake, further reduced the discomforts for the patients and, thus, probably also diminished the possibilities of detecting differences between the placebo and sucralfate groups. The results are in accordance with earlier open studies [14-161. In contrast to these results, there is a report from an animal model of irradiation-induced proctitis that was unable to describe positive effects of sucralfate [18]. The method used, however, was difficult to evaluate strictly. The mode of action by which sucralfate exerts its effect is not clearly established. Sucralfate is known to be effective in healing gastric ulcer [19-211. Sucralfate acts locally by forming a viscous coagulum 1991 The American Journal of Medicine
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andby forming a protective barrier for the denuded mucosa.Thus, it selectively coats areas of ulceration, providing local protection for raw areasfrom the effectsof acids,enzymes,andother irritants for severalhours after ingestion [22,23].Oneplausible explanation could consequentlybe that sucralfate protects mucosal damage induced by irradiation from the effect of local irritants such as bile acids and foodconstituents.The proposedcytoprotective properties [23] also seem to be an additional and interesting explanationfor the prevention of radiation-induced injury. This cytoprotective effect of mucosalprotection includesa wide diversity of factors suchas mucus and bicarbonatesecretion,gastric microcirculation, proliferative zone stimulation, and protection and binding of epidermal growth factor [20]. Although prostaglandins are suggestedto be involved, irradiation-induceddiarrheais not affectedby prostaglandininhibitors [24]. In addition, the binding capacity of bile acids [25,26]can also be an additive effect in preventing bowel discomfort, especially when small intestine and terminal ileum are thought to be in the treatment volume. Bile-acid sequestering resins have been proposedto be effective in preventing acute diarrhea induced by pelvic irradiation [2,3]. However, in patients receiving radiotherapy, no direct relationship has been shown between severity of diarrhea and degreeof bile acid malabsorption,indicating that other factors also can be the cause [27]. Indeed, it is known that enteric organisms causediarrheain severalways [17], and recently, it hasbeendemonstratedthat irradiation hasinduced alterations in the bacterial contamination of the small intestine [ll]. Endoscopicevaluationduring the period of investigation has, of course,beenof someinterest, especially when discussing the mechanismsof action. However, mainly for ethical considerations,we did not perform recta-sigmoidoscopic assessments, since we presumed logically that the bowel symptoms were due to an inflammatory reaction caused by the irradiation. Moreover, in our experiencean intervention during the acute phase should be avoidedbecauseof the risk of irreversible damage to the internal sphincter, and examination of the urinary bladder during the acute phaseis not preferable due to the risk of its causing incontinence. The advantagesof using sucralfateare its simple meansof administration and especiallythe low frequencyof side effects despiteits extensiveuse [19211.Virtually no sucralfate is absorbedfrom the gastrointestinaltract [22,28].In this study we have usedgranulesthat are introducedfor usein healing gastric ulcer. From a pharmacokineticstandpointit
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may be preferableto have the drug designedin another way (e.g., slow-release preparation or dragee)for optimal effect in the lower part of the gastrointestinal tract. Moreover, whether a decreasedintake (e.g., two dosesper day) of sucralfate canbe aseffective asthe six dosesper day used in the current study remains to be seen. It is obvious that by reducing the irradiationinducedbowel symptoms, the quality of life during (and following) therapy can be enhanced,and it may be possibleto increasethe therapeutic ratio by escalating the dose and hyperlsuper-fractionating it, without alteration in the acute side effects. It hasbeenshown,for example,that colorectalcancer and bladder cancer(grade III) have a short potential doublingtime [6,29],indicating that accelerated radiotherapy could improve the therapeutic results. However, the acute side effects have been shownto hamperthe possibility of achievingan optimal total irradiation dose [30]. Sucralfate could thus be of value in combination with accelerated radiotherapy to counteract its acute side effects, consequentlygiving clinicians the possibility of enhancing the therapeutic ratio. In conclusion, this double-blind placebocontrolled study clearly suggestssucralfate to be promising in preventing radiation-induced bowel discomfort. A reduction in the risk of irradiation complications enhancesthe quality of life during and after treatment, and alsoincreasesthe possibility of carrying through planned treatment and avoiding unfavorableintermissions, and, thus, curing the patient with cancerof the pelvis by radiotherapy. Finally, a larger follow-up is of interest to evaluatethe potential role of sucralfatein preventing chronic disturbancesin bowel habits following radiotherapy. ACKNOWLEDGMENT The skillful technical assistance of Mikael Arevarn, and the statistical evaluations by H&an Jonsson are acknowledged. We also thank Kristina Puzey and Farmos Group AB, Stockholm, Sweden, for supply of drugs and support during the study.
REFERENCES 1. Rubin P, Casarett G. A direction for clinical radiation pathology: the tolerance dose. In Vaeth JM. ed: Frontiers of Radiation Therapy and Oncology. Baltlmore: University Park Press, 1972; 6: l-16. 2. Stryker JA, Chung CK, Layser JD. Colestipol hydrochloride prophylaxis of diarrhea during pelvic radiotherapy. Int J Radiat Oncol Biol Phys 1983; 9: 185-90 3. Chary S, Thomson 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: 1885-90. 4 Yoonessi M, Romney S, Dayem 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, Levin W, Myers HS, Marks IN. The natural history of radiation-induced proctosigmoiditis: an analysis of 88 patients. Q J Med 1983; 52: 40-53.
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SYMPOSIUM 6. Steel GG. Growth kinetics of turnours. Cavendish Press, Oxford: 1977 191. 7. Pilepich MV, Krall J, George FW,et a/. Treatment-related morbrdity in phase Ill RTOG studies of extended-field irradiabon for carcinoma of the prostate. Int J Radiaat Oncol Biol Phys 1984; 10: 1861-7. 8. Hartog Jager FC, Cohen P, van Haastert M. Late radration injury of the rectum and srgmoid colon: banum enema findings rn 92 patients. Br J Radio1 1989; 62: 807-12. 9. Andersson H, Bosaeus I, Nystrdm C. Brie salt malabsorptron rn the radratron syndrome. Acta Radrol Oncol Radiat Phys Biol 1978; 17: 312. 10. Kinsella TJ, Bloomer WD. Tolerance of the intestine to radration therapy. Surg Gynecol Obstet 1980; 151: 273-84. 11. Danrelsson A, Nyhltn H, Persson H, Stendahl U. Stenling R, Suhr 0. Chronrc drarrhea after radrotherapy for gynecologrcal cancer. An investigation of occurrence and etrology. Gut, in press. 12. Varma JS, Smith AN, Busuttil A. Function of the anal sphincters after chronic radiation injury Gut 1986; 27: 528-33. 13. Goldstein F, Khoury J, Thornton JJ. Treatment of chronic radiation enterrtis and colitis with salicylazosulfapyridine and systemic corhcosteroids. Am J Gastroenterol 1976; 65: 201-B. 14. Henriksson R, Franzen L, Littbrand B. Does sucralfate reduce radrabon-induced drarrhea? Acta Radrol Oncol 1987; 26: 76-7. 15. Henriksson R, Arevarn M, Franzen L, Persson H, Stendahl U. Beneficial effects of sucralfate in radiatron induced diarrhea. An open randomized study in gynecological cancer patients. Eur J Gyn Oncol 1990; 11: 299-302. 16. Kochar R, Sharma SC, Gupta BB, Mehta SK. Rectal sucralfate in radration proctitis (Letter). Lancet 1988; 2: 400. 17. Freld M, Rao MC, Chang EB. Intestinal electrolyte transport and diarrhea1 disease. N Engl J Med 1989; 321: 879-83. 18. Northway MG, Scobey MW, Geisinger KR. Radiahon proctitis rn the rat. Sequential changes and effects of anti-inflammatory agents. Cancer 1988; 62: 1962-9.
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19. Hallerback 8, Solhaug JH, Carling L,et al. Recurrent
ulcer after treatment
ET AL with
cimetidine or sucralfate. Stand J Gastroenterol 1987; 22: 791-7. 20. Hollander D, ed. Proceedings of the 5th International Sucralfate Research Conference. Am J Med 1989; 86 (Suppl 6A): 1-153. 21. Martin F, Farley A, Gagnon M, Bensemana D. Companson of the healrng capacrtres of sucralfate and cimetrdrne in the short-term treatment of duodenal ulcer: a double-blrnd randomrzed trial. Gastroenterology 1982; 82: 401-5. 22. Nagashima K. Mechanrsm of actron of sucralfate. J Clan Gastroenterol 1981; 3: 117-23. 23. Tamawski A. Sucralfate. Is it more than lust a barner? Cytoprotecbon-future drrection in prevention and treatment of gastrointestinal mucosal Injury. Curr Concepts Gastroenterol 1984; 1: 5-8. 24. Mennie AT, Dalley VM, Dinneen LC, Collier HO. Treatment of radiatton-Induced gastrorntestrnal distress wrth acetylsalicylate. Lancet 1975; 2: 942-3. 25. Tobiasson P, Stenstam M. Effects of sucralfate and cholestyramine on brie acid absorptron. Gastroenterology 1985; 88: 393-6. 26. Tanghbj H, Stenstam M, Tobiasson P. Effects of sucralfate and cholestyramine on bile acid absorphon (Abstr). Gastroenterology 1985; 88: 1699. 27. Yeoh EK, Lui D, Lee NY. The mechanism of diarrhea resulting from pelvic and abdomrnal radiotherapy; a prospective study using selenium-75 labelled conlugated bile acid and cobalt-58 labelled cyanocobolamin. Br J Radrol 1984; 57: 1131-6. 28. lshimorr A. Safety experience with sucralfate in Japan. J Ckn Gastroenterol 1981; 3 (Suppl 2): 169-73. 29. Trott KR, Kummermehr J. What is known about tumor prolrferation rates to choose between accelerated fractronation or hyperfractronation? Radiother Oncol 1985; 3: 1-9. 30. Saunders MJ, Drsche S, Fowler JF,et al. Radiotherapy with three fractions per day for twelve consecutive days for tumors on the thorax, head and neck. Front Radiat Ther Oncol 1988; 22: 99-104.
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