A randomized double blind placebo controlled multicenter study of mesalazine for the prevention of acute radiation enteritis

doi:10.1016/S0167-8140(97)00064-9

Radiotherapy and Oncology

Volume 44, Issue 1, July 1997, Pages 59-63

https://doi.org/10.1016/S0167-8140(97)00064-9 Get rights and content

Abstract

Background and purpose: Symptoms of acute radiation enteritis (ARE), dominated by diarrhea, occur in more than 70% of patients receiving pelvic irradiation. Eicosanoids and free radicals release have been implicated in the pathogenesis. Mesalazine (5-ASA) is a potent inhibitor of their synthesis in the mucosa and could therefore be of some interest in preventing ARE.

Patients and methods: The study was performed in six radiotherapy units in France who agreed on standardized irradiation procedures. One hundred and fifty-three patients planned for external beam radiotherapy to the pelvis ≥45 Gy for prostate (n = 97) or uterus (n = 54) cancer were randomized on a double blind basis to receive prophylactic 5-ASA (4 g/day Pentasa^®) or placebo. Patients with concomitant chemotherapy were excluded. Prostate and uterus cancers were chosen since these centropelvic tumors require a similar radiotherapy protocol during the first step of treatment and involve a comparable volume of small intestine. The symptoms of ARE and their severity were assessed every week during irradiation, and 1 and 3 months after its end. All patients followed a low fiber and low lactose diet. End points were diarrhea, use of antidiarrheal agents, abdominal pain, and body weight. Effficacy was evaluated using intention to treat.

Results: (means ± SD) Groups did not differ for age (mean 64 ± 9 years), sex, tumor site, or irradiation procedure. During irradiation, diarrhea occurred in 69% and 66% of the 5-ASA and placebo groups, respectively (χ², P = 0.22). Curves of survival without diarrhea did not differ between groups (logrank P = 0.09). Severity of diarrhea did not differ between groups except at d15 where it was significantly more severe in the 5-ASA group (ANOVA P = 0.006). Duration of diarrhea did not differ (22 ± 15 days in both groups, P = 0.88). Abdominal pain was less frequently reported in the 5-ASA group at d28 (34% vs. 51%, P = 0.048). Use of antidiarrheal agents and body weight did not differ between groups.

Conclusion: Mesalazine 4 g/day did not decrease the symptoms of ARE.

References (22)

I. Ahnfelt-Ronne et al.
Clinical evidence supporting the radical scavenger mechanism of 5-aminosalicylic acid
Gastroenterology
(1990)
C.A. Baughan et al.
A randomized trial to assess the efficacy of 5-aminosalicylic acid for the prevention of radiation enteritis
Clin. Oncol.
(1993)
R.G. Bourne et al.
The relationship between early and late gastrointestinal complications of radiation therapy for carcinoma of the cervix
Int. J. Radiat. Oncol. Biol. Phys.
(1983)
M.J. Gallagher et al.
A prospective study of treatment techniques to minimize the volume of pelvic small bowel with reduction of acute and late effects associated with pelvic irradiation
Int. J. Radiat. Oncol. Biol. Phys.
(1986)
M.J. Gallagher et al.
A prospective study of the acute and late small bowel effects in 300 patients receiving pelvic radiation. An update
Int. J. Radiat. Oncol. Biol. Phys.
(1987)
S.H. Herbert et al.
Decreasing gastrointestinal morbidity with the use of small bowel contrast during treatment planning for pelvic irradiation
Int. J. Radiat. Oncol. Biol. Phys.
(1991)
P.H. Layer et al.
Delivery and fate of oral mesalamine microgranules within the human small intestine
Gastroenterology
(1995)
J.A. Martenson et al.
Olsalazine is contraindicated during pelvic radiation therapy: result of a double blind, randomized trial
Int. J. Radiat. Oncol. Biol. Phys.
(1996)
E. Salminen et al.
Preservation of intestinal integrity during radiotherapy using live Lactobacillus acidophilus cultures
Clin. Radiol.
(1988)
S.M. Greenfield et al.
Review article: the mode of action of the aminosalicylates in inflammatory bowel disease
Aliment. Pharmacol. Ther.
(1993)

Th. Gyrinsky et al.

Overall treatment time in advanced cervical carcinomas: a critical parameter in treatment outcome

Int. J. Radiat. Oncol. Biol. Phys.

(1993)

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Radiotherapy and Oncology

Abstract

References (22)

Clinical evidence supporting the radical scavenger mechanism of 5-aminosalicylic acid

Gastroenterology

A randomized trial to assess the efficacy of 5-aminosalicylic acid for the prevention of radiation enteritis

Clin. Oncol.

The relationship between early and late gastrointestinal complications of radiation therapy for carcinoma of the cervix

Int. J. Radiat. Oncol. Biol. Phys.

A prospective study of treatment techniques to minimize the volume of pelvic small bowel with reduction of acute and late effects associated with pelvic irradiation

Int. J. Radiat. Oncol. Biol. Phys.

A prospective study of the acute and late small bowel effects in 300 patients receiving pelvic radiation. An update

Int. J. Radiat. Oncol. Biol. Phys.

Decreasing gastrointestinal morbidity with the use of small bowel contrast during treatment planning for pelvic irradiation

Int. J. Radiat. Oncol. Biol. Phys.

Delivery and fate of oral mesalamine microgranules within the human small intestine

Gastroenterology

Olsalazine is contraindicated during pelvic radiation therapy: result of a double blind, randomized trial

Int. J. Radiat. Oncol. Biol. Phys.

Preservation of intestinal integrity during radiotherapy using live Lactobacillus acidophilus cultures

Clin. Radiol.

Review article: the mode of action of the aminosalicylates in inflammatory bowel disease

Aliment. Pharmacol. Ther.

Overall treatment time in advanced cervical carcinomas: a critical parameter in treatment outcome

Int. J. Radiat. Oncol. Biol. Phys.

Cited by (89)

Physiopathology and pharmacological perspectives in the treatment of radiation enteritis

Current Status of Targeted Radioprotection and Radiation Injury Mitigation and Treatment Agents: A Critical Review of the Literature

Application of <sup>1</sup>H NMR spectroscopy-based metabonomics to feces of cervical cancer patients with radiation-induced acute intestinal symptoms

Management of Intestinal Complications in Patients With Pelvic Radiation Disease

Effects of a dietary intervention on acute gastrointestinal side effects and other aspects of health-related quality of life: A randomized controlled trial in prostate cancer patients undergoing radiotherapy

ICRP publication 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs Ã¢â‚¬â€ Threshold Doses for Tissue Reactions in a Radiation Protection Context