ATLANTA – Severe diarrhea is a frequent complication of pelvic irradiation, but a guideline-recommended prophylactic agent, sulfasalazine, may actually make radiation-induced diarrhea worse, reported investigators at the annual meeting of the American Society for Radiation Oncology.
Updated 2007 guidelines for the prevention and treatment of mucositis recommend 500 mg oral sulfasalazine twice daily to help reduce the incidence and severity of radiation-induced enteropathy in patients treated with external beam radiotherapy to the pelvis.
Dr. Robert C. Miller
But in a randomized phase III investigational study, 29% of patients who received sulfasalazine prophylactically had grade 3 or 4 diarrhea, compared with only 11% of patients who received placebo (P = .037)
The trial was halted and sulfasalazine discontinued after the data safety and monitoring board for the N08C9 trial determined that trial would not be positive even if all future toxicities in the trial occurred in the placebo arm.
"Sulfasalazine does not reduce radiotherapy-related diarrhea when used as a prophylactic agent and may increase that risk. Inclusion of sulfasalazine in clinical guidelines for radiotherapy-related enteritis prophylaxis should be reconsidered on the basis of our trial," said Dr. Robert C. Miller, professor of radiation oncology at the Mayo Clinic in Rochester, Minn.
The results highlight the need for randomized trials to confirm preliminary studies or validate clinical practices for which there is not robust evidence. Dr. Miller said.
Sulfasalazine is more widely used in Europe than in the United States, said Dr. Beth A. Erickson, professor of radiation oncology at the Medical College of Wisconsin in Milwaukee.
The standard of care in the United States for managing patients with radiation-induced diarrhea is a combination of a low-residue diet, agents that slow gastric motility and, in some cases, the use of stool-bulking agents, she said in a briefing a few days after Dr. Miller’s presentation.
The target accrual for the trial was 140 patients, but only 78 were enrolled and evaluable for the primary endpoint – maximal severity of diarrhea during and up to 6 weeks after radiotherapy according to Common Terminology Criteria for Adverse Events 4.0 – before the trial was stopped. Eligible patients were those receiving pelvic radiotherapy to a dose of more than 45 Gy, with or without chemotherapy.
Dr. Beth A. Erickson
Of the 40 patients in the placebo group, 8 had no diarrhea, 15 had grade 1 diarrhea, 13 had grade 2, and 4 had grade 3 diarrhea. There were no patients with grade 4 events in this group.
In the sulfasalazine group, 9 patients had no diarrhea, 11 had grade 2, 7 had grade 3 diarrhea, 10 had grade 3, and 1 had grade 4 diarrhea.
Although there were significantly more cases of grade 3 or greater diarrhea in patients treated with active drug, when all cases of diarrhea in each group were considered together, there were no significant differences between the sulfasalazine-treated patients and placebo-treated controls.
The trial was supported by the North Central Cancer Treatment Group and the Mayo Clinic. Sulfasalazine was supplied by Pfizer. Dr. Miller reported serving on the scientific advisory board of Tekcapital Ltd.