Sulfasalazine Fails to Prevent Radiotherapy-Induced Diarrhea
Atlanta, GA—Patients with cancer treated with pelvic radiation did not have fewer bouts of diarrhea when treated prophylactically with the anti-inflammatory drug sulfasalazine (Azulfidine), a randomized trial showed. Patients receiving sulfasalazine had radiation-associated severe diarrhea almost 3 times as often as patients receiving placebo.
The trial ended prematurely when an interim analysis showed that treatment with sulfasalazine was unlikely to demonstrate a benefit, reported Robert C. Miller, MD, Professor of Radiation Oncology, Mayo Clinic, Rochester, MN, at the 2013 American Society for Radiation Oncology meeting.
“The toxicity did not meet the a priori stopping-rule requirements,” said Dr Miller. “A futility analysis showed that the trial would not be positive if all future toxicities—based on the frequency of toxicity to date in both arms—were in the placebo arm. As a result, the data safety and monitoring board halted recruitment and active-agent use.”
Available for more than 70 years, sulfasalazine has often been used empirically to prevent diarrhea in patients with cancer who are treated with pelvic irradiation. The evidence to support this use consisted of a small, phase 3, placebo-controlled trial in 2001 showing a significantly lower incidence of grade ≥2 diarrhea in patients randomized to sulfasalazine.
Despite the limited supporting evidence, sulfasalazine received a recommendation for mucositis prevention and treatment in a clinical guideline published in 2007 in Cancer.
To confirm the only published report of efficacy in 2001, Dr Miller and colleagues conducted a phase 3, randomized, placebo-controlled trial of sulfasalazine for the prevention of diarrhea in patients undergoing pelvic radiotherapy. Eligible patients were receiving a >45-Gy dose of radiation once daily, with or without chemotherapy.
Patients were randomized to sulfasalazine 1000 mg twice daily or to matching placebo during radiation therapy and continuing for 4 weeks afterward. The primary end point was the maximal grade of treatment-associated diarrhea.
Patients were assessed weekly for their maximum severity of diarrhea, rectal bleeding, abdominal cramping, tenesmus, and constipation. Patients also completed weekly bowel function questionnaires during radiation and for 6 weeks afterward, and then at 12 and 24 months postradiation.
The trial had an accrual target of 140 patients, with 73 enrolled patients who were evaluable at the interim data analysis. At that point, 4 of 38 patients in the placebo arm had grade ≥3 diarrhea (≥7 stools daily) compared with 10 of 35 in the sulfasalazine arm.
“We were very surprised to find that patients receiving sulfasalazine experienced worse diarrhea than those receiving placebo,” said Dr Miller. “For the prevention of radiotherapy-related diarrhea, we now know that sulfasalazine will not benefit patients.”
“This trial clearly illustrates the necessity for large, phase 3, randomized controlled trials to understand which drugs and therapies will relieve the more negative side effects of patients receiving radiation therapy,” he said.