Sulfasalazine does not reduce diarrhea for patients receiving pelvic radiation therapy

Atlanta, September 22, 2013—Patients receiving radiotherapy (RT) for cancers in the pelvic region can experience diarrhea, a negative side effect of radiation treatment. Sulfasalazine, an oral tablet used to treat inflammation of the bowels, had been shown in a past trial of 31 patients to decrease diarrhea during pelvic RT (Killic 2001). Sulfasalazine does not reduce diarrhea, according to research presented today at the American Society of Radiation Oncology’s (ASTRO’s) 55thAnnual Meeting. The study also determined that the medication may be associated with a higher risk of diarrhea than placebo.

The multi-institutional, randomized, double-blind, placebo-controlled phase III trial was conducted through the Alliance for Clinical Trials in Oncology (NCCTG/CALGB/ACOSOG) to evaluate the effectiveness of sulfasalazine versus placebo in the treatment of enteritis (inflammation of the intestinal tract) during pelvic RT (> 45 Gy). A total of 87 patients, with 78 patients evaluable for the primary endpoint and with evenly distributed baseline factors, were enrolled in the study at 24 institutions in the U.S. from 2011 until 2013. The patients received 1,000 mg sulfasalazine or placebo orally, twice each day during RT and for four weeks after RT. The primary endpoint was maximal severity of diarrhea, based on the Common Terminology Criteria for Adverse Events (CTCAE 4.0), during and up to six weeks after RT. A health care provider graded on a weekly basis the maximum severity and the duration of maximum severity of diarrhea, rectal bleeding, abdominal cramping, tenesmus (a sensation of incomplete defecation) and constipation. Patients completed bowel function questionnaires weekly during RT treatment, afterwards for six weeks and at 12 and 24 months post-RT. A two-sided, Wilcoxon rank-sum test was used to test the equality of the distributions of maximum diarrhea severity grades.

An interim analysis of the study revealed a statistically significant excess of grade ≥ 3 diarrhea (passing seven or more stools per day) in patients receiving sulfasalazine versus placebo (29 percent versus 11 percent, p=0.037). The study was halted in May 2013 when it was determined that it was unlikely for the sulfasalazine to indicate beneficial results.

“Although 2001 research had suggested a benefit for sulfasalazine, we were very surprised to find that patients receiving sulfasalazine experienced worse diarrhea than those receiving placebo,” said Robert C. Miller, MD, MS, lead author of the study, a professor of radiation oncology at the Mayo Medical School and vice chairman of research in the department of radiation oncology at the Mayo Clinic in Rochester, Minn. “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 III, randomized controlled trials to understand which drugs and therapies will relieve the more negative side effects for patients receiving radiation therapy.” 

The abstract, “A Phase III Randomized Study of Sulfasalazine versus Placebo in the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy,” will be presented in detail at a scientific session at ASTRO’s Annual Meeting at 1:45 p.m. Eastern time on Sunday, September 22, 2013. To speak with Dr. Miller, call Michelle Kirkwood on September 22 – 25, 2013, in the ASTRO Press Office at the Georgia World Congress Center in Atlanta at 404-222-5303 or 404-222-5304, or email michellek@astro.org.

ASTRO’s 55thAnnual Meeting, held in Atlanta, September 22-25, 2013, is the premier scientific meeting in radiation oncology and brings together more than 11,000 attendees including oncologists from all disciplines, medical physicists, dosimetrists, radiation therapists, radiation oncology nurses and nurse practitioners, biologists, physician assistants, practice administrators, industry representatives and other health care professionals from around the world. The theme of the 2013 meeting is “Patients: Hope • Guide • Heal” and focuses on patient-centered care and the importance of the physician’s role in improving patient-reported outcomes and the quality and safety of patient care. The four-day scientific meeting includes presentation of four plenary papers, 363 oral presentations, 1,460 posters and 144 digital posters in 70 educational sessions and scientific panels for 19 disease sites/tracks. Keynote and featured speakers include: William B. Munier, director of the Center for Quality Improvement and Patient Safety at the Agency for Healthcare Research and Quality; Darrell G. Kirch, MD, president and CEO of the Association of American Medical Colleges; James Cosgrove, PhD, director of the U.S. Government Accountability Office; Otis W. Brawley, MD, chief medical officer of the American Cancer Society; and Peter Friedl, MD, PhD, of St. Radboud University Nijmegen Medical Centre at the University of Nijmegen and MD Anderson Cancer Center.

ABOUT ASTRO

ASTRO is the premier radiation oncology society in the world, with more than 10,000 members who are physicians, nurses, biologists, physicists, radiation therapists, dosimetrists and other health care professionals that specialize in treating patients with radiation therapies. As the leading organization in radiation oncology, the Society is dedicated to improving patient care through professional education and training, support for clinical practice and health policy standards, advancement of science and research, and advocacy. ASTRO publishes two medical journals, International Journal of Radiation Oncology • Biology • Physics (www.redjournal.org) and Practical Radiation Oncology (www.practicalradonc.org); developed and maintains an extensive patient website, www.rtanswers.org; and created the Radiation Oncology Institute (www.roinstitute.org), a non-profit foundation to support research and education efforts around the world that enhance and confirm the critical role of radiation therapy in improving cancer treatment. To learn more about ASTRO, visit www.astro.org.

###

Embargoed until September 22, 2013, 1:45 p.m. ET

2013 American Society for Radiation Oncology (ASTRO) 55th Annual Meeting

News Briefing, Tuesday, September 24, 2013, 8:15 a.m. Eastern time

Scientific Session: Sunday, September 22, 2013, 1:45 - 3:15 p.m. ET, Georgia World Congress Center

LBA2  N08C9 (Alliance) - A Phase III Randomized Study of Sulfasalazine versus Placebo in the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy

R. C. Miller1, D. G. Petereit*2, J. A. Sloan*3, H. Liu*3, J. A. Martenson*1, J. D. Bearden*4, R. Sapiente*5, G. R. Seeger*6, M. J. Iott*1, C. L. Loprinzi*1. , 1Mayo Clinic, Rochester, MN, 2Rapid City Regional Oncology Group, Rapid City, SD, 3Alliance Statistics and Data Center, Rochester, MN, 4Upstate Carolina CCOP, Spartanburg, SC, 5Carle Cancer Center CCOP, Urbana, IL, 6Altru Health Systems, Grand Forks, ND

Purpose/Objective(s): Sulfasalazine has been reported in a previous Phase III trial to decrease enteritis during pelvic radiotherapy (RT) (Kiliç 2001) and has been recommended in evidence based guidelines as a prophylactic agent to reduce RT enteritis (Keefe 2007). This study was undertaken to provide confirmatory evidence in regard to the value of sulfasalazine during pelvic RT.

Materials/Methods: A multi-institution, randomized, double-blind, placebo-controlled, phase III trial was designed to assess the efficacy of sulfasalazine versus placebo in the treatment of RT-related enteritis during pelvic RT (>45 Gy) and conducted through the Alliance for Clinical Trials in Oncology (NCCTG/CALGB/ACOSOG). Patients received 1000 mg sulfasalazine or placebo p.o. b.i.d. during and 4 weeks after RT. The primary endpoint was maximal severity of diarrhea (CTCAE version 4.0) during and up to 6 weeks after RT. The maximum severity and the duration of maximum severity of diarrhea, rectal bleeding, abdominal cramping, tenesmus, and constipation were graded weekly during RT by a health care provider. Bowel function was assessed using a self-administered bowel function questionnaire weekly during RT, for six weeks afterwards, and at 12 and 24 months. A two-sided 0.05-level Wilcoxon rank-sum test was used to test the equality of the distributions of maximum diarrhea severity grades. At the 5% significance level, there was an 80% power to detect a clinically meaningful standardized effect size of 0.5 with 128 patients (64 patients for each arm) based on the two-sample t-test with equal-variance assumption.

Results: 87 patients (78 evaluable for the primary endpoint) were enrolled at 24 participating institutions between 4/29/2011 and 5/13/2013, with evenly distributed baseline factors. An interim analysis revealed a statistically significant excess of grade >3 diarrhea in patients receiving sulfasalazine vs. placebo (29% vs. 11%, p=0.037). Although not sufficient to suspend the study due to existing stopping rules, a futility analysis revealed that continuation of the trial would be highly unlikely to yield a positive result and the Alliance Data and Safety Monitoring Board halted study treatment on 5/13/2013.

Conclusions: Sulfasalazine does not appear to reduce the risk of enteritis during pelvic RT and may be associated with a higher risk of adverse events than placebo. Its inclusion in clinical guidelines for RT-enteritis prophylaxis should be reconsidered.

Author Disclosure Block: R.C. Miller: L. Stock Options; Tekcapital Limited. D.G. Petereit: None. J.A. Sloan: None. H. Liu: None. J.A. Martenson: None. J.D. Bearden: None. R. Sapiente: None. G.R. Seeger: None. M.J. Iott: None. C.L. Loprinzi: None.

Michelle Kirkwood
703-286-1600
michellek@astro.org

Nancy Mayes
Mayes Communications
703-772-2510
nancy@mayescommunications.com

Press Room in Atlanta
September 22-25
404-222-5303
404-222-5304