Doxepin Rinse Significantly Reduces Mouth Pain for Head and Neck Cancer Patients Who Receive Radiation Therapy

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| Source: American Society for Radiation Oncology

BOSTON, Oct. 29, 2012 (GLOBE NEWSWIRE) -- When used as a rinse, doxepin, a tricyclic antidepressant, reduces oral mucositis (OM) in patients who receive radiation therapy (RT) for head and neck cancer, according to research presented today at the American Society for Radiation Oncology's (ASTRO's) 54th Annual Meeting.

The multi-institution, randomized, double-blind, placebo-controlled, phase III trial, with a cross-over phase, assessed the efficacy of doxepin oral rinse versus placebo for the treatment of OM associated with RT. The study included 140 patients between December 2010 and May 2012 who received RT for their head and neck cancer (> 50.0 Gy) and which involved more than one-third of the oral cavity. Throughout the study, patients completed a numerical, analog pain questionnaire to rate their OM pain on a scale of one to 10. The patients included in this study all reported OM pain scores above four prior to the study protocol to receive doxepin or placebo.

On the first day of the protocol, patients received a single, blinded dose of doxepin rinse or placebo and then crossed over to the opposite study group on a subsequent day. Results indicate that the addition of doxepin significantly decreased pain, which was measured by the area under the curve (AUC) on the pain scale over time. Patients who received doxepin reported a reduction in pain to a -9.1 vs. -4.7 for those who received the placebo. Analysis of the crossover data revealed similar findings, with an AUC score of -7.9 in the doxepin group vs. -5.6 in the placebo group. Doxepin was well tolerated, but patients reported increased stinging/burning with doxepin compared to the placebo (mean pain score of 3.7 for doxepin vs. 1.1 for placebo), unpleasant taste (mean unpleasant taste at five minutes of 2.9 for doxepin vs. 1.6 for placebo) and greater drowsiness (mean drowsiness score of 3.9 for doxepin vs. 2.8 for placebo). Sixty-four percent of patients elected to continue doxepin after the study was completed.

The study was conducted through the Alliance for Clinical Trials in Oncology (NCCTG/CALGB/ACOSOG), and patients received doxepin as an oral rinse and spit at a dosage of 25 mg in 5 ml water. The pain questionnaire was administered at baseline and at five, 15, 30, 60, 120 and 240 minutes after receiving the rinse, and patients were given the option to continue doxepin after completing the study. The study evaluated total OM pain reduction as measured by the AUC beginning on the first day of treatment. The baseline-adjusted AUC between the two treatment groups was compared using the Wilcoxon rank-sum test. Baseline factors were evenly distributed across arms.
"Doxepin rinse has previously been proven to be a well-tolerated treatment for mouth pain due to radiation and chemotherapy treatment," said Robert C. Miller, MD, lead author of the study and a radiation oncologist at the Mayo Clinic in Rochester, Minn. "Radiation for head and neck cancer often causes painful mouth sores and oral mucositis. Our study validates doxepin rinse as an effective way to alleviate oral pain and sets a new standard of care."

The abstract, "N09C6 (Alliance) - A Phase III, Randomized Double-Blind Study of Doxepin Rinse versus Placebo in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Head and Neck Radiotherapy with or without Chemotherapy," will be presented in detail during the plenary session at ASTRO's 54th Annual Meeting at 2:30 p.m. Eastern time on Monday, October 29, 2012. To speak with Dr. Miller, call Michelle Kirkwood on October 28 – 31, 2012, in the ASTRO Press Office at the Boston Convention and Exhibition Center at 617-954-3461 or 617-954-3462, or email michellek@astro.org.

ASTRO's 54th Annual Meeting, held in Boston, October 28 – 31, 2012, 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 2012 Annual Meeting is "Advancing Patient Care through Innovation" and examines how innovation in technology and patient care delivery can lead to improved patient outcomes. The four-day scientific meeting includes six plenary papers and 410 oral presentations in 63 oral scientific sessions, and 1,724 posters and 130 digital posters in 18 tracks/topic areas.

ABOUT ASTRO

ASTRO is the largest radiation oncology society in the world, with more than 10,000 members who specialize in treating patients with radiation therapies. As the leading organization in radiation oncology, biology and physics, the Society is dedicated to improving patient care through education, clinical practice, advancement of science and advocacy. For more information on radiation therapy, visit www.rtanswers.org. To learn more about ASTRO, visit www.astro.org.

2012 American Society for Radiation Oncology (ASTRO) 54th Annual Meeting
News Briefing, Monday, October 29, 2012, 11:00 a.m. – 11:45 a.m. Eastern time
Scientific Session: Monday, October 29, 2012, 2:30 p.m. – 3:45 p.m. ET, Boston Convention & Exhibition Center

LBA2 N09C6 (Alliance) - A Phase III, Randomized Double-Blind Study of Doxepin Rinse versus Placebo in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Head and Neck Radiotherapy with or without Chemotherapy

R. C. Miller1, J. Leenstra2, R. Qun1, J. A. Martenson1, K. J. Dornfeld3, J. D. Bearden4, D. Puri5, P. J. Stella6, R. L. Foote1, C. L. Loprinzi1, 1Mayo Clinic, Rochester, MN, 2Saint Vincent Hospital, Green Bay, WI, 3Essentia Health Duluth Clinic CCOP, Duluth, MN, 4Spartanburg Regional Medical Center, Spartanburg, SC, 5Iowa Oncology Research Association, Des Moines, IA, 6St. Joseph Mercy Health System, Ann Arbor, MI

Purpose/Objective(s): Oral mucositis (OM) remains a significant toxicity in patients receiving radiotherapy (RT) for malignancies of the head and neck (H &N). Previous pilot research (J Pain Symptom Manage, 2007. 33(2): 111-4.) has suggested that doxepin, a tricyclic antidepressant, reduces RT induced OM when used as a mouth rinse.

Materials/Methods: A multi-institution, randomized, double-blind, placebo-controlled, phase III trial with a cross-over phase and subsequent optional continued active agent usage, was designed to assess the efficacy of doxepin oral rinse and spit (25 mg in 5 ml water) versus placebo for the treatment of RT related OM and conducted through the Alliance for Clinical Trials in Oncology (NCCTG/CALGB/ACOSOG). Patients undergoing definitive H &N RT (> 50.0 Gy) including > 1/3 of the oral cavity, with OM pain rated > 4 using a patient reported numerical analog pain questionnaire (scale 0 to 10) were eligible. Patients received a single blinded dose of doxepin or placebo on day 1 and then crossed over to the opposite study arm on a subsequent day. To assess OM related pain after doxepin/placebo rinse, a pain questionnaire was administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes. After completing the study, patients were given the option to continue doxepin. The study's primary endpoint was total OM pain reduction as measured by the area under the curve (AUC) of the pain scale over time using data from day 1. The baseline-adjusted AUC between two treatment arms was compared using the Wilcoxon rank-sum test. 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: 155 patients (140 eligible for the primary endpoint) were enrolled in the study between 12/17/2010 and 5/17/2012. Baseline factors were evenly distributed across arms. Analysis of the primary endpoint revealed that the pain reduction AUC was greater for doxepin (-9.1) vs. placebo (-4.7), p=0.0003. Analysis of the crossover data revealed similar findings: doxepin (-7.9) vs. placebo (-5.6), p=0.009. Doxepin was well tolerated, but had more rinse stinging/burning and unpleasant taste and caused greater drowsiness, compared to the placebo. 64% of patients elected to continue doxepin (p=0.002) in the optional continuation phase.

Conclusion: OM pain was significantly less following doxepin rinse than placebo. The majority of patients elected to continue doxepin during RT for OM pain, after the double-blind, cross-over portion of the study. This study sets a new standard of care for the treatment of oral pain due to radiation-related OM.

Disclosure Block:

R.C. Miller: None. J. Leenstra: None. R. Qun: None. J.A. Martenson: None. K.J. Dornfeld: None. J.D. Bearden: None. D. Puri: None. P.J. Stella: None. R.L. Foote: D. Employment Other; Editor, Int J Rad Onc Biol Phys. C.L. Loprinzi: None.

Michelle Kirkwood
703-286-1600