BOSTON—An oral rinse containing the tricyclic antidepressant doxepin significantly relieved pain in head and neck cancer patients with acute oral mucositis due to radiation therapy, according to the results of a randomized, double-blind, Phase III trial (Abstract LBA1) presented during the plenary session of the American Society for Radiation Oncology Meeting here.
Speaking at a news conference at the meeting, the study's lead author, Robert C. Miller, MD, Professor of Radiation Oncology at the Mayo Clinic, called doxepin “a new standard of care” for pain due to oral mucositis, and said that all patients with oral mucositis-related pain at the Mayo Clinic are now treated with the rinse.
The condition is caused by tissue damage and scarring due to radiation therapy, and patients with oral mucositis are typically treated with narcotics, but many still develop breakthrough pain. Lidocaine and other mouth rinses are popular even though none have been shown to be effective, he said. “And some of the rinses people think can help can actually be harmful.”
It is thought that doxepin interacts locally with nerves in the oral cavity to keep them from transmitting pain signals, he added.
Pain Scores Drop
The Phase III study was undertaken after several pilot studies suggested that oral topical doxepin as a rinse had an analgesic effect in patients with oral mucosal pain due to cancer or cancer therapy. The study he reported at the ASTRO meeting involved 155 patients who had a pain score of 4 or more on a 10-point scale in which 0 corresponds to no pain and 10 to the worst imaginable pain. On the first day, patients received a single blinded dose of doxepin rinse (25 mg in 5 mL water) or placebo; after a one-minute rinse and gargle, they spit out the solution. On the second day, patients crossed over to the opposite group.
Patients were asked to rate their pain at baseline and at 5, 15, 30, 60, 120, and 240 minutes later. The median pain score at baseline was 5.5 points, “which is the point at which it starts to interfere with eating and drinking,” he said.
During the four-hour period after the drug was administered, pain scores dropped an average of one point in the placebo group compared with two points for the doxepin group, a significant difference. After the two-day period two-thirds of patients elected to continue doxepin.
Doxepin was generally well tolerated, Miller reported. However, patients taking doxepin experienced three adverse effects significantly more frequently than patients on placebo: stinging/burning (3.7 vs. 1.1 points), “unpleasant taste” at five minutes (2.9 vs. 1.6 points), and drowsiness (3.9 vs. 2.8 points).
‘Exciting Development’ But Caveats…
The moderator of the news conference, Benjamin Movsas, MD, Chair of Radiation Oncology at Henry Ford Hospital, called the results “an exciting development, because other than pain medication, there is nothing out there for oral mucositis.”
However, he said, he would need to review the eventual published peer-reviewed paper before recommending the treatment to patients.
The Discussant for the study, Paul M. Harari, MD, Chair of Human Oncology at the University of Wisconsin School of Medicine and Public Health, said a major strength of the trial is an obvious one—that it is a randomized, Phase III trial for a toxicity issue affecting head and neck cancer patients. “These patients experience so much toxicity and there are very few studies looking at treatments for them,” he said.
“There are many, many local institutional recipes for mouth rinse and numbing rinses, so it is nice to see a controlled trial. However, the trial looks at only one single aspect of oral mucositis — pain, and I would like to have seen swallowing and other endpoints evaluated as well.”
He also questioned how clinically meaningful “a transient improvement of one point on a 10-point pain scale really is to patients who are already on narcotics. Perhaps the same could be achieved by giving them one extra pill when they have breakthrough pain, rather than introduce an entire new class of drugs with their own set of side effects.”
The fact that patients on placebo improved one point on the pain scale could be just “a wonderful testament to the placebo effect,” Harari added.
The bottom line: Before the doxepin rinse is considered for widespread use, there should be a Phase III trial comparing the rinse with an extra narcotic capsule or with a numbing rinse, rather than placebo, he said.
Hurricane Sandy Puts Unusual Spin on Plenary Session
There was nothing typical about the plenary talks at the ASTRO meeting. It wasn't just the focus on patient-reported outcomes rather than on new tests and drugs. After all, that could almost be expected: With cancer patients living longer than ever thanks in part to new ways of delivering radiation, the oncology community now wants to ensure that patients enjoy the best possible quality of life during the extra years.
And so this year's ASTRO plenaries introduced new uses for existing treatments: In addition to the studies noted here and on page 22, also see this Online First article about a study showing that the Alzheimer's drug memantine appears to slow cognitive decline in patients undergoing whole-brain radiation therapy for brain metastases (http://bit.ly/OT-Memantine).
What was unusual was that all the speakers recommended that their colleagues discuss these new treatments with their patients as soon as they returned home, pointing out that currently, there are no good options for these problems. (It should be notend, though, that discussants and other experts did urge caution.)
What made the session truly remarkable was that it never really happened—at least not in real time with a live audience. As Hurricane Sandy whipped up the East coast, bringing wind speeds upward of 65 mph to the city, the Convention Center closed early on Monday Oct. 29—in advance of the afternoon plenary session.
Not to be thwarted, the ASTRO staff whipped into action even more quickly than the blustering winds and came up with a revised plan: Videotape the plenary speakers along with discussants (at least those whose travel plans to Boston hadn't been thwarted altogether), and make the recordings as well as the slides available online, where they are posted now.
Fortunately, the plenary news briefing was in the morning, and so we reporters had already heard an abridged version of the talks. Key slides spelled out the objectives, some results, and the conclusions of each study. And we had the all-important opportunity to ask questions and interact with the speakers.
But as everyone knows, the devil—or at least the P value—is in the details. So while we would have liked to report those results and share them with our readers immediately, that would be like offering the CliffsNotes without the novel. We had to wait for ASTRO's online post so we could paint a full picture of each study and relay the discussants' critiques. At the time, we thought it would be a matter of a few hours.
But again, the once-in-a-lifetime storm outwitted us, disrupting power Monday night. In fact, the building was dark when the first ASTRO officials arrived Tuesday morning at 5:30 am. Luckily, the power came back on shortly after that, and the meeting resumed. And by Wednesday, technical problems were fixed and the plenaries were posted online.