HOLLYWOOD, FL—The ever-present danger of mucositis—especially oral mucositis—has risen to the top of the list of concerns for doctors and patients undergoing intense therapy to defeat cancer, according to speakers here at the National Comprehensive Cancer Network (NCCN)'s Annual Conference on Clinical Practice Guidelines and Quality Cancer Care.
“Mucositis is becoming an increasingly recognized problem in cancer care,” said Mark Schattner, MD, Assistant Professor at Memorial Sloan-Kettering Cancer Center. The keystones for dealing with mucositis, he said, include: (1) Educating the patient that mucositis represents a strong possibility; and (2) Treating mucositis in an additive, stepwise algorithm—that is, not substituting one therapy for another.
Task Force Report
Dr. Schattner reported preliminary findings of the NCCN's Task Force on Prevention and Management of Mucositis in Cancer Care. “This task force is now bringing mucositis to the forefront as one of the most problematic symptoms for cancer patients today,” he said.
“It is not an insignificant problem. It is associated with a lot of complications, including the need for total parenteral nutrition, an increased risk for systemic infections and increased morbidity, more visits to emergency rooms, longer lengths of stay in the hospital, increased costs, and subsequent dose reduction and its corollary, diminished response.”
“And oral mucositis is just the tip of the iceberg. Mucositis can affect the entire digestive tract.” This task force report, however, did concentrate on just oral mucositis.
The Task Force was chaired by William Bensinger, MD, Director of the Autologous Stem Cell Transplantation Program at Fred Hutchinson Cancer Research Center.
Dr. Schattner said that many patients who undergo curative cancer regimens are prepared for some of the common side effects such as alopecia and immunosuppression, but patients are less aware of oral mucositis. “We need to educate our patients and their families on the expected symptoms, the anticipated severity, and the course and duration of mucositis,” he said.
“Patients may not be aware that they won't be able to eat and drink because their mouth may be too painful,” Dr. Schattner continued. “It is important to educate patients that this is coming and may last for a very long time—several weeks or months—especially in the setting of radiation therapy for the head and neck.
Clinicians should encourage their patients to report signs of mucositis early in treatment. They should also reinforce that encouragement by telling patients that the doctor is expecting these reports and needs to be aware of them.
“When patients arrive with a mouth affected by mucositis they require either a feeding tube or parenteral nutrition,” Dr. Schattner said. “The best way to handle mucositis is to prevent it, or if you can't prevent it, then treat it, and if you can't do that at least anticipate it and have things in place to minimize the effects.”
He explained that the debilitating condition grows out of the use of radiation or chemotherapy, which produces an abundance of reactive oxygen species that directly damage cells. These species upregulate the nuclear factor-kappa B (NF-kB) pathway, a primary roadway to cell death tissue injury and future rounds of upregulation.
“This inflammatory response eventually leads to ulceration, superinfection, further inflammation, and further upregulation of NF-kB. Only when these things can be revved down do you start to get healing. Although the mucosa may look normal again, some of the damage is permanent, including the ability of the mucosa to maintain its health.”
While Grades 1 and 2 oral mucositis can cause some difficulties for patients, the major problems are Grade 3 and Grade 4 toxicity, he said, because these are the conditions that can cause treatment interruption, hospitalization, and dehydration, and may result in a need for emergency room visits.
Intensity Yields Problems
“Treatment-related risk factors almost always correlate with the intensity of the chemotherapy,” Dr. Schattner said. “These are, by definition, modifiable, but like anything else in medicine you have to weigh the risks and benefits in reducing or changing regimens.
Regimens that most frequently result in mucositis are those containing cisplatin, fluorouracil, methotrexate, and cyclosporin.
“The effects of additional cycles of chemotherapy are cumulative on the risk of oral mucositis,” he said. “Having prior mucositis during one cycle of chemotherapy does predict that you are likely to have oral mucositis in subsequent rounds of chemotherapy. Radiation risk is additive. The risk in clinical practice appears to be higher than the risk of oral mucositis in clinical trials and that may be due to an earlier recognition and treatment that occurs in the trials.”
In treating mucositis doctors should begin treatment with bland rinses and topical treatments, he noted. “These strategies should be used additively. Once you start systemic agents you shouldn't stop bland rinses and topical formulas. When you begin systemic analgesics you should escalate to an effective dose and then put patients on a standing dose. When you are treating patients for pain, you don't substitute one therapy for another, but you add it in a stepwise fashion.”
Oral Hygiene Key
A key to prevention, Dr. Schattner said, is oral hygiene. Patients undergoing treatment should brush their teeth softly twice a day and floss once a day. Bland rinses of saline and bicarbonate of soda should be employed frequently during the day.
Xerostomia should be treated by first reviewing the patients' medications and removing products such as anticholinergics and other medications known to cause dry mouth conditions. Patients should also be advised to use sialagogues such as sugarless candy or pilocarpine or cevimeline.
Dr. Schattner said some doctors recommend that patients undergoing chemotherapy should hold ice chips in their mouth at the beginning of chemotherapy administration and then continue to use the chips until several hours after drug administration.
“Local vasoconstriction is thought to reduce drug delivery to the oral mucosa,” he explained. “It may work for chemotherapy drugs with a short duration of action.”
Another prevention treatment is the use of glutamine, although trial results are mixed. Saforis, an investigational oral suspension, is designed to enhance absorption by oral mucosa, Dr. Schattner said. In a randomized, placebo-controlled trial, Grade 3/4 oral mucositis occurred only about 1.2% of the time, compared with 6.7% of patients receiving placebo.
Another prevention treatment he mentioned is palifermin (Kepivance), a keratinocyte growth factor designed to increase mucosal epithelium, radical oxygen scavengers. Use of palifermin decreases tumor necrosis factor (TNF), angiogenesis, and apoptosis, and studies have shown that it decreases the rate and duration of severe mucositis, while causing minimal side effects.
Amifostine (Ethyol), also approved for treatment of xerostomia in postoperation radiotherapy for head and neck cancer, has been shown to reduce mucositis associated with high-dose melphalan, Dr. Schattner added, although the drug is associated with significant adverse effects such as nausea and hypotension
The use of low-level laser therapy has demonstrated prevention efficacy in small studies of bone marrow transplantation patients or those with head and neck cancer, Dr. Schattner said. The treatments are well tolerated, although standards for treatment—such as the optimal wave length and energy density—still need refinement.
In managing mucositis, topicals are the first line for treatment, using bland saline rinses first. These rinses have been found to be as effective as the “magic mouth wash” concoctions that doctors, hospitals, and entrepreneurs often create from over-the-counter items—usually flavored saline solutions that ease pain and taste better than plain salt water—with the aim of relieving mucositis when it appears.
Topical lidocaine that can be used to coat the mucosal surface before it is spit out also has been successful as a therapy, Dr. Schattner said. The maximum dose of lidocaine is 25 ml/day. He said its use can diminish gag reflex; however, patients are advised to avoid eating when the mouth is numb to prevent trauma.
Antimicrobials do not treat mucositis but should be considered in patients with immunosuppression to prevent superinfection or systemic infection.
Analgesics can also be used to reduce pain associated with mucositis. Systemic analgesics should be escalated to an effective dose, and non-steroidal anti-inflammatory drugs (NSAIDs) should be added when possible.
Dr. Schattner said that special precautions are required for patients who will be receiving radiotherapy. Use of intensity-modulated radiotherapy and shielding can potentially modify risk. In addition, a pretreatment dental evaluation is mandatory so that dental problems can be corrected.
Funding for the NCCN Mucositis Task Force was supported by educational grants from Amgen and Cytogen.