Mucositis is one of the most significant adverse symptoms of cancer therapy. It is associated with a need for parenteral nutrition, increased risk of systemic infections, need for dose reductions (and, therefore, reduced treatment response), emergency room visits, prolonged hospital stays, and increased cost of care.
“Oral mucositis…is just the tip of the iceberg. Mucositis can affect the entire digestive tract and, therefore, must be taken very seriously,” said Mark Schattner, MD, of the Memorial Sloan-Kettering Cancer Center, New York, and a member of the National Comprehensive Cancer Network (NCCN) Oral Mucositis Task Force, which met with the goal of producing a management strategy for the prevention and treatment of oral mucositis based on the evaluation of available data.
“We want to be able to prevent oral mucositis and, secondly, to treat it effectively,” Dr. Schattner explained. “And if you can’t do either of these things, we want to at least anticipate it and have things in place to minimize its effects.”
In the current model of pathogenesis, mucositis occurs in five steps:
Oral mucositis can be evaluated by several metric scales that assess function (such as the ability to swallow) or clinical manifestations (such as ulcerations). In the clinical care setting, metrics should be applied frequently and uniformly, Dr. Schattner said. The World Health Organization scale and the National Cancer Institute scales are the most commonly used instruments.
Of most concern are grade 3 and grade 4 mucositis, as these grades can cause treatment interruptions, dehydration, emergency room visits, and hospitalization.
Is it possible to identify patients at risk and thus prevent oral mucositis? To some degree, Dr. Schattner asserted. The most important factors are those related to chemotherapy, transplantation, and irradiation. Although these risks can be adjusted by reducing dosages, for example, one runs the risk of diminishing efficacy.
Risk related to chemotherapy mainly correlates with the intensity of treatment, although cisplatin, 5-fluorouracil (5-FU), methotrexate, and cyclosporine are especially mucotoxic. Additional cycles of myelosuppressive therapy exert a cumulative risk, and prior mucositis during treatment increases the risk with subsequent therapy. Radiation therapy provides an additional risk when given concurrently with chemotherapy. Risk in clinical practice seems higher than in published trials, Dr. Schattner noted, likely due to earlier recognition and intervention in clinical trials.
With stem cell transplantation, risk is conveyed by the conditioning regimen and by the use of methotrexate for acute graft-versus-host disease prophylaxis. The risk peaks 6–12 days after transplant, and the duration of mucositis varies from 7 to 14 days. Data comparing allogeneic and autologous transplant are inconsistent.
“When we have a patient who may be especially susceptible to mucositis—for instance, the patient [who] had a prior episode or has poor dentition—adjusting the conditioning regimen should be considered to minimize the chance of mucositis,” Dr. Schattner emphasized.
Radiation therapy is “a big offender” for oral mucositis, he said. The incidence, based on a literature review of patients with head and neck cancer, is 34% with conventional radiotherapy, 57% with accelerated radiotherapy, and 43% with chemoradiation (Trotti A et al. Radiother Oncol 2003;66:253–262).
“I would argue that in clinical practice, these numbers might be even higher, depending on the tumor being treated,” he added. “For example, if you have a tumor at the base of the tongue, concurrent cisplatin-based chemotherapy with radiation gives you nearly a 100% chance of oral mucositis.”
Risk factors for radiation treatments are related to the target, total dose, fraction size, volume irradiated, treatment time, and fractionation regimen. Risk peaks around week 5 or 6, and its duration is approximately 8–12 weeks, much longer than for transplantation. “Patients should be warned and educated about this,” he said.
“While you might not be able to alter these [risk factors] much without affecting the patient’s response to treatment, you can at least anticipate that a patient may develop severe mucositis and take early intervention, such as placing a gastrostomy tube,” he said.
Most patient-related factors have not been firmly correlated with risk, though it is suggested that risk is higher for females and lower for African-Americans, especially with 5-FU–based regimens. This information might suggest to the clinician that dose could be increased in African-Americans.
Risk factors that are somewhat modifiable include a body mass index that is extremely low or high; medication-related poor salivary gland function; and, most importantly, poor dentition, ill-fitting prosthetic appliances or dentures, and fractured or sharp teeth.
“Poor dentition is by far the most significant modifiable risk factor,” he maintained. Especially before radiotherapy or before intensive chemotherapy, it is a good idea to have the patient seen by a dentist, who can remove sharp prostheses and design shielding to prevent back-scatter radiation that occurs when fillings or metal prostheses reflect the radiation beam. A dental examination is of paramount importance.”
For prevention, good daily oral hygiene is recommended, along with frequent bland rinses (saline and bicarbonate). Underlying xerostomia should be treated; anticholinergics should be eliminated if possible, and patients should try using sialagogues (sugarless candy pilocarpine, cevimeline) to promote salivary flow.
Oral cryotherapy often helps, according to results from several clinical trials (Lilleby K et al. Bone Marrow Transplant 2006;37:1031–1035; Aisa Y et al. Support Care Cancer 2005;13:266–269; Tartarone A et al. Leuk Lymphoma 2005;46:633–634). The patient holds ice chips in his or her mouth before the infusion of chemotherapy and up to several hours afterward to induce local vasoconstriction, which, at least theoretically, may reduce the delivery of drug to the oral mucosa. This is most effective for drugs that have a short duration of action, such as 5-FU and melphalan (Alkeran).
Results with systemic glutamine for preventing mucositis have been mixed, according to Dr. Schattner. However, a new proprietary formulation of glutamine designed to enhance absorption by the oral mucosa has recently undergone a promising randomized, placebo-controlled trial in 326 breast cancer patients with prior mucositis (Peterson DE et al. Cancer 2007;109:322–331). Patients treated with glutamine had less grade 3 or 4 oral mucositis (1.2%) compared with those given placebo (6.7%; P = 0.005). Full US Food and Drug Administration (FDA) approval of this formulation is expected.
Palifermin (Kepivance), a keratinocyte growth factor, is “the sexy drug on the market,” Dr. Schattner commented. It increases mucosal epithelium and reactive oxygen species scavengers and prevents augmentation of NF-kB. “The strongest data are in patients undergoing autologous stem cell transplant whose conditioning regimen included total body irradiation, but the data are growing beyond this area,” he observed. In patients with hematologic cancers and treated with intensive chemotherapy, palifermin has been shown to reduce both the rate and duration of severe mucositis (Spielberger R et al. N Engl J Med 2004;351:2590–2598). It is also well tolerated, with few side effects. “This drug is one to keep an eye out for,” Dr. Schattner added.
Amifostine (Ethyol), a free-radical scavenger that is given subcutaneously, is another effective agent for mucositis that is currently FDA-approved for the treatment of xerostomia (a risk factor) in patients undergoing postoperative radiotherapy for head and neck cancer. Amifostine has also been shown to reduce the incidence of mucositis itself caused by high-dose melphalan (Spencer A et al. Bone Marrow Transplant 2005;35:971–977). “But it is not an easy drug to tolerate,” Dr. Schattner commented. “It is associated with significant nausea and hypotension.”
Low-level laser treatment is one of the newest approaches to preventing mucositis. Administered prior to treatment, it has proven effective in small studies of autologous transplant patients (Antunes HS et al. Blood 2007;109:2250–2255) and head-and-neck cancer patients (Arun M et al. Indian J Med Res 2006;124:399–402). Few patients receiving autologous transplants who were treated with low-level laser irradiation had grade 3 or 4 mucositis; severity of mucositis was shifted downward to grades 1 and 2, which were more manageable (Antunes HS et al. Blood 2007;109:2250–2255).
“I have not used [laser therapy] myself, but according to the dentists and oral surgeons who have, it is fairly easy and safe to do if you have the proper equipment,” Dr. Schattner said. “This is another approach to keep an eye out for, and I think it holds a lot of promise.”
Among other novel therapies, the investigational agent RK-0202, an N-acetylcysteine oral rinse, shows potential in head-and-neck cancer patients, although the data are preliminary. The field of mucositis prevention is also moving ahead with pharmacogenetic studies, which may identify susceptible patients. It is already known that MTHFR polymorphisms can affect methotrexate metabolism and increase the mucotoxicity of the drug.
Management of oral mucositis consists primarily of topical agents—bland, non–alcohol-based saline rinses or “magic mouthwashes” provided by the hospital pharmacy. If these approaches are insufficient, local analgesics and anesthetics, such as topical lidocaine, can be prescribed for pain. Patients should be instructed to rinse first, apply the lidocaine solution (up to 25 mL/d) to coat the mucosal surface, and then spit it out. Since the gag reflex may be diminished, to prevent mucosal trauma, patients should avoid eating when their mouth is numb. Systemic analgesics, accompanied by constipation prophylaxis, can be prescribed by escalating to an effective, standing dose (taken regularly), with rescue dosing as needed. The key is to apply strategies additively in a stepwise fashion, “so once you start systemic agents, you shouldn’t stop using bland rinses and topicals,” Dr. Schattner pointed out.
Patients who develop acute pain should be evaluated for superinfection (herpesvirus or fungal infection). Antimicrobials do not treat mucositis but should be considered in immunosuppressed patients to prevent superinfection or systemic infection.
Patient education is another cornerstone of management. “Patients go into cancer treatment knowing about nausea, vomiting, and alopecia, but they are often unaware of what may be their most bothersome symptom, oral mucositis,” Dr. Schattner observed. “Clinicians should educate patients and staff that mucositis is an important problem, that it can be prolonged, and [that] they should alert you when it occurs so that interventions can be taken.”