The number of cancer patients affected by oral mucositis each year is close to one million and there is a large amount of interest in developing new treatment options for this painful side-effect
Stephen T Sonis
Boston, MA, USA
Oral mucositis is a common side-effect of drug and radiation therapy used for the treatment of cancer. In its most dramatic form, it produces large-spread, deep and extremely painful ulcers of the movable mucosa of the mouth and oropharynx. It does not affect the gingiva, dorsal tongue, or hard palate. Patients receiving radiation to treat cancers of the head and neck, with or without concomitant chemotherapy, and patients infused with high doses of chemotherapy in preparation for haematopoietic stem cell transplants are especially at risk for severe forms of the condition. In contrast, patients receiving standard forms of cycled chemotherapy for solid tumors (colorectal or breast cancers) are at lesser risk. However, patients who develop ulcerative mucositis during their first cycle of treatment are much more likely to develop the condition in subsequent cycles. In general, the overall risk of mucositis in cancer patients being treated for the first time is about 40%.
Mucositis develops in a predictable sequence. The time course is dependent on the type of cancer treatment the patient is receiving. Patients receiving radiation for head and neck cancers typically develop early mucosal changes at cumulative doses of radiation of 10Gy to 20Gy (radiation is given in daily 2Gy fractions, 5 days per week for about 7 weeks). The early changes of mucositis consist of mucosal erythema and superficial sloughing, but the underlying mucosa is intact. Symptomatically, patients complain of burning discomfort similar to that caused by a bad food burn. By 30Gy the integrity of the mucosa is disrupted and ulceration develops. Ulcers may be singular at first and then coalesce. They are often covered by a necrotic and bacteria- laden pseudomembrane and are very painful. The discomfort associated with these lesions is so severe as to require systemic analgesics, usually an opiod. Unfortunately, it is not uncommon for patients to have break-through pain. Eating, even liquids, becomes impossible and patients must rely on gastrostomytube feedings for nutrition. Dehydration is common, often necessitating emergency room visits and hospital admission. Ulceration lasts through the remainder of radiation and for 2 to 4 weeks after it is completed at which time lesions usually heal spontaneously.
Chemotherapy-induced mucositis follows a more acute course. Mucosal breakdown usually begins 4-5 days after chemotherapy infusion, peaks from 7 to 12 days, and then spontaneously resolves. The mucositis curve is about the reciprocal of that of myelosuppression. Consequently, peak mucositis often corresponds to white blood cell nadir. Local infection, bacteremia, and sepsis are therefore a major concern in this population.
Much has been elucidated in the past decade about the pathobiology of mucositis. Once thought of as being the sole consequence of clonogenic cell death of rapidly dividing stem cells with resulting atrophy and ulceration, it is now clear that multiple biological pathways, activated by radiation and chemotherapy have a major responsibility for mucosal injury. This finding is particularly important relative to developing treatment interventions that are mechanistically-based.
Treatment options for mucositis
Despite the fact that mucositis has long been known to be a complication of cancer therapy the treatment options are limited. Evidence-based approaches to the management of oral mucositis have been developed by a number of organisations (MASCC, ESMO, ASCO,NCCN) and, in general, are similar.
There is overwhelming consensus that basic oral care is an essential component in reducing the risk and minimising the course of oral mucositis. This consists of regular assessment of the patient’s oral health and good oral hygiene measures.
Palliation of early, mild mucositis can be achieved with topical analgesics such as viscous lidocaine or benadryl used in combination with a Maalox or Kaopectate vehicle. These agents are used as rinses andare frequent components of ‘magic mouthwashes’. The latter tend to be home grown concoctions containing a variety of agents which vary by sight and may include antifungal and antibiotic agents. Efficacy studies have concluded that such rinses are equivalent to saline in their effectiveness.
Cryotherapy, in the form of ice chips, may be of value when used at the time of chemotherapy infusion for certain agents such as bolus 5-FU, melphalan and edatrexate.
A number of devices, such as GelClair, Mugard, and Caphosol have been introduced and heavily marketed as mucositis interventions. None are recommended for use in conventional guidelines as they lack substantive evidence of their value.
GelClair is provided to patients in unit dose packets containing a dry powder which patients reconstitute in water. The patient can adjust the viscosity of the product by adding water. Patients are instructed to rinse, gargle and expectorate. GelClair’s palliative efficacy is presumably based on its ability to form a barrier between ulcerated mucosa and the rest of the oral environment. GelClair did not prove to be superior to standard of care in a randomised, preliminary trial.
MuGard is a newly approved mucoadhesive rise which provides a protective hydrogel to the oral mucosa. A device, it was originally developed as a vehicle for the delivery of an active agent to treat aphthous stomatitis. Its use as a mucositis intervention was serendipitously discovered when investigators noted that patients in a clinical trial reported less discomfort with their mucositis than would have been expected. When the study was unblinded, the vehicle outperformed the active and when compared to historical controls suggested that it was of benefit in controlling symptoms associated with mucositis (Access Pharmaceuticals. MuGard Fact Sheet). Additional prospective, randomised, blinded controls are necessary to confirm its value as a mucositis treatment.
Caphosol is a calcium phosphate solution artificial saliva that was originally developed as a re-mineralising rinse to protect teeth in patients with xerostomia. Its rationale for use as a mucositis treatment is apparently based on the hypothesis that it augments or replaces salivary function. The influence of saliva in modifying mucositis risk and course has not been proved and studies evaluating pilocarpine’s efficacy in mucositis showed no benefit. A single institution study in which Caphosol used in conjunction with topical fluoride demonstrated a benefit vs fluoride alone in patients receiving conditioning regimens in preparation of HSCT. The only other data supporting its use are provided by open-labeled, uncontrolled trials, and the lack of a dose response (the recommended dosing schedule is 4 to 10 times per day) suggests that proper, controlled, studies are needed to verify its efficacy and optimise its application.
Palifermin (Kepivance) is the only pharmaceutical/ biological approved for use for the prevention and treatment of mucositis. Its use is limited to patients receiving stomatotoxic conditioning regimens in preparation for HSCT for the treatment of hematological malignancies. Palifermin (keratinocyte growth factor) is administered intravenously for 3 days before the start of the conditioning regimen and again for 3 days beginning on the day of transplant.6 Palifermin effectively reduces the duration and intensity of mucositis and favorably impacts pain and health and economic outcomes associated with mucositis. Its current scope limits its application to only 4% of the ‘at risk’ population. Despite its high cost, palifermin’s ability to limit unfavorable outcomes has suggested that it is a cost-effective approach in the HSCT population. Importantly, it provided proof of concept that a mechanistically-based approach could be effective in attenuating regimenrelated mucosal injury.
Benzydamine is a non-steroidal anti-inflammatory rinse that may be used for alleviation of mucositis in patients receiving radiation therapy (without concomitant chemotherapy) for the treatment of head and neck cancers. The compound has been available for some time. Studies evaluating its efficacy have had mixed results, especially among patients receiving concomitant chemoradiation. The following agents have been specifically not recommended for use in the prevention or treatment of oral mucositis: chlorhexidine gluconate (for head and neck radiation and established mucositis in patients receiving chemotherapy), antimicrobial lozenges, sucralfate, acyclovir or its analogues, pentoxifylline (in HSCT), and GM-CSF(in HSCT).
Mucositis represents a significant unmet need for cancer patients. The number of patients affected by the condition is close to one million per year. Consequently, there is a large amount of interest in developing new treatment options and a number of investigational agents are actively being pursued.
1. Sonis ST, et al. Cancer 2004;100:1995-2025.
2. Barber C, et al. Support Care Cancer 2007;15:427-40.
3. Papas A. Community Oncol 2008;5:172-3.
4. Lockhart PB, et al. Bone Marrow Transplant 2005;35:713-20.
5. Papas AS, et al. Bone Marrow Transplant 2003;31:705-12.
6. Spielberger R, et al. N Engl J Med 2004;351:2590-8.
7. Keefe DM, et al. Expert Opin Emerg Drugs 2008;13:511-22.