Oropharyngeal Mucositis in Cancer Therapy

Oropharyngeal mucositis has been reported as the most bothersome side effect by patients undergoing myeloablative regimens, and it remains a therapy-limiting toxicity of radiation and chemotherapy for head and neck cancer. Joel Epstein and Mark Schubert provide an informative review of progress made over more than a decade of research on the pathophysiology and management of oropharyngeal mucositis in patients undergoing cancer treatment. The search for effective measures has been arduous, with successes usually limited to a small impact. Thus, palliation remains the main form of management despite a variety of agents (antimicrobials, anti-inflammatories, growth factors, antiseptics, mucosal protectants, radioprotectors, and laser therapy) studied for their potential ameliorating effects on mucositis. Reasons for Conflicting Results
Although some measures such as intensive oral hygiene have been unequivocal in their reduction of mucositis among hematologic cell transplant patients, the clinical trials of many agents have shown conflicting results. In addition to variability in mucositis by type of cancer treatment, some of the conflicting results are likely due to differences in clinical trial design and the lack of reliable objective measures of outcome. Many studies have enrolled small numbers of patients and were not controlled despite known differences in patient and treatment factors. Even in the randomized, controlled trials, it is difficult to eliminate the subjectivity of mucosal scoring by health-care professionals or misleading serial symptom assessment by patients. For instance, given that symptoms tend to increase during the course of mucositis, patients may feel that an agent is not helpful even if it inhibits symptom progression. Objective Measures of Outcome
Further development of objective measures of outcome should facilitate the recognition of agents with true benefit. Strictly objective toxicity grading systems (for example, based on laboratory values) have not been established and effectively applied to oral mucositis assessment. Even seemingly objective measures, such as the number of days patients indicate that they cannot swallow liquids, can be expected to vary with pain tolerance and the amount of analgesia used. Among efforts to decrease subjectivity are the development and validation of a multiple index scoring system (Epstein and Schubert's references 22 and 23), stratification, and visual aids. Illustrative reference pictures have been added to descriptions for mucositis toxicity grading in an effort to increase consistency among observers. Also, the analysis of results has included stratification by observer or institution. Based on the limitations of objective outcome assessments, agents that provide modest benefit may be reported as ineffective. In general, however, it is expected that if an agent or technique has a major impact, this will be recognized despite the limitations of objectivity in clinical trials. Antimicrobial Agents
Although many reports suggest at least a small benefit from the prophylactic use of various antimicrobial agents among head and neck cancer patients receiving radiation therapy, other trials have proven negative, and therefore, this practice has not become a universal standard of care. Disappointingly, even the newer antimicrobial peptide iseganan has not shown the anticipated benefit in a phase III study.[1] In addition to the need for confirmatory studies, the lack of widespread availability of a nonabsorbable lozenge containing polymixin, tobramycin(Drug information on tobramycin), and amphotericin B(Drug information on amphotericin b) has limited its use. Newer Areas of Research
Despite the lack of overwhelmingly positive results from any of multiple past strategies, there remains hope that progress with newer agents-such as the mucosal proliferation stimulant keratinocyte growth factor[2] and the tumor necrosis factor-alpha suppressant benzydamine(Drug information on benzydamine)[3]-may prove more fruitful. Further research into the mechanisms of mucositis and implementation of agents targeting these is a step forward from palliation with local anesthetics and analgesics. Because there are a large number of pathways involved in the pathogenesis of mucositis, optimal management will likely include a combination of interventions. The agent most recommended by Epstein and Schubert, benzydamine, may be more effective than other current single agents in that it combines several methods of management including anti-inflammatory, antimicrobial, and local anesthetic approaches. As in most aspects of cancer therapy, progress in the control of mucositis will likely come as small, possibly additive improvements with the emergence of newer, more targeted agents.