This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Oral mucositis refers to inflammatory, erythematous, erosive or ulcerative lesions of the oral mucosa seen in 60-90% of patients undergoing radiation therapy for head and neck cancer to fields involving the oral cavity. These lesions are painful, compromise nutrition and become secondarily infected. Hospitalization is required for pain control and nutritional support in approximately 15% of cases. Further, severe oral mucositis can necessitate interruptions in radiation therapy thus compromising cancer therapy. No agent is currently available to prevent oral mucositis or reduce its severity.Available evidence implicates inflammatory responses to radiation therapy and to products of colonizing microorganisms in the pathogenesis of oral mucositis. The use of anti-inflammatory agents in oral mucositis has not been well-studied. However, the limited available data using non-steroidal anti-inflammatory drugs (NSAIDS) indicates that this is a promising approach. The use of celecoxib, a selective Cyclooxygenase-2 (COX-2) inhibitor, in radiation-induced oral mucositis has not been previously studied. Celecoxib offers several potential advantages in this setting as compared to conventional NSAIDS.This pilot study is intended to generate preliminary data in preparation for submission to extramural funding sources. This randomized, double-blind, placebo-controlled pilot study will evaluate celecoxib in ten subjects at high risk for developing radiation-induced oral mucositis. Subjects will be randomized to 200 mg bid celecoxib or placebo (both by mouth) in a 1:1 ratio. They will be asked to use the study medication daily starting 5 days before the first day of radiation therapy until 3 days after the end of radiation therapy. The primary endpoint will be the investigator's evaluation of severity of oral mucositis using the Oral Mucositis Assessment Scale (OMAS). OMAS scores will be compared between the two groups to assess the impact of celecoxib on mucosal injury. The secondary endpoint will be evaluation of pain severity using the severity subscale of the Brief Pain Inventory. Additional assessments will include evaluation of 1. medications used for pain management 2. normalcy of diet 3. type, dose, duration and fields of radiation therapy and 4. mucosal injury using the World Health Organization (WHO) and Common Toxicity Criteria (CTC) mucositis scales. Further, 2 mm punch biopsies of the oral mucosa will be obtained from consenting subjects in both groups at four time-points. Levels of selected enzymes, prostanoids and receptors involved in the cyclooxygenase pathway will be measured. In addition, a 10 ml blood sample will be obtained from subjects in both groups at four time-points. These blood samples will be used to measure levels of selected prostanoids generated via the cyclooxygenase pathway and of selected cytokines that induce COX-2 expression. Comparison between the two groups will allow assessment of the role of the cyclooxygenase pathway in radiation mucositis and the impact of celecoxib. Correlations will be examined between levels of prostaglandins whose synthesis is mediated by COX-2 and mucosal injury and pain in radiation-induced oral mucositis. This line of research could lead to the development of an agent to prevent or reduce the severity of oral mucositis. This would substantially decrease morbidity in these patients. In addition, it may also improve patient prognosis by avoiding breaks in cancer therapy.
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