Assessment of dose-response relationship of 5-fluorouracil to murine intestinal injury.

5-Fluorouracil (5-FU) is the most frequently prescribed anti-tumor drug, but has been reported to result in intestinal injury. Although some progress has been made in understanding the intestinal toxicity of 5-FU, confusion remains about animal models of 5-FU-induced intestinal injury, especially the dosage of 5-FU. This study aims to assess the dose-response relationship between the severity of intestinal injury and different doses of 5-FU, and to determine a proper dosing for the murine model. We found that mice in the 5-FU groups gradually lost body weight over time. Increasing doses of 5-FU resulted in more severe diarrhea, with a concomitant increase in mortality. Histopathological damage was more severe in mice that received higher doses of 5-FU. In addition, plasma diamine oxidase (DAO) activity decreased in experimental mice with intestinal injury in a dose-dependent way. TUNEL and western blot analysis showed cell apoptosis in the ileum and colon related to 5-FU dosage. However, administration of 200 and 400 mg/kg 5-FU caused extremely high mortality, severe diarrhea and histopathological damage, but 25 mg/kg 5-FU did not result in significant intestinal injury. The severity of intestinal injury induced by 5-FU appeared to be dose-dependent and we concluded that the proper dosage of 5-FU to induce a murine model with intestinal mucositis ranged from 50 mg/kg to 100 mg/kg.

Association of human papillomavirus and p16 status with mucositis and dysphagia for head and neck cancer patients treated with radiotherapy with or without cetuximab: Assessment from a phase 3 registration trial.

BACKGROUND: Mucositis and dysphagia are common adverse effects of radiotherapy (RT) treatment of locally advanced squamous cell cancer of the head and neck (LA-SCCHN). Chemotherapy added to RT increases survival rates but causes worse mucositis and dysphagia. The aim of this analysis was to assess the impact of p16 status on mucositis, dysphagia, and feeding tube use in LA-SCCHN among patients treated with RT±cetuximab in the phase 3 IMCL-9815 trial. METHODS: Patients received RT plus weekly cetuximab or RT alone. Subgroup analyses were conducted on patients with p16-positive (n=75) or p16-negative (n=106) oropharyngeal cancer (OPC), as determined by immunohistochemical analysis. The onset and duration of mucositis and dysphagia by treatment arm and p16 status were displayed using Kaplan-Meier curves and the log-rank test. P values for the incidence of mucositis and dysphagia were calculated using the Fisher exact test. Feeding tube use was assessed as the percent of patients reporting use. RESULTS: The baseline characteristics of patients treated with RT±cetuximab were similar in both the p16-positive and p16-negative OPC subgroups. Patients within the p16-positive OPC subgroup had higher Karnofsky scores and were more likely to have stage T1-T3 cancer and be from the United States. Regardless of p16 status, there was no difference in the onset or duration of grade 3/4 mucositis or dysphagia in patients receiving RT plus cetuximab compared with those receiving RT alone. In the overall population, and the p16-positive and p16-negative OPC subpopulations, feeding tube use was not different for patients receiving RT plus cetuximab compared with RT alone. CONCLUSION: Regardless of p16 status, the addition of cetuximab to RT did not alter the incidence, time to onset, severity, or duration of mucositis and dysphagia and did not impact the frequency of feeding tube use.

Chemotherapy- and radiotherapy-induced oral mucositis: pathobiology, epidemiology and management.

Oral mucositis is a debilitating complication of anticancer treatment, characterised by erythematous, atrophic, erosive or ulcerative lesions. Oral mucositis is almost always painful, affects eating, sleeping, and speech and affects the physiological and social well-being of the patient. The pathophysiology of the condition is not well understood. Guidelines to the treatment of oral mucositis are often contradictory so that there is no evidence based standard treatment protocol. Therefore the treatment is empiric. This paper offers a brief review of current knowledge of the pathophysiology and treatment of oral mucositis.