The effect on the small bowel of 5-FU and oxaliplatin in combination with radiation using a microcolony survival assay

BACKGROUND: In locally advanced rectal cancer, 5-Fluorouracil (5-FU)-based chemoradiation is the standard treatment. The main acute toxicity of this treatment is enteritis. Due to its potential radiosensitizing properties, oxaliplatin has recently been incorporated in many clinical chemoradiation protocols. The aim of this study was to investigate to what extent 5-FU and oxaliplatin influence the radiation (RT) induced small bowel mucosal damage when given in conjunction with single or split dose RT. METHODS: Immune competent balb-c mice were treated with varying doses of 5-FU, oxaliplatin (given intraperitoneally) and total body RT, alone or in different combinations in a series of experiments. The small bowel damage was studied by a microcolony survival assay. The treatment effect was evaluated using the inverse of the slope (D(0)) of the exponential part of the dose-response curve. RESULTS: In two separate experiments the dose-response relations were determined for single doses of RT alone, yielding D(0 )values of 2.79 Gy (95% CI: 2.65 - 2.95) and 2.98 Gy (2.66 - 3.39), for doses in the intervals of 5-17 Gy and 5-10 Gy, respectively. Equitoxic low doses (IC5) of the two drugs in combination with RT caused a decrease in jejunal crypt count with significantly lower D(0): 2.30 Gy (2.10 - 2.56) for RT+5-FU and 2.27 Gy (2.08 - 2.49) for RT+oxaliplatin. Adding both drugs to RT did not further decrease D(0): 2.28 Gy (1.97 - 2.71) for RT+5-FU+oxaliplatin. A clearly higher crypt survival was noted for split course radiation (3 × 2.5 Gy) compared to a single fraction of 7.5 Gy. The same difference was seen when 5-FU and/or oxaliplatin were added. CONCLUSION: Combining 5-FU or oxaliplatin with RT lead to an increase in mucosal damage as compared to RT alone in our experimental setting. No additional reduction of jejunal crypt counts was noted when both drugs were combined with single dose RT. The higher crypt survival with split dose radiation indicates a substantial recovery between radiation fractions. This mucosal-sparing effect achieved by fractionation was maintained also when chemotherapy was added.