Lethal hepatic injury by combined treatment of radiation plus chemotherapy in rats with thioacetamide-induced liver cirrhosis

Purpose: To assess lethal hepatic injury by combined treatment of radiation (RT) plus chemotherapy in a rat model with thioacetamide (TAA)-induced liver cirrhosis. Methods and Materials: Male Wistar rats were treated with 0.3 g/L TAA in drinking water. The development of liver ciirhosis was histologically confirmed, and the degree of liver function impairment was assessed by indocyanine green retention test (ICG R15). The established cirrhotic rats were given one of the following treatments; partial liver radiotherapy (25 Gy on about one-third of the whole liver), 5-fluorouracil (5-FU) chemotherapy (50 mg/kg), and combined treatment of partial RT plus 5-F/U. The treated rats were closely followed until either death or 30 weeks after the treatment, and the postmortem liver sampling was examined for lethal hepatic injury by the treatments. Results: The rats developed overt liver cirrhosis after 30 weeks of TAA treatment. At that time, the mean ICG R15 level in the TAA-treated rats (TAA-rats) was 14.1% +/- 0.7% compared to 4.6% 0.7% in the control (p < 0.05). The 30-week survival rates in the control and TAA-rats were 100% (515) and 75% (6/8), respectively, after partial liver RT (p = 0.72). In the 5-FU chemotherapy group, the survival in TAA-rats was only one-half of that in the controls (100% vs. 50%,p = 0.06). Poor survival in TAA-rats was shown also in the combined group of partial RT plus 5-FU (87.5% vs. 16.7%,p = 0.06). The rats that died before the last observation time showed advanced cirrhosis with areas of lobular collapse, in contrast to the moderate cirrhotic features in those that survived. Conclusion: In a rat cirrhosis model with mildly impaired liver function, combined treatment of partial RT plus 5-FU resulted in significantly high incidence of lethal liver injury. The results in this study show that a combined treatment of RT plus chemotherapy in cirrhotic patients should be applied with extreme caution. (C) 2003 Elsevier Inc.