Radiation-induced rectal complications are not influenced by age: a dose fractionation study in the rat

Radiation-induced complications of the rectum are an important dose-limiting factor in radiotherapy of pelvic malignancies. In general, animal studies demonstrated no differences in acute and late normal tissue toxicity with age, but little is known about rectal complications in relation to age. For this purpose, an extensive histological and dose fractionation study was carried out on the rectum of young (12 weeks) and older (77-80 weeks) rats. In this paper, the results of dose fractionation are presented in relation to age at the time of irradiation. Young and older animals were irradiated with single and fractionated doses. After irradiation, rectal complications could lead to occlusion and stenosis, eventually resulting in the clinical symptoms of a megacolon and a possible fistula. For each dose group, cumulative survival rates were obtained with Kaplan-Meier analysis, from which dose-effect curves and the associated LD(50) values for a megacolon/fistula were calculated. The majority of responders died between 8 and 24 weeks after irradiation, irrespective of age. For both age groups, only the fractionation data showed a reduction in the mean latency with increasing dose. In the older age group, 39% of the responders developed a fistula compared to 26% for the younger animals. The LD(50) values increased from around 30 Gy after single doses to nearly 65 Gy after 10 fractions. The increases in LD(50) values with the number of fractions were independent of the age of the rats. For each of the dose fractionation schedules, log-rank testing indicated no significant differences in cumulative survival rates between younger and older animals (P > 0.10). The high alpha/beta ratios obtained for both the young and older animals strongly suggested that the late rectal complications were a consequence of early epithelial injury. Associated histological findings indicated that blood vessel damage, which was already evident at a high incidence at 4 weeks after irradiation, could also play a significant role in the occurrence of consequential late injuries. In conclusion, data obtained for the latent period of rectal occlusion, for the dose-effect curves, for the log-rank testing of cumulative survival rates, and for the alpha/beta ratios strongly support the hypothesis that the incidence of radiation-induced rectal complications is independent of age. Late rectal complications could be a consequence of radiation-induced acute injury.