Treatment-time-dependence models of early and delayed radiation injury in rat small intestine

Background: The present study modeled data from a large series of experimen ts originally designed to investigate the influence of time, dose, and frac tionation on early and late pathologic endpoints in rat small intestine aft er localized irradiation. The objective was to obtain satisfactory descript ions of the regenerative response to injury together with the possible rela tionships between early and late endpoints. Methods: Two- and 26-week pathologic radiation injury data in groups of Spr ague-Dawley rats irradiated with 27 different fractionation schedules were modeled using the incomplete repair (IR) version of the linear-quadratic mo del with or without various time correction models. The following time corr ection models were tested: (1) No time correction; (2) A simple exponential (SE) regenerative response beginning at an arbitrary time after starting t reatment; and (3) A bi-exponential response with its commencement linked to accumulated cellular depletion and fraction size (the 'intelligent respons e model' [INTR]), Goodness of fit of the various models was assessed by cor relating the predicted biological effective dose for each dose group with t he observed radiation injury score. Results: (1) The incomplete repair model without time correction did not pr ovide a satisfactory description of either the 2- or 26-week data. (2) The models using SE time correction performed better, providing modest descript ions of the data. (3) The INTR model provided reasonable descriptions of bo th the 2- and 26-week data, confirming a treatment time dependence of both early and late pathological endpoints, (4) The most satisfactory descriptio ns of the data by the INTR model were obtained when the regenerative respon se was assumed to cease 2 weeks after irradiation rather than at the end of irradiation. A fraction-size-dependent delay of the regenerative response was also suggested in the best fitting models. (5) Late endpoints were asso ciated with low-fractionation sensitivity and treatment-time dependence eve n in animal groups that exhibited minimal early mucosal reactions. Conclusion: Radiation injury scores in this rat small intestinal experiment al model cannot be adequately described without time correction. 'Consequen tial' mechanisms contribute to the development of late effects, even in ani mals that do not develop severe early mucosal injuries. The initiation of t he regenerative response is subject to a fraction size-dependent mitotic de lay and is linked to the level of accumulated cellular depletion. The respo nse does not cease at the end of therapy but probably continues until maxim al healing has taken place. (C) 2000 Elsevier Science Inc.