BACKGROUND: Because many cancer patients are diagnosed earlier and live longer 
than in the past, second cancers induced by radiation therapy have become a 
clinically significant issue. An earlier biologically based model that was 
designed to estimate risks of high-dose radiation-induced solid cancers included 
initiation of stem cells to a premalignant state, inactivation of stem cells at 
high radiation doses, and proliferation of stem cells during cellular 
repopulation after inactivation. This earlier model predicted the risks of solid 
tumors induced by radiation therapy but overestimated the corresponding leukemia 
risks.
METHODS: To extend the model to radiation-induced leukemias, we analyzed--in 
addition to cellular initiation, inactivation, and proliferation--a repopulation 
mechanism specific to the hematopoietic system: long-range migration through the 
blood stream of hematopoietic stem cells (HSCs) from distant locations. 
Parameters for the model were derived from HSC biologic data in the literature 
and from leukemia risks among atomic bomb survivors who were subjected to much 
lower radiation doses.
RESULTS: Proliferating HSCs that migrate from sites distant from the high-dose 
region include few preleukemic HSCs, thus decreasing the high-dose leukemia 
risk. The extended model for leukemia provides risk estimates that are 
consistent with epidemiologic data for leukemia risk associated with radiation 
therapy over a wide dose range. For example, when applied to an earlier 
case-control study of 110,000 women undergoing radiotherapy for uterine cancer, 
the model predicted an excess relative risk (ERR) of 1.9 for leukemia among 
women who received a large inhomogeneous fractionated external beam dose to the 
bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% 
confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases 
observed). As a corresponding example for brachytherapy, the predicted ERR of 
0.80 among women who received an inhomogeneous low-dose-rate dose to the bone 
marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% CI = -0.2 
to 1.9).
CONCLUSIONS: An extended, biologically based model for leukemia that includes 
HSC initiation, inactivation, proliferation, and, uniquely for leukemia, 
long-range HSC migration predicts, with reasonable accuracy, risks for 
radiation-induced leukemia associated with exposure to therapeutic doses of 
radiation.