Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically signifi cant 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 prolife ration of stem cells during cellular repopulation after inactivation. This earlier

more »

... del predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. Methods: To extend the model to radiationinduced leukemias, we analyzed -in addition to cellular initiation, inactivation, and proliferation -a repopulation mechanism specifi c 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% confi dence 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 lowdose-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 radiationinduced leukemia associated with exposure to therapeutic doses of radiation. [J Natl Cancer Inst 2006;98: 1794 -806 ] Radiation therapy inevitably exposes normal healthy organs to ionizing radiation and thus involves risks for radiation-induced