Risk of secondary cancers: Bridging epidemiology and modeling.

Epidemiological studies of long term radiotherapy survivors provide useful insights into dose-response relationships for secondary cancer induction risk at high doses. There are uncertainties involved in estimating the dose to the location of the second malignancy, because the dose distributions in radiotherapy patients can be spatially highly heterogeneous and the size of the diagnosed tumor is on the order of a few cm. Therefor it is nearly impossible to obtain the exact dose corresponding to the exact tumor induction location and so organ specific dose-response relationships have large errors not only in the reported risk, but also in the estimated dose. In this work two alternative methods are proposed for future applications involving investigations into dose response relationships for second cancer induction risk, the method of organ sub-division and the method of risk equivalent dose. The method of organ sub-division takes the inevitable inhomogeneous dose distribution into account by applying epidemiological methods to organ sub-divisions which have a nearly homogenous dose. The method of risk equivalent dose combines risk modeling and epidemiological data analysis. Risk models can be optimized by using an iterative procedure assuming a variation of organ specific dose-responses. The advantage of the alternative methods is that the inhomogeneity of the dose in the organs at risk is taken into account. The second method has the additional advantage that the dose to the location of the tumor site must not be known and that epidemiologically obtained risks that were not stratified by organ specific risk can be used.