From clinical observations of intensity-modulated radiotherapy to dedicated in vitro designs.

In this review, an overview of intensity-modulated radiotherapy (IMRT) and related high precision radiation techniques is presented. In addition, the related radiobiological issues are discussed. Hereby, we try to point to the potential differences in radiobiological effect between popular intensity-modulated radiotherapy and related techniques (IMRT+) and conventional or three-dimensional radiotherapy (3D-RT). Further, an overview of the existing in vitro and in vivo radiobiological models to investigate the effect of spatially and/or temporally fractionated dose distributions, as applied in IMRT+, on the biological outcome is given. More in detail, our radiobiological models will be presented. Additionally, we will discuss the (dis)advantages of the presented models, and give some consideration to improve the existing radiobiological models in terms of set-up and clinical relevance.