Dependence of LET on material and its impact on current RBE model.

Biological uncertainty remains one of the main sources of uncertainties in proton therapy, and is encapsulated in a scalar quantity known as relative biological effective (RBE). It is currently recognised that a constant RBE of 1.1 is not consistent with radiobiological experiment and may lead to sub-optimal exploitation of the benefits of proton therapy. To overcome this problem, several RBE models have been developed, and in most of these models, there is a dependence of RBE on dose-averaged linear energy transfer (LET), [Formula: see text]. In this work, we show that the [Formula: see text] estimation in these models during the data-fitting (or parameter estimation) phase could be subjected to a huge uncertainty due to not taking into account cellular materials during simulation, and this uncertainty can propagate down to the resulting RBE models. The dosimetric impact of this [Formula: see text] uncertainty is then evaluated on a simple clinical spread out Bragg peak (SOBP) and a prostate example. Our simulation shows that [Formula: see text] uncertainty due to the use of water as cellular material is non-negligible under low [Formula: see text] and low dose (2 Gy), and can be neglected otherwise. Thus, this study indicates that further dose and range margins may be required for low [Formula: see text] target under low dose. This is due to greater uncertainties in RBE model associated with incomplete knowledge of cellular composition for [Formula: see text] computation.