The relative biological effectiveness (RBE) of protons varies with multiple physical and biological factors. Phenomenological RBE models have been developed to include such factors in the estimation of a variable RBE, in contrast to the clinically applied constant RBE of 1.1. In this study, eleven published phenomenological RBE models and two plan-based models were explored and applied to simulated patient cases. All models were analysed with respect to the distribution and range of linear energy transfer (LET) and reference radiation fractionation sensitivity ((α/β) ) of their respective experimental databases. Proton therapy plans for a spread-out Bragg peak in water and three patient cases (prostate adenocarcinoma, pituitary adenoma and thoracic sarcoma) were optimised using an RBE of 1.1 in the Eclipse treatment planning system prior to recalculation and modelling in the FLUKA Monte Carlo code. Model estimated dose-volume parameters for the planning target volumes (PTVs) and organs at risk (OAR) were compared. The experimental in vitro databases for the various models differed greatly in the range of (α/β) values and dose-averaged LET (LET). There were significant variations between the model estimations, which arose from fundamental differences in the database definitions and model assumptions. The greatest variations appeared in organs with low (α/β) and high LET, e.g. biological doses given to late responding OARs located distal to the target in the treatment field. In general, the variation in maximum dose (D) was larger than the variation in mean dose and other dose metrics, with D of the left optic nerve ((α/β) =  2.1 Gy) in the pituitary adenoma case showing the greatest discrepancies between models: 28-52 Gy(RBE), while D for RBE was 30 Gy(RBE). For all patient cases, the estimated mean RBE to the PTV was in the range 1.09-1.29 ((α/β) =  1.5/3.1/10.6 Gy). There were considerable variations between the estimations of RBE and RBE-weighted doses from the different models. These variations were a consequence of fundamental differences in experimental databases, model assumptions and regression techniques. The results from the implementation of RBE models in dose planning studies should be evaluated in light of these deviations.

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