Does the uncertainty in relative biological effectiveness affect patient treatment in proton therapy?

Clinical treatment with protons uses the concept of relative biological effectiveness (RBE) to convert the absorbed dose into an RBE-weighted dose that equals the dose for radiotherapy with photons causing the same biological effect. Currently, in proton therapy a constant RBE of 1.1 is generically used. However, empirical data indicate that the RBE is not constant, but increases at the distal edge of the proton beam. This increase in RBE is of concern, as the clinical impact is still unresolved, and clinical studies demonstrating a clinical effect of an increased RBE are emerging. Within the European Particle Therapy Network (EPTN) work package 6 on radiobiology and RBE, a workshop was held in February 2020 in Manchester with one day of discussion dedicated to the impact of proton RBE in a clinical context. Current data on RBE effects, patient outcome and modelling from experimental as well as clinical studies were presented and discussed. Furthermore, representatives from European clinical proton therapy centres, who were involved in patient treatment, laid out their current clinical practice on how to consider the risk of a variable RBE in their centres. In line with the workshop, this work considers the actual impact of RBE issues on patient care in proton therapy by reviewing preclinical data on the relation between linear energy transfer (LET) and RBE, current clinical data sets on RBE effects in patients, and applied clinical strategies to manage RBE uncertainties. A better understanding of the variability in RBE would allow development of proton treatments which are safer and more effective.