Towards harmonizing clinical linear energy transfer (LET) reporting in proton radiotherapy: A European multi-centric study

Background: Clinical data suggest that the relative biological effectiveness (RBE) in proton therapy (PT) varies with linear energy transfer (LET). However, LET calculations are neither standardized nor available in clinical routine. Here, the status of LET calculations among European PT institutions and their comparability are assessed and a consensus for harmonized LET reporting is presented.
Materials and methods: Eight European PT institutions used suitable treatment planning systems with their centre-specific beam model to create treatment plans in a water phantom covering different field arrangements and fulfilling commonly agreed dose objectives. They employed their locally established LET simulation environments and procedures to determine the corresponding LET distributions. Dose distributions D1.1 and DRBE assuming constant and variable RBE, respectively, and LET were compared among the institutions. Inter-centre variability was assessed based on dose- and LET-volume-histogram parameters.
Results: Treatment plans from six institutions fulfilled all clinical goals and were eligible for common analysis. D1.1 distributions in the target volume were comparable among PT institutions with variability <2.7%. However, corresponding LET values varied substantially between institutions for all field arrangements (≤57.1%), primarily due to differences in LET averaging technique and considered secondary particle spectra. Consequently, DRBE using nonharmonized LET calculations increased inter-centre dose variations substantially compared to D1.1 and significantly in mean dose to the target volume of perpendicular and opposing field arrangements (p<0.05). Harmonizing LET reporting (dose-averaging, all protons, LET to water) reduced the inter-centre variability in LET to the order of 10-15% within and outside the target volume for all beam arrangements. Consequentially, inter-institutional variability in DRBE decreased to that observed for D1.1 (p>0.05).
Conclusion: Harmonizing the reported LET among PT centres is feasible and allows for consistent multi-centric analysis and reporting of tumour control and toxicity in view of a variable RBE. It may serve as basis for harmonized variable RBE dose prescription in PT.