Can the mean linear energy transfer of organs be directly related to patient toxicities for current head and neck cancer intensity-modulated proton therapy practice?

Background and purpose: The relative biological effectiveness (RBE) of proton therapy is predicted to vary with the dose-weighted average linear energy transfer (LET d ). However, RBE values may substantially vary for different clinical endpoints. Therefore, the aim of this study was to assess the feasibility of relating mean DLET d parameters to patient toxicity for HNC patients treated with proton therapy. Materials and methods: The delivered physical dose (D) and the voxel-wise product of D and LET d (DLET d ) distributions were calculated for 100 head and neck cancer (HNC) proton therapy patients using our TPS (Raystation v6R). The means and covariance matrix of the accumulated D and DLET d of all relevant organs-at-risk (OARs) were used to simulate 2.500 data sets of different sizes. For each dataset, an attempt was made to add mean DLET d parameters to a multivariable NTCP model based on mean D parameters of the same OAR for xerostomia, tube feeding and dysphagia. The likelihood of creating an NTCP model with statistically significant parameters (i.e. power) was calculated as a function of the simulated sample size for various RBE models. Results: The sample size required to have a power of at least 80% to show an independent effect of mean DLET d parameters on toxicity is over 15,000 patients for all toxicities. Conclusion: For current clinical practice, it is not feasible to directly model NTCP with both mean D and mean DLET d of OARs. These findings should not be interpreted as a contradiction of previous evidence for the relationship between RBE and LET d .