In Reply to Horst et al.

We thank Horst et al 1 Horst F Karsch L Pawelke J et al. In regard to Boehlen et al. Int J Radiat Oncol Biol Phys. 2023; 115: 1005-1007 Abstract Full Text Full Text PDF Scopus (1) Google Scholar for their interest in our work and for the addition of their data set that is compatible with a piecewise linear parameterization of DFMF versus D, as proposed in our systematic analysis. 2 Böhlen TT Germond J-F Bourhis J et al. Normal tissue sparing by FLASH as a function of single fraction dose: A quantitative analysis. Int J Radiat Oncol. 2022; 114: 1032-1044 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Their data set is remarkable in that it evidences a shallower slope for a normal tissue endpoint for ultra-high dose rate irradiation compared with conventional dose rate irradiation for an unprecedented large dose range of ∼15 to 50 Gy. These kind of long-range data sets allow to evidence fundamental behaviors of FLASH normal tissue sparing as a function of irradiation parameters. Such behaviors have important implications for the clinical transfer of FLASH and provide validity tests for proposed mechanistic explanations. In particular, the added experimental data set from Horst et al (in agreement with other currently available data sets 2 Böhlen TT Germond J-F Bourhis J et al. Normal tissue sparing by FLASH as a function of single fraction dose: A quantitative analysis. Int J Radiat Oncol. 2022; 114: 1032-1044 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar ) suggests a saturation of the effect magnitude when increasing dose in a single fraction (parametrized by FMFmin in Böhlen et al 2 Böhlen TT Germond J-F Bourhis J et al. Normal tissue sparing by FLASH as a function of single fraction dose: A quantitative analysis. Int J Radiat Oncol. 2022; 114: 1032-1044 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar ). This is underlining the interest in a better understanding of the FLASH effect also as a function of temporal irradiation parameters. As discussed in Böhlen et al, 2 Böhlen TT Germond J-F Bourhis J et al. Normal tissue sparing by FLASH as a function of single fraction dose: A quantitative analysis. Int J Radiat Oncol. 2022; 114: 1032-1044 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar present data suggest that there is no unique time-averaged dose rate (TADR), intra-pulse dose rate or exposure time threshold for the onset of the FLASH effect (Fig. 1 for TADR). Instead, its onset appears to be specific to the biological model, tissue endpoint and, possibly, a combination of irradiation parameters for a given particle. For the design of optimal FLASH radiation therapy devices, it will be of particular interest to evaluate in more detail whether (and where) the magnitude of normal tissue sparing by FLASH saturates, similar as observed for large single fraction doses, or if further substantial magnitude gains (ie, smaller FMF) can be achieved for systems and endpoints with clinical relevance. Most of the data sets from Fig. 1 suggest a saturation of the sparing effect as a function of TADR in the region of ∼50 to 1000 Gy/s. Instead, some data sets are compatible with a further sparing effect increase at large TADR.