A Comprehensive Analysis of the Relationship Between Dose Rate and Biological Effects in Preclinical and Clinical Studies, From Brachytherapy to Flattening Filter Free Radiation Therapy and FLASH Irradiation

For many years, the effect of dose rate (DR) was considered negligible in external beam radiation therapy (EBRT) until very-high DR (10 Gy/min) became possible and ultrahigh DR (40 Gy/s) showed dramatic protection of normal tissues in preclinical experiments. We propose a critical review of preclinical and clinical studies to investigate the biological and clinical effects of DR variation in the range covering brachytherapy to flattening filter free EBRT and FLASH.Preclinical and clinical studies investigating biological and clinical DR effects were reviewed extensively. We also conducted an in silico study to assess the effect of pulse DR (DRPreclinical studies have shown that an increase in DR in the range of 0.01 to 20 Gy/min (not including ultralow or ultrahigh DR) resulted in decreased survival of both normal and tumor cells. This effect was attributed primarily to increasingly unrepaired "sublethal" DNA damage with increasing the DR. However, the models and irradiation conditions have often been very different from one radiobiological study to another. Moreover, the physical parameters on the spatial and temporal microstructure of the beam were not considered systematically. In particular, the DRKnowledge of the beam microstructure is critical to understanding the biological impact and the clinical outcomes of radiation at the DR commonly used in radiation therapy.