Review of radiobiological dose rate effects at the edge between conventional and FLASH

The shift from passive scattering to active pencil beam scanning (PBS) in proton therapy, alongside techniques such as flattening filter-free photon therapy, has increased dose rates in clinical radiotherapy from <0.4 Gy/s to 0.4-35 Gy/s. Meanwhile, ultra-high dose rate radiotherapy (FLASH, ≥40 Gy/s) has emerged as a novel modality that spares normal tissue while maintaining tumor control. Yet, dose rate effects within the 0.4-35 Gy/s range have traditionally been considered negligible. Recent reports of unexpected necroses after proton PBS irradiations challenge this assumption, prompting a reevaluation of potential dose-rate-dependent effects in this intermediate range. This review summarizes current evidence on dose rate effects within 0.4-35 Gy/s, derived from in vivo models (including zebrafish embryos and rodents), in-vitro experiments and water radiolysis studies. Selected experimental and retrospective observations suggest that dose rates in this inter mediate range may modify the biological response and, under certain conditions, increase toxicity relative to conventional reference dose rates (<0.4 Gy/s). The magnitude and even direction of dose rate effects appear to depend on radiation quality, total dose, temporal delivery structure, oxygenation, linear energy transfer, tissue type and biological endpoint. The observations described in this review are hypothesis-generating rather than threshold-defining, highlighting the need for further investigation in experimental conditions, preclinical models, and clinical settings.