Alternative Radiotherapy Delivery Approaches to Modulate Radiation Response

Spatially fractionated (SFRT) and FLASH radiotherapy (RT) are alternative means of dose delivery that are expected to widen the therapeutic window of clinical RT. The biological mechanisms for the observed effects of normal tissue-sparing with maintained tumor control probability are unknown. First, we introduce the preclinical research technologies for SFRT and FLASH-RT with photon beams, which include carbon nanotubes and modifications of standard small animal irradiators. As a novel concept, we highlight the potential importance of line-focussed x-ray tubes. Following that, we review immunological anti-tumor responses observed in various animal models for both alternative irradiation modalities. While there is agreement that SFRT and FLASH modulate the tumor immune microenvironment, at present, it is not clear if the anti-tumor immunity generated is more beneficial than that resulting from conventional RT. Further preclinical research is required to determine which aspects of the SFRT-mediated or FLASH-mediated anti-tumor immune response could be exploited for the eventual benefit of cancer patients.