Bystander Effects in Spatially Fractionated Radiation Therapy: From Molecule To Organism To Clinical Implications

The standard of care for radiation therapy is numerous, low-dose fractions that are distributed homogeneously throughout the tumor. An alternative strategy under scrutiny is to apply spatially fractionated radiotherapy (high and low doses throughout the tumor) in one or several fractions, either alone or followed by conventional radiation fractionation . Spatial fractionation allows for significant sparing of normal tissue, and the regions of tumor or normal tissue that received sublethal doses can give rise to beneficial bystander effects in both cases. Bystander effects are broadly defined as biological responses that are significantly greater than would be anticipated based on the radiation dose received. Typically these effects are initiated by diffusion of reactive oxygen species and secretion of various cytokines. As demonstrated in the literature, spatial fractionation related bystander effects can occur locally from cell to cell and in what are known as "cohort effects," which tend to take the form of restructuring of the vasculature, enhanced immune infiltration, and development of immunological memory. Other bystander effects can take place at distant sites in what are known as "abscopal effects." While these events are rare, they are mediated by the immune system and can result in the eradication of secondary and metastatic disease. Currently, due to the complexity and variability of these bystander effects, they are not thoroughly understood, but as knowledge improves they may present significant opportunities for improved clinical outcomes.