Prospect of radiotherapy technology development in the era of immunotherapy.

Radiotherapy (RT) is one of the important modalities for cancer treatments. Mounting evidence suggests that the host immune system is involved in the tumor cell killing during RT, and future RT technology development should aim to minimize radiation dose to the immune system while maintaining a sufficient dose to the tumor. A brief history of RT technology development is first summarized. Three RT technologies, namely FLASH RT, proton therapy, and spatially fractionated RT (SFRT), are singled out for the era of immunotherapy. Besides the technical aspects, the mechanism of FLASH effect is discussed, which is likely the combined results of the recombination effect, oxygen depletion effect and immune sparing effect. The proton therapy should have the advantage of causing much less immune damage in comparison to X-ray based RT due to the Bragg peak. However, the relative biological effectiveness (RBE) uncertainty and range uncertainty may hinder the translation of this advantage into clinical benefit. Research approaches to overcome these two technical hurdles are discussed. Various SFRT approaches and their application are reviewed. These approaches are categorized as single-field 1D/2D SFRT, multi-field 3D SFRT and quasi-3D SFRT techniques. A 3D SFRT approach, which is achieved by placing the Bragg peak of a proton 2D SFRT field in discrete depths, may have special potential because all 3 technologies (FLASH RT, proton therapy and SFRT) may be used in this approach.