FLASH Radiotherapy Versus Conventional Cancer Therapy: Promises, Paradoxes and Problems

Abstract

A novel means of applying radiotherapy in cancer treatment is the application of a radiation dose at a very high intensity for a very short time in FLASH radiotherapy (FLASH-RT). This technique involves the exposure of tumors to >40 Gy/s, usually for less than one second. Studies conducted in cell and preclinical models suggest that FLASH-RT seems less damaging to normal tissues from adverse effects relative to the same overall dose of radiation administered in conventional therapy (CONV-RT), which involves the administration of lower levels of radiation repeated intermittently over a protracted period. In contrast, the susceptibility of tumor tissues to FLASH-RT is not diminished relative to CONV-RT. Within solid tumors, both modes of dispensation of radiation produce an equivalent degree of cell damage. The differential treatment between normal and malignant material has been found in isolated tissues, animal studies and, more recently, in clinical trials. However, the classic radiation concept is that high-energy linear transfer radiation (LET) is more damaging than the equivalent total dose of low LET. Thus, the susceptibility of cells should be greater after short-term exposure to high LET. This article discusses the potential reasons that may account for this discrepancy. While the relative protection given to untransformed tissues by FLASH-RT relative to tumor tissue is a major step forward in radiation therapy for cancer, the processes that lie behind this phenomenon are incompletely understood and are considered here.