Physical Challenges of FLASH Radiotherapy

Abstract

The possibility of killing tumors with ionizing radiation (radiotherapy) was demonstrated shortly after the discovery of X-rays in 1895. The first experience demonstrated that high doses 1 of radiation can kill a tumor but simultaneously induce toxicity in surrounding normal tissues. In other words, to be therapeutically exploited, radiation should control the tumor at a dose lower than the one causing severe toxicity. The region between the normal tissue complication probability (NTCP) and the tumor control probability (TCP) curves is the therapeutic region (Figure 1). Widening the therapeutic windows is the main goal of radiotherapy research. In fact, treatment of radioresistant tumors is still restricted by normal tissue complications and metastatic spread. The standard dose rate 2 during the radiotherapy treatment ranges between 0.5 and 20 Gy/min, depending on the technology used, and the outcome was considered independent of the dose rate in this range. The paradigm-shift set of experiments performed by a Franco-Swiss collaboration in 2014 [1] demonstrated, surprisingly, that the toxicity in a mouse was reduced at ultra-high dose rate (40 Gy/s) while tumor control remained the same. This unexpected differential effect was named the FLASH effect (Figure 1) and has been since replicated in different preclinical models using radiation of different qualities. Interestingly, as the field was progressing, it became obvious that quoting average dose rate was an oversimplification and today, the FLASH effect is known to depend on the combination of multiple beam parameters and biological factors that are intensively investigated [2] while the clinical translation has already started [3]. Many questions remain to be answered before FLASH can be applied in clinics at a large scale. These challenges will be analyzed and discussed in the following sections.