## Friday, July 22, 2022

### FLASH

In radiotherapy, a dose of radiation is usually not given all at once, but instead is applied in fractions. In Intermediate Physics for Medicine and Biology, Russ Hobbie and I discuss fractionation this way.
The central problem of radiation oncology is how much dose to give a patient, over what length of time, in order to have the greatest probability of killing the tumor while doing the least possible damage to surrounding normal tissue. While the dose is sometimes given all at once (over several minutes), it is usually given in fractions five days a week for four to six weeks.
We can gain insight into why fractionation works from Eric Hall and Amato Giaccia’s book Radiobiology for the Radiologist.
The basis of fractionation in radiotherapy can be understood in simple terms. Dividing a dose into several fractions spares normal tissues because of repair of sublethal damage between dose fractions and repopulation of cells if the overall time is sufficiently long. At the same time, dividing a dose into several fractions increases damage to the tumor because of reoxygenation and reassortment of cells into radiosensitive phases of the cycle between dose fractions.
 True Tales of Medical Physics,by Jacob Van Dyk.
Despite the apparent advantages of delivering radiation in many fractions, recently a new technique has been proposed in which the radiation is applied very quickly all at once. In True Tales of Medical Physics (2022), Dr. Radhe Mohan writes
At the time of writing of this chapter, ultra-high dose rate radiotherapy, called FLASH radiotherapy, has become the rage. In contrast with the conventional low dose rate protracted radiotherapy, which requires a fractionated course of up to 40 (sometimes even more) treatments, with each daily fraction taking between 15 and 60 min, in FLASH radiotherapy, the entire treatment can be delivered in a fraction of a second. The question is whether FLASH is something real or just a flash in the pan. Around 2015, a medical physicist, Dr. Alejandro Mazal of Institut Curie, in Paris, France, presented results of a study conducted by Favaudon, et al. (https://www.ncbi.nlm.nih.gov/pubmed/25031268) at his institution showing sparing of normal tissues at ultrahigh dose rates. I was skeptical. Naively, I thought why should the dose rate matter? It is the dose deposited that determines the biological damage. Since Favaudon’s work, many experiments have been carried out all over the world confirming the normal tissue sparing effect of FLASH and, equally importantly, showing that the response of tumours to FLASH and conventional low dose rates is about the same. The number of researchers involved in FLASH as well as the number of publications is increasing exponentially. The underlying mechanisms are not yet understood; however, multiple hypotheses are being offered. It turns out that the sparing effect of ultra-high dose rates was discovered in the 1960s and 70s for electron beams. Research activities remained on the back burner until Favaudon’s efforts. The rekindling of interest in FLASH radiotherapy is being thought of as akin to “sleeping beauty awakened.”
What is the mechanism by which FLASH preferentially kills tumor cells while sparing normal cells? Mohan offers some speculation.
The more we learn about FLASH, the more questions arise. Our team is contributing to understanding the basic mechanisms, to designing and conducting experiments to acquire in vivo and in vitro data, and to interpreting the results. The current dominant hypothesis for FLASH seems to be that, at extremely high dose rates, oxygen is depleted, making normal tissues hypoxic (i.e., low in oxygen content) and, therefore, resistant to radiationdamage. Tumours are not spared, possibly because they are already low in oxygen. I have a different hypothesis: FLASH also spares cells of the immune system (T-lymphocytes) that infiltrate the tumour and kill tumour cells. Another hypothesis, that seems to be appropriate at least for radiationtherapy with carbon ions, is that FLASH may actually generate oxygen within the tumour, which sensitizes tumours. The FLASH effect overall may be a combination of all of these factors.

So, should we dribble radiation out in fractions over many weeks, or give it all in one big burst? I don’t know. I do know that if FLASH pans out, we textbook writers need to update our textbooks. I’m rooting for FLASH, because it will certainly be easier on the patient to have only one treatment instead of daily hospital visits over a month. But beware: you'd better aim your radiation beam accurately, because you only have one chance. Don’t throw away your shot!

The Emerging Story of FLASH Radiotherapy, presented by Marie-Catherine Vozenin.

My Shot, from Hamilton, by Lin-Manuel Miranda.