FLASH Radiotherapy: the excitement of a promising breakthrough

This technique destroys the tumor cells while sparing the healthy tissue. If the next research steps validate the future clinical application, “FLASH” radiotherapy will provide new opportunities for cancer treatment.

Surgery remains the leading weapon in the fight against cancer, very often accompanied by radiotherapy. In France around 2 out of 3 patients with a cancer - nearly 190,000 people each year - are treated with radiotherapy. The principle is to deliver ionizing rays locally, destroying cancerous cells by causing damage to their DNA. In recent decades, a lot of progress has been made in terms of precision of imaging, ballistics and dosimetry, has allowing to significantly improve patient survival. However there has been few developments both in the technologies associated with electron accelerators (gun, accelerator section, X-ray producer) or in the modalities of the dose delivery. On this last point, the discovery in 2014 in Institut Curie’s laboratories of the “FLASH” effect could well change the landscape in coming years.

2014, the discovery : striking the tumor hard and fast 

It all began in 1995: Vincent Favaudon, an Inserm radiobiology researcher at Institut Curie, found a radio-sensitizer effect in cells in vitro, which took place in a few seconds after exposure to radiation. This observation led to a long-haul research effort on the effects of the dose rate, culminating in 2014 in the publication of major results demonstrating the “FLASH effect” in a preclinical model. This work showed that high doses of radiation delivered within a very short time have the same tumor-fighting effect as classic radiotherapy but with two crucial benefits: sparing the healthy tissue and significantly reducing treatment time. In conventional radiotherapy, the dose rate is around one Gray (Gy) per second with daily total fractions of 2 Gy, whereas the FLASH technique delivers a high dose of irradiation (10 Gy or more, corresponding to the dose received in a week of conventional radiotherapy) for a very short period of time (typically one tenth of a second), thus 1,000 to 10,000 times more intense than in conventional radiotherapy.

It took us 7 years to amass enough data and to unequivocally demonstrate this FLASH effect. Since then, a number of teams have reproduced our results, in different models, each time demonstrating unchanged tumor-fighting performance and protection from complications of radiotherapy, in particular pulmonary fibrosis or memory loss caused by irradiation of the brain

explains Vincent Favaudon.

Healthy tissues spared, what are the underlying biological phenomena ? 

How do we explain this differential effect between healthy tissue and tumorous tissue? Institut Curie researchers at Orsay are closely examining the physiological compartments, the different molecular, cellular and genetic pathways, in order to shed light on the mechanisms at play under the effect of an ultra-high dose rate. A first step was published in 2020.

Vincent Favaudon continues : « Why do healthy tissues regenerate when they undergo FLASH radiotherapy, whereas they do not do so after conventional irradiation? We showed that the nature of the DNA damage is different and that the alterations vary according to the type of irradiation, but there remains much to be understood... and proven! »

One of the areas being looked at is oxygen, since we know that it is a powerful radio-sensitizer.  Several projects coordinated by Institut Curie are currently in progress: FlashOx (ITMO Cancer, NanoTheRad IDEX). These projects aim to quantitively analyze the oxidation of certain lipids and of DNA under the effect of irradiation (FLASH versus conventional). The goal is to study the radio-induced damage at the molecular level, along with the associated cell response in the healthy and tumorous cells, in order to offer the best treatment protocol for patients to benefit from the properties of FLASH irradiation. Institut Curie researchers are deciphering the biological effects of “FLASH” via transcriptomic studies (analysis of the genome transcription activity according to irradiation) of all cells making up a tissue.

A state-of-the-art experimental device for validating clinical applications 

The next generation of electron accelerators used in the clinical setting, particularly in intra-operative radiotherapy, could emerge in the coming years. Patients would receive less aggressive treatment with a potentially greater tumor-fighting performance

explains Marie Dutreix, CNRS Research Director and team leader at Institut Curie

It had been sitting for over 30 years in the Institut Curie research center laboratories at Orsay: the Kinetron, an experimental linear electron accelerator. This is how the FLASH effect was discovered. It has paved the way for a new generation of electron accelerators, namely a prototype device (Electron-Flash 4000), manufactured in Italy by SIT. In the first half of 2021, this device entered the operational phase to embark on a series of new and indispensable physical, physical-chemical and biological studies aimed at bringing the technique to the clinical trial phase. Current projects revolve around the treatment of deep tumors, and researchers, radiologists and physicists are all working collaboratively and planning to explore the feasibility of pre-operative radiotherapy of the pancreas using FLASH radiotherapy.

Prof. Gilles Créhange, Head of the department of oncological radiotherapy at Institut Curie, explains : 

FLASH is causing a scientific boiling, the like of which were rarely seen in recent years in the radiotherapy field. Remember that the greatest revolutions in radiotherapy have been linked to discoveries in medical physics. Two years ago in Switzerland, the first case of a patient treated by FLASH radiotherapy for a skin tumor produced good results. This technique is extremely promising on a global level, but we need several years of practice to confirm that FLASH irradiation reduces long-term after-effects in clinical use.

 

On the trail of protons... 

The FLASH methodology could be applied to another type of particle, namely protons. The Proton Therapy Center at Institut Curie is a French and European leader in this field. This expertise legitimizes the research work on the “FLASH proton”, an area that is being seriously explored and for which researchers and physicians are imagining potential applications, particularly for uveal melanoma, a highly radio-resistant cancer.

Marie-Dutreix concludes : « With FLASH radiotherapy, using electrons or protons, we are seeing to something emerging that could cause a truly radical shift in radiotherapy. But we will only be able to carry it out successefully through team work and inter-disciplinary collaboration, strongly involving researchers and the teams of physicians, physicists, biologists, radio-biologists of the hospital and the research center at Institut Curie ».