Mechanisms of the FLASH Effect: Current Insights and Advances

I’ve written about FLASH radiotherapy previously in this blog (here and here). FLASH is when you apply radiation in a single brief pulse rather than slowly or in several fractions. It’s one of the most important developments in radiation therapy in the last decade, but no one is sure why FLASH works better than conventional methods. (Skeptics might say no one is sure if FLASH works better than conventional methods, but I’ll assume in this post that it’s better.) FLASH is too new for Russ Hobbie and I to mention it in the 5th edition of Intermediate Physics for Medicine and Biology, but Gene Surdutovich and I will add a discussion of it to the 6th edition.

“Mechanisms of the FLASH Effect:
Current Insights and Advances,”
by Giulia Rosini, Esther Ciarrocchi,
and Beatrice D’Orse

I recently read a fascinating mini review in Frontiers in Cell and Developmental Biology by Giulia Rosini, Esther Ciarrocchi, and Beatrice D’Orse of the Institute of Neuroscience in Pisa, Italy. They’re trying to address that why question. Their article, titled “Mechanisms of the FLASH Effect: Current Insights and Advances,” is well worth reading. (Some scientific leaders in the United States claim that modern medicine focuses on treating symptoms rather than addressing underlying causes. This article shows that scientists do just the opposite: They search for basic mechanisms. Bravo! At least in Italy science is still alive.)

Below I reproduce their introduction (references removed and Wikipedia links added). If you want more detail, I suggest reading the review in its entirety (it’s open access, so you don’t need a subscription to the journal).

Radiotherapy is one of the most effective treatments for cancer, used in more than 60% of cancer patients during their oncological care to eliminate/reduce the size of the tumor. Currently, conventional radiotherapy (CONV-RT) remains the standard in clinical practice but has limitations, including the risk of damage to surrounding healthy tissues. A recent innovation, FLASH radiotherapy (FLASH-RT), employs ultra-high-dose rate (UHDR) irradiation to selectively spare healthy tissue while maintaining its therapeutic effect on tumors. However, the precise radiobiological mechanism behind this protective “FLASH effect” remains unclear. To understand the FLASH effect, several hypotheses have been proposed, focusing on the differential responses of normal and tumor tissues to UHDR irradiation: (i) Oxygen depletion: FLASH-RT may rapidly deplete oxygen in normal tissues, creating transient hypoxia that reduces oxygen-dependent DNA damage; (ii) Radical-radical interaction: The rapid production of reactive oxygen species (ROS) during UHDR irradiation may lead to radical recombination, preventing oxidative damage to healthy tissues; (iii) Mitochondrial preservation: FLASH-RT appears to preserve mitochondrial integrity and ATP production in normal tissues, minimizing oxidative stress. Conversely, FLASH-RT may promote oxidative damage and apoptosis in tumor cells, potentially improving therapeutic efficacy; (iv) DNA damage and repair: The differential response of normal and tumor tissues may result from variations in DNA damage formation and repair. Normal cells rely on highly conserved repair mechanisms, while tumor cells often exhibit dysregulated repair pathways; and (v) Immune response: FLASH-RT may better preserve circulating immune cells and reduce inflammation in normal tissues compared to CONV-RT. In this mini-review, we summarize the current insights into the cellular mechanisms underlying the FLASH effect. Preclinical studies in animal models have demonstrated the FLASH effect, and early-phase clinical trials are now underway to evaluate its safety and efficacy in human patients. While FLASH-RT holds great promise for improving the balance between tumor control and normal tissue sparing in cancer treatment, continued research is necessary to fully elucidate its mechanisms, optimize its clinical application, and minimize potential side effects. Understanding these mechanisms will pave the way for safer and more effective radiotherapy strategies.

I’ll take advantage of this paper being open access to reproduce Rosini et al.’s Figure 1, which is a beautiful summary of their article. 

Figure 1 from “Mechanisms of the FLASH Effect: Current Insights and Advances,”
by Giulia Rosini, Esther Ciarrocchi and Beatrice D’Orsi

If I were a betting man, I’d put my money on the radical-radical interaction mechanism. But don’t trust me, because I’m not an expert in this field. Read this well-written review yourself and draw your own conclusion.

I’ll end by giving Rosini, Ciarrocchi, and D’Orse the final word. Their conclusion is quoted below.

FLASH-RT has emerged as a promising alternative to CONV-RT, offering potential advantages in reducing normal tissues toxicity while maintaining or even potentially enhancing tumor control. However, the underlying mechanisms remain incompletely understood. Oxygen depletion, radical recombination, mitochondrial preservation, DNA repair and immune response modulation, have all been proposed as contributing factors… but no single mechanism fully explains the FLASH effect. This further highlights the complex interplay between physical, biological, and immunological factors that might behind the FLASH effect. Importantly, combining FLASH-RT with adjuvant therapies, such as radioprotectors, immunotherapy or nanotechnology, could synergize with these mechanisms to further widen the therapeutic window. FLASH-RT’s ability to reduce inflammation, preserve immune function, and minimize damage to healthy tissues contrasts sharply with CONV-RT, which often induces significant toxicity. However, despite promising preclinical findings, critical questions remain regarding the precise mechanisms driving the FLASH effect and its clinical applicability. Continued research is essential to fully elucidate these mechanisms, optimize FLASH-RT delivery, and translate its benefits into safe and effective clinical applications. By addressing these challenges, FLASH-RT has the potential to significantly improve therapeutic outcomes for cancer patients, offering a paradigm shift in radiation oncology.