A Brief History of FLASHRadiotherapy

When we hear about "FLASH" radiotherapy, it sounds like a brand-new, cutting-edge technology. It’s a promising approach that delivers radiation at ultra-high dose rates (UHDR), potentially transforming cancer treatment. But you might be surprised to learn that the first hints of this phenomenon were observed more than 60 years ago.

The journey of FLASH-RT is a fascinating story of an early discovery, conflicting results, a long pause, and a dramatic "rediscovery" that sparked the intense research we see today.

The Earliest Observations (1950s - 1980s)

The story begins in 1959, when researchers Dewey and Boag made an interesting observation. They found that bacteria were actually less sensitive to a single, high-dose pulse of radiation compared to the same dose delivered with conventional X-rays [1]. This was the first report of an altered biological response to UHDR. This initial finding was followed by others.

• In 1967, Town et al. demonstrated a similar sparing effect, this time in mammalian cells after single pulse delivery with an average dose rate of ~107 Gy/s2) [2].

• In 1982, Hendry et al. showed that UHDR radiation induced resistance to epithelial necrosis in the tails of mice at average dose rates of ~103 Gy/s [3], 

Despite these intriguing results, the idea didn't take off. Why? A few key reasons:

1. Conflicting Data: Some studies from the same period reported no difference at all between UHDR and conventional radiation [4].

2. Clinical Feasibility: It was believed that the total dose needed to see the sparing effect was too high to be clinically useful [5].

3. Unknown Tumor Effect: Researchers didn't know if this sparing effect also applied to tumors, which would make it ineffective for cancer treatment [5].

4. Technology: Clinical UHDR sources simply weren't widely available at the time [6,7].

Because of these hurdles, the concept of UHDR radiotherapy lay dormant for decades.

The "Rediscovery" and the "FLASH Effect" (2014-2017)

Interest in UHDR was suddenly renewed in 2014 with a landmark study by Favaudon et al.[8]. This study delivered a single high dose of radiation to the thorax of mice using either UHDR (FLASH, ≥40~Gy/s$) or conventional dose rates (CONV, ≤1.8~Gy/min$).

The results were stunning. Mice that received 17 Gy of conventional radiation suffered severe, radiation-induced pulmonary fibrosis. In stark contrast, the mice that received 17 Gy of FLASH radiation had dramatically lower lung damage [8].

Crucially, the same publication also investigated tumor-bearing mice. It found that FLASH and CONV were equally effective in delaying tumor growth. This was the breakthrough. It suggested you could have the best of both worlds: sparing of normal, healthy tissue while maintaining the anti-tumoral effect. This phenomenon was termed the 'FLASH effect' [9,10].

This "rediscovery" opened the floodgates. In 2017, another key study by Montay-Gruel et al. showed that FLASH whole-brain irradiation in mice fully preserved working memory. In contrast, conventional radiation at the same dose caused significant cognitive impairment [11]. The evidence was building.

From the Lab to the Clinic (2019-Present)

With strong preclinical evidence, the next logical step was carefully moving toward human patients.

The First Patient (2019): In 2019, Bourhis et al. reported on the first human patient treated with FLASH-RT [12]. The patient was a 75-year-old man with a cutaneous T-cell lymphoma who had already been treated over 100 times with conventional radiotherapy, which had led to poor skin tolerance. He received a single 15 Gy fraction of FLASH-RT, delivered in just 90 milliseconds. The results were remarkable: he achieved a complete tumor response, and the skin toxicity was "substantially milder" than what he had experienced with conventional treatment [12,13]. Interestingly, in 2021, the same patient was treated for two different tumors: one with FLASH-RT and one with CONV-RT. In this direct comparison, no difference was found between the two treatments regarding side effects or tumor control [14].

Source: Bourhis et al. Radiotherapy and Oncology, 2019

The First Clinical Trial (2021): More recently, the results of the first human clinical trial, FAST-01, were published. In this trial, ten patients with symptomatic bone metastases were treated with proton FLASH radiotherapy. The trial demonstrated that the treatment was feasible and achieved the desired therapeutic benefit [15].

This journey—from a curious observation in bacteria in 1959 to the first human clinical trials—shows how a promising idea can be rediscovered and, with new technology and understanding, finally begin its path toward clinical translation [16].

The evidence from studies in living organisms (in vivo) is becoming hard to ignore: FLASH Radiotherapy (FLASH-RT), which delivers radiation at ultra-high speeds, appears to have a unique, protective benefit. Under specific conditions, FLASH-RT demonstrates a remarkable ability to spare healthy tissue while remaining just as lethal to tumors. This phenomenon is known as the "FLASH effect," and it directly addresses the single biggest challenge in radiation oncology: collateral damage.

In essence, this could lead to a significantly expanded therapeutic window. Think of this window as the "sweet spot" where a radiation dose is high enough to destroy the cancer but low enough to avoid permanently damaging nearby critical organs. A wider window means doctors could potentially:

1. Increase the tumor dose for a higher chance of a cure, without increasing side effects.

2. Treat tumors previously considered "untreatable" because they were too close to vital structures (like the spinal cord or brain stem).

3. Drastically reduce long-term side effects for patients, improving their quality of life.

Source: Vozenin,  et al. Nature Reviews Clinical Oncology, 19, 791–803.

FLASH  is no longer just a laboratory theory. The fact that the FAST-01 clinical trial was successfully conducted—and that the very first human patient was treated safely—proves that translating this technology from the lab bench to the patient's bedside is technically feasible. These initial human studies are the critical first step, demonstrating that the complex machinery required to deliver radiation hundreds of times faster than normal can be controlled safely in a clinical setting.

References

1. Dewey, D.L. & Boag, J.W. "Modification of the Oxygen Effect when Bacteria are given Large Pulses of Radiation." Nature 183, 1450–1451 (1959). (doi: 10.1038/1831450a0​)

2. Town, C.D. "Effect of high dose rates on survival of mammalian cells." Nature 215(5103), 847-8 (1967). (doi: 10.1038/215847a0​)

3. Hendry, J.H., Rushton, D.A., et al. "Epidermal kinetics and ultrastructure of tolerance to radionecrosis in mouse tails." Radiation Research 89(3), 513-27 (1982). (https://doi.org/10.2307/3575620)

4. Held KD. Dose Rate Effects from the 1950s through to the Era of FLASH. Radiation Research. 2024;202(1):1-23. doi:10.1667/RR-2024-11426361.

5. Wardman P. Radiotherapy Using High-Intensity Pulsed Radiation Beams (FLASH): A Tale of Radical Times. Radiation Research. 2020;194(6):587-594. doi:10.1667/RADE-19-00016.

6. Ronga MG, et al. Back to the Future: Very High-Energy Electrons (VHEEs) and FLASH. Frontiers in Oncology. 2021;11:650146. doi:10.3389/fonc.2021.650146. 

7. Lowe D. Radiation dose rate effects: what is new and what is needed? Radiation and Environmental Biophysics. 2022;61:507–543. doi:10.1007/s00411-022-00955-z.

8. Favaudon V, Caplier L, Monceau V, Pouzoulet F, Sayarath M, Fouillade C, Poupon MF, Brito I, Hupé P, Bourhis J, Hall J, Fontaine JJ, Vozenin MC. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Science Translational Medicine. 2014;6(245):245ra93. doi: 10.1126/scitranslmed.3008973.

9. Gesualdi F, et al. A multidisciplinary view of flash irradiation. Cancer/Radiothérapie. 2024;28(2):155-160. doi:10.1016/j.canrad.2024.02.008.

10. Lokody I. FLASHing tumours. Nature Reviews Cancer. 2014 Aug;14(8):514. doi:10.1038/nrc3812.

11. Montay-Gruel P, Acharya MM, Petersson K, et al. Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species. Proceedings of the National Academy of Sciences. 2017;114(10):1198-1203. doi:10.1073/pnas.1614203114.

12. Bourhis J, Jeanneret Sozzi W, Gonçalves Jorge P, Gaide O, Bailat C, Duclos F, Patin D, Ozsahin M, Bochud F, Germond J-F, Moeckli R, Vozenin M-C. Treatment of a first patient with FLASH-radiotherapy. Radiotherapy and Oncology. 2019 Oct;139:18-22. doi:10.1016/j.radonc.2019.06.019. PMID: 31303340.

13. Bourhis J, Montay-Gruel P, Gonçalves Jorge P, Bailat C, Petit B, Ollivier J, Jeanneret-Sozzi W, Ozsahin M, Bochud F, Moeckli R, Germond J-F, Vozenin M-C. Clinical translation of FLASH radiotherapy: Why and how? Radiotherapy and Oncology. 2019. doi:10.1016/j.radonc.2019.04.008.

14. Gaide, O., et al. "Comparison of ultra-high versus conventional dose rate radiotherapy in a patient with cutaneous lymphoma." Radiotherapy and Oncology 174 (2022): 87–91. (doi: 10.1016/j.radonc.2022.07.016)

15. Vozenin M-C, De Fornel P, Petersson K, et al. Feasibility of Synchrotron-Based Ultra-High Dose Rate FLASH Radiotherapy in a First Clinical Trial (FAST-01: Proton Therapy of Symptomatic Bone Metastases). International Journal of Radiation Oncology, Biology, Physics. 2024 Jan 1

16. Lin, B., et al. "Current views on mechanisms of the FLASH effect in cancer radiotherapy." National Science Review 11.10 (2024): nwae350. (doi: 10.1093/nsr/nwae350)