FLASH Radiotherapy- A new era in radiotherapy?

What’s new?

Radiation therapy has evolved considerably over more than a century since its inception with the use of x-rays and radium-226. With each decade that passes, we see more and more advances that push it closer to being a cost-effective option of choice for many types of cancer. Currently, approximately half of all patients with solid tumors will be treated with radiotherapy. This figure continues to rise with the adoption of radiation treatments such as carbon ion therapy and boron neutron capture therapy which can treat even very radio-resistant tumors whilst significantly reducing the dose to surrounding healthy tissue.

FLASH radiotherapy holds much promise to deliver ultrafast radiotherapy and spare normal tissue. The goal is to use charged particle beams of protons or electrons to kill cancer cells while seemingly protecting healthy tissue thus allowing for higher tolerance of total doses to increase cure rates.

Pre-2014 FLASH radiotherapy (FLASH-RT) was referred to as the flash effect and was first documented in 1956 by Dewey and Boag. The last seven decades has seen research delve further into understanding what the flash effect is and how it can be applied to contemporary radiation therapy. To date over 30 studies have been carried out using different types of tissues and methods of delivering this ultrafast radiation.

When we refer to FLASH-RT as ultrafast we refer to its ability to deliver 8 Gy in 0.2 seconds. It has a dose rate of at least 40 Gy/second, which is about 250 times faster than conventional photon radiotherapy.

Based on pre-clinical outcomes published by Lausanne University Hospital, the very first human was treated with FLASH-RT by Professor Bourhis in 2018 with an Oriatron machine. The patient was a 75-year-old individual with multiresistant CD30+T-Cell cutaneous lymphoma. With a single session of Ultra High Dose Rate electron FLASH-RT, the tumor response was rapid, complete and durable. Side effects were minimal as the patient presented with only grade 1 epithelitis and edema in the soft tissues surrounding the tumor.

2022 saw the first ‘in-human’ palliative FLASH-RT trial. Ten patients each with 1-3 painful bone metastases to the extremities were irradiated with 8 Gy in a single fraction. Pain, pain medications and adverse effects were measured on the day of treatment, 15 days after and monthly for three months post-treatment and then bi-monthly for up to 14 months post-treatment. 7 out of the 10 patients experienced complete or partial pain relief. Half of the treatment sites experienced complete pain relief and another two partial pain relief. Side effects were mild; four patients had mild hyperpigmentation, two experienced pruritis, two had mild limb edema, one experienced fatigue and one had extremity pain.

Human trials continue with the commencement of the LANCE trial comparing FLASH electrons with conventional electrons and also the IMPULSE trial which explored dose escalation on melanomas.

However, with any novel care, applied to multiple subjects, each with individual symptoms and side effects, the volume of data is critical. Recent FLASH-RT research revealed that studies irradiating cats for nasal squamous cell carcinoma had some unexpected bone necrosis, 9 to 15 months after irradiation. The late effect behavior is reminiscent of late effects following neutron irradiation. Radiation therapy sometimes has a steep dose response which means that this damage could possibly be explained by uncertainties in dosimetry in this complex heterogeneous treatment environment. This indicates the need to gather more data to build our understanding of the side effects and build a picture of the types of cancers treated with FLASH RT.

How does FLASH Radiotherapy work?

The selling point for this treatment option is its ability to seemingly ‘protect’ healthy tissue allowing for dose escalation and greater tumor control. An early study in 2014 treating lung disease in mice  found less lung fibrosis, less pneumonitis, and less scarring of the lungs in the mice treated with FLASH-RT. Research has attempted to explain this phenomenon with theories exploring whether biologically this is due to an affected immune response or whether oxygen depletion plays a large role in its success.

Dewey and Boag first noticed hypoxia was induced when bacteria were exposed to ultra high-dose rate radiotherapy. This formed the foundation of the research into the flash effect. Modern research has been able to explain a little further how this phenomenon likely works and how it can be used clinically.

Some research suggests that FLASH radiation consumes all available oxygen inducing oxygen depletion and transient hypoxia which reduced the effect of the radiation, whereas tumors are often chronically hypoxic already.  

Acknowledging the five Rs of radiobiology: DNA repair, reoxygenation, repopulation, redistribution, and intrinsic radiosensitivity. The delivery time of FLASH-RT is too short for reoxygenation, repopulation, and redistribution to occur. Reoxygenation, repopulation, and redistribution may occur but cannot influence the effect of radiotherapy because FLASH-RT is performed only once. Therefore, FLASH-RT may be related to two Rs: DNA repair and intrinsic radiosensitivity where the cell is inhibited from repairing DNA damage, but the hypoxic condition created within the cancer cell makes it more sensitive to radiation.

While oxygen concentration may have a role in the success of FLASH-RT another area of exploration within research is considering the effect this treatment might have on the immune system. It is already widely acknowledged that the immune system plays a pivotal role in normal tissue toxicity. When exposed to ultrafast radiation an immune microenvironment is created, undergoing direct or indirect alterations. It is already known that the production of reactive oxygen series (ROS) following ionizing radiation can activate TGF-β. TGF-β plays crucial roles in various biological processes, including DNA damage repair, cellular inflammation, and side effects.  In studies involving lung fibrocytes, it was reported that TGF-β increased 6.5 times after conventional radiotherapy, whereas FLASH-RT resulted in only a 1.8-fold increase.

Another interesting hypothesis relates to the fraction of total blood volume irradiated. With conventional radiotherapy taking longer the amount of blood passing through the target volume is greater but it is irradiated with a lower dose compared to FLASH-RT where less blood is irradiated but at a higher dose. Previous studies have highlighted the importance of circulating cells and blood components for mediating classical radiation-induced toxicities.

What’s next?

The radiation world is excited about FLASH-RT and extensive research is investigating its properties especially how this treatment works and if there are late effects to be wary of.

FLASH-RT could completely change the face of radiotherapy, Ultra-fast treatments with seemingly less side effects will mean higher daily departmental patient throughput, shorter waiting lists, increased comfort for patients during treatment due to short treatment times and fractionations and less complex recovery in weeks after treatment due to the reduced effect on healthy tissue.

References

Bourhis, J., et al (2019) Treatment of a first patient with FLASH-radiotherapy. Radiotherapy and Oncology 139:18-22. doi: 10.1016/j.radonc.2019.06.019.

Limoli, C., Vozenin, M-C (2023). Reinventing Radiobiology in the Light of FLASH Radiotherapy. Annual Review of Cancer Biology. 7:1-21. Available at: https://www.annualreviews.org/doi/full/10.1146/annurev-cancerbio-061421-022217#:~:text=FLASH%20radiotherapy%20provides%20a%20unique,a%20variety%20of%20preclinical%20models

Lin, B., et al (2021) FLASH Radiotherapy: History and Future. Frontiers in Oncology. 11. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185194/

Liu, J., et al (2023) The clinical prospect of FLASH radiotherapy. Radiation Medicine and Protection. 4(4): 190-196

Matuszak, N., et al (2022) FLASH radiotherapy: an emerging approach in radiation therapy. Reports of Practical Oncology and Radiotherapy. 27(2): 344-351. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9591027/#:~:text=FLASH%20radiotherapy%20(RT)%20is%20a,compared%20to%20conventional%20radiation%20therapy.

Polevoy G, Kumar D S, Daripelli S, et al. (October 12, 2023) Flash Therapy for Cancer: A Potentially New Radiotherapy Methodology. Cureus 15(10). Available at: https://www.cureus.com/articles/191571-flash-therapy-for-cancer-a-potentially-new-radiotherapy-methodology#!/