FLASH radiotherapy is an emerging form of radiotherapy which delivers a high dose of radiation to the patient in an ultra-short time frame which produces a tumour killing effect comparable to conventional radiotherapy but with less damage to surrounding healthy tissue. The treatment is in the early stages of development and is not yet widely available as a form of cancer therapy.[1]
FLASH-RT development
editResearch into high-dose radiotherapy yielding cells which were more resistant to radiation was first performed in the 1950s, but without any breakthrough achievements, research dwindled after the 1960s.[2] However, in 2014 a research paper published by V. Favaudon et al. coined the term FLASH, which was defined as irradiating tissue with a dose ≥ 40 Gy/s.[3] The research involved comparing conventional radiotherapy performed on mice to FLASH radiotherapy administered using a linear electron accelerator (LINAC) able to generate 4.5 MeV electrons with a high beam current, such that a high dose could be administered by a single beam in less than 500ms. This research showed that when compared to CONV-RT, the onset and progression of pneumonia and pulmonary fibrosis were measurably inhibited following a solitary exposure to 17 Gy FLASH-RT, yet the effect on a tumour was comparable.[3] More recently, in 2019 first human FLASH-RT treatment was performed at Lausanne University Hospital, which concluded that FLASH-RT was both feasible and safe.[4] Subsequently, in 2023 the first proton clinical trial of FLASH-RT was performed at the Cincinnati Children's Hospital Medical Center. The trial focussed on bone metastases of 10 patients with an age range of 27-81 years old, and a 50/50 split in sex, it concluded that FLASH-RT was clinically feasible and that the findings supported further exploration into FLASH-RT.[5]
Comparison of FLASH-RT and CONV-RT
edit| Parameter | FLASH-RT | CONV-RT |
|---|---|---|
| Mean dose rate | ≥ 40 Gy/s (minimum threshold) | ≤ 1 Gy/min |
| Delivery time | < 200 ms | > 1 min |
| Dose delivery | High dose in a single fraction | Low dose in a single fraction |
| Tumor control | A similar antitumor effect as CONV-RT | Effective tumor killing |
| Normal tissue sparing | Damage to healthy tissues reduced | Acute and late damage to healthy tissues |
| Defects | Early stages of development/few facilities | Radiation injury, limited treatment window |
Oxygen depletion hypothesis
editThe increased radiosensitivity of cells in an oxygenated environment compared to a hypoxic one is known as the oxygen effect, this is the basis of one of the first and most widely investigated hypotheses which could explain the FLASH effect. Many research papers have been published investigating whether FLASH RT creates a hypoxic environment in healthy tissue, which makes it less radiosensitive. The oxygen depletion was thought to be caused by radiolysis of water molecules, where water breaks down into hydrogen peroxide, hydrogen radicals and other oxygen compounds. [6][7] However, experimental studies demonstrated that oxygen depletion does not occur. [8] [9] [10][11] A new hypothesis is needed to explain the FLASH effect, which can also account for the differential response between healthy tissue and cancer at ultra-high dose rates.[12]
Blood volume as a target for FLASH radiotherapy
editSince blood is constantly flowing around the human body, during CONV-RT a large volume of this blood is expected to be irradiated. A possible reason for FLASH-RT sparing normal tissues is that a lower total blood volume is irradiated when compared with CONV-RT. Blood carries more than just oxygen throughout the body, it contains immune cells which help to fight infection and disease. Multiple studies have investigated this possibility, one being Jin. et al., 2020, where it was observed that circulating blood cells experienced a significantly lower impact during FLASH-RT, resulting in the killing of only 5-10% of cells, in contrast, CONV-RT exhibited a much more substantial effect, leading to the death of 90-100% of cells.[13] Aside from immune cells, studies have shown that the proinflammatory signalling in the form of the secretion of proinflammatory cytokines is reduced during FLASH-RT when compared to CONV-RT.[14]
Stem cell niche preservation
editAdult stem cells are found throughout the human body in locations known as niches. These cells multiply by cell division to replenish dying cells and regenerate tissue. These cells are essential for recovery from certain forms of cancer such as leukemia, where some treatment plans can involve stem cell transplants. A more recent hypothesis which may explain the FLASH effect is that hypoxic stem cell niches are preserved more readily through FLASH RT.[12][6] Pratx and Kapp, 2019, suggest that stem cells which reside in a hypoxic niche are relatively radioresistant, but whenever surrounding tissue is damaged, the stem cells become more oxygenated and therefore more radiosensitive.[12] This theory suggests that as FLASH-RT is delivered in a single, ultra-short dose, the stem cells do not have time to react to the damage done to the surrounding tissue, therefore maintaining their radio-resistance and increasing the overall survivability of the niche.
References
edit- ^ Wang, S; Gonzalez, G; Owen, DR; Sun, L; Liu, Y; Zwart, T; Chen, Y; Xiang, L (29 July 2024). "Toward real-time, volumetric dosimetry for FLASH-capable clinical synchrocyclotrons using protoacoustic imaging". Medical Physics. 51 (11): 8496–8505. doi:10.1002/mp.17318. PMC 11530303. PMID 39073707.
- ^ Wilson, Puthenparampil; Jones, Bleddyn; Yokoi, Takeichiro; Hill, Mark; Vojnovic, Boris (October 2012). "Revisiting the ultra-high dose rate effect: implications for charged particle radiotherapy using protons and light ions". British Journal of Radiology. 85 (1018) (1018): e933-9. doi:10.1259/bjr/17827549. PMC 3474025. PMID 22496068.
- ^ a b Favaudon, Vincent; Caplier, Laura; Monceau, Virginie; Pouzoulet, Frédéric; Sayarath, Mano; Fouillade, Charles; Poupon, Marie-France; Brito, Isabel; Hupé, Philippe; Bourhis, Jean; Hall, Janet; Fontaine, Jean-Jacques; Vozenin, Marie-Catherine (2014-07-16). "Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice". Science Translational Medicine. 6 (245): 245ra93. doi:10.1126/scitranslmed.3008973. ISSN 1946-6234. PMID 25031268.
- ^ Bourhis, Jean; Sozzi, Wendy Jeanneret; Jorge, Patrik Gonçalves; Gaide, Olivier; Bailat, Claude; Duclos, Fréderic; Patin, David; Ozsahin, Mahmut; Bochud, François; Germond, Jean-François; Moeckli, Raphaël; Vozenin, Marie-Catherine (October 2019). "Treatment of a first patient with FLASH-radiotherapy". Radiotherapy and Oncology. 139: 18–22. doi:10.1016/j.radonc.2019.06.019. ISSN 0167-8140. PMID 31303340.
- ^ Mascia, Anthony E.; Daugherty, Emily C.; Zhang, Yongbin; Lee, Eunsin; Xiao, Zhiyan; Sertorio, Mathieu; Woo, Jennifer; Backus, Lori R.; McDonald, Julie M.; McCann, Claire; Russell, Kenneth; Levine, Lisa; Sharma, Ricky A.; Khuntia, Dee; Bradley, Jeffrey D. (2023-01-01). "Proton FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases". JAMA Oncology. 9 (1): 62–69. doi:10.1001/jamaoncol.2022.5843. ISSN 2374-2437. PMC 9589460. PMID 36273324.
- ^ a b Pratx, Guillem; Kapp, Daniel S (2019-09-11). "A computational model of radiolytic oxygen depletion during FLASH irradiation and its effect on the oxygen enhancement ratio". Physics in Medicine & Biology. 64 (18): 185005. arXiv:1905.06992. Bibcode:2019PMB....64r5005P. doi:10.1088/1361-6560/ab3769. ISSN 1361-6560. PMID 31365907.
- ^ Petersson, Kristoffer; Adrian, Gabriel; Butterworth, Karl; McMahon, Stephen J. (July 2020). "A Quantitative Analysis of the Role of Oxygen Tension in FLASH Radiation Therapy". International Journal of Radiation Oncology*Biology*Physics. 107 (3): 539–547. doi:10.1016/j.ijrobp.2020.02.634. ISSN 0360-3016. PMID 32145319.
- ^ Jansen, Jeannette; Knoll, Jan; Beyreuther, Elke; Pawelke, Joerg; Skuza, Raphael; Hanley, Rachel; Brons, Stephan; Pagliari, Francesca; Seco, Joao (July 2021). "Does FLASH deplete oxygen? Experimental evaluation for photons, protons, and carbon ions". Medical Physics. 48 (7): 3982–3990. arXiv:2102.12762. Bibcode:2021MedPh..48.3982J. doi:10.1002/mp.14917. PMID 33948958.
- ^ Cao, Xu; Zhang, Rongxiao; Esipova, Tatiana V.; Allu, Srinivasa Rao; Ashraf, Ramish; Rahman, Mahbubur; Gunn, Jason R.; Bruza, Petr; Gladstone, David J.; Williams, Benjamin B.; Swartz, Harold M.; Hoopes, P. Jack; Vinogradov, Sergei A.; Pogue, Brian W. (September 2021). "Quantification of Oxygen Depletion During FLASH Irradiation In Vitro and In Vivo". International Journal of Radiation Oncology*Biology*Physics. 111 (1): 240–248. doi:10.1016/j.ijrobp.2021.03.056. ISSN 0360-3016. PMC 8338745. PMID 33845146.
- ^ Boscolo, Daria; Scifoni, Emanuele; Durante, Marco; Krämer, Michael; Fuss, Martina C. (September 2021). "May oxygen depletion explain the FLASH effect? A chemical track structure analysis". Radiotherapy and Oncology. 162: 68–75. arXiv:2101.09010. doi:10.1016/j.radonc.2021.06.031. ISSN 0167-8140. PMID 34214612.
- ^ El Khatib, Mirna; Motlagh, Azar O.; Beyer, Jenna N.; Troxler, Thomas; Allu, Srinivasa Rao; Sun, Qi; Burslem, George M.; Vinogradov, Sergei A. (March 2024). "Direct Measurements of FLASH-Induced Changes in Intracellular Oxygenation". International Journal of Radiation Oncology*Biology*Physics. 118 (3): 781–789. doi:10.1016/j.ijrobp.2023.09.019. ISSN 0360-3016. PMC 11474819. PMID 37729972.
- ^ a b c Limoli, Charles L.; Vozenin, Marie-Catherine (2023-04-11). "Reinventing Radiobiology in the Light of FLASH Radiotherapy". Annual Review of Cancer Biology. 7 (1): 1–21. doi:10.1146/annurev-cancerbio-061421-022217. ISSN 2472-3428. PMC 11486513. PMID 39421564.
- ^ Jin, Jian-Yue; Gu, Anxin; Wang, Weili; Oleinick, Nancy L.; Machtay, Mitchell; (Spring) Kong, Feng-Ming (August 2020). "Ultra-high dose rate effect on circulating immune cells: A potential mechanism for FLASH effect?". Radiotherapy and Oncology. 149: 55–62. doi:10.1016/j.radonc.2020.04.054. ISSN 0167-8140. PMC 7442672. PMID 32387486.
- ^ Zhang, Y.; Ding, Z.; Perentesis, J.P.; Khuntia, D.; Pfister, S.X.; Sharma, R.A. (November 2021). "Can Rational Combination of Ultra-high Dose Rate FLASH Radiotherapy with Immunotherapy Provide a Novel Approach to Cancer Treatment?". Clinical Oncology. 33 (11): 713–722. doi:10.1016/j.clon.2021.09.003. ISSN 0936-6555. PMID 34551871.