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Ryan Rispman
Since its discovery, radiation has been a double-edged sword. On the one hand, radiation is a killer. It can break apart DNA, leading to mutations that can cause cancer and other diseases. Many of the early scientists who studied radioactive materials eventually ended up dying of radiation-induced illnesses1, including, most famously, Marie Curie2. But radiation can also save lives. While radiation damages the DNA of all tissues, it has a larger effect on actively reproducing cells3. Since one of the hallmarks of cancer is sustained replication4, radiation therapy tends to harm the cancerous cells more than the normal cells3. These days, radiation is a part of cancer treatment for about 50 percent of cancer patients5. Radiation therapy can be used as the primary treatment for a tumor, in combination with other treatment modalities like chemotherapy, or as a palliative measure to help patients at the end of life to alleviate discomfort6.
Over the years, radiation therapy has changed a lot. Many of the major innovations have centered around a common goal: maximizing the amount of radiation the cancerous cells receive and minimizing the amount of damage that normal, non-cancerous cells receive. Because of radiation’s carcinogenic properties, normal tissue exposed to radiation therapy can develop cancers years after a patient’s original tumor has gone into remission7. Therefore, ensuring that non-cancerous tissue receives as little radiation as possible is crucial.
One way scientists maximize the amount of radiation a cancer patient receives is by calibrating the “Bragg peak”. In the context of radiation therapy, the Bragg peak refers to the depth in the human body where the particles stop moving, and the largest amount of radiation is delivered. Only particles which have mass, like protons, have a Bragg peak. An example of a Bragg peak is shown below. The location and size of the peak depend on the type of radiation that is used8.
Radiation is a catch-all term for high-energy particles that travel through the air and can come in many different forms. Originally, radiation therapy was given using X-ray radiation9, a type of high-energy electromagnetic wave. Electromagnetic waves are the type of wave responsible for visible light, but X-ray radiation is not visible due to its high frequency10. In some cases, X-rays are not the ideal vehicle for radiation therapy because they release the most energy at low depth. Since tumors are often located deep within a person’s body, X-rays do not deposit most of their energy in the tumor in many cases11.
The amount of energy deposited at a certain depth depends on two factors. The first factor is the amount of radiation that passes through that depth, which decreases with depth as radiation is delivered to the tissue. The second factor is how likely a radiation-carrying particle is to collide with the surrounding tissue. The probability of collision is inversely related to the average speed of the particles, meaning when the particles are moving slower, they are more likely to collide with the surrounding cells. It turns out, the second factor is the dominant factor in most cases, which means that the Bragg peak of most types of radiation particles occur deep in the tissue right before the particles stop moving12,13. However, since X-rays are waves and not particles, they travel through the body at a constant speed and deliver the most radiation at a low depth before the X-rays begin to be absorbed by the body’s tissue11.
In the modern age, radiation therapy uses many different types of particles, in addition to X-rays, depending on the depth of the tumor and other clinical features14. But researchers are still looking for new types of radiation-delivering particles with a sharper Bragg peak and can deliver more energy to the tumor. One prospective form of radiation that has received considerable attention is antiprotons15. Antiprotons are a type of antimatter, a form of matter that is not typically found outside particle accelerators on Earth. Antimatter particles annihilate when they touch normal matter, releasing a huge amount of energy16. Scientists have shown in experiments on cell models that antiprotons have a much larger Bragg peak compared to most commonly used radiation-delivering particles17. More research, including human clinical trials, will need to be conducted before antiproton therapy could become a widespread cancer treatment. However, since producing antiprotons requires large amounts of time, energy, and expensive specialized equipment, antiprotons can only be produced in a few research facilities18. As a result, antiproton therapy research has been slow, and antiproton therapy may never be a practical cancer treatment.
Outside of new radiation-delivering particles, an arguably more promising approach is called FLASH radiation therapy. Scientists have recently found that delivering radiation in an extremely short time frame (under 200 milliseconds) leads to less normal tissue damage without reducing the amount of damage done to the tumor. This effect is called the FLASH effect. Even if the same total amount of radiation is delivered, the FLASH approach reduces the harm done to normal tissue19.
The biological mechanism behind the FLASH effect is still unclear. One hypothesis is that when the radiation is delivered in a fast burst, the patient’s blood does not have time to fully circulate, so fewer white blood cells are exposed to radiation. Because fewer white blood cells are harmed, patients undergoing flash radiation therapy may experience less immune depletion, leading to more immune cells infiltrating and attacking the tumor. As a result, even if the tumor experienced less harm during the initial radiation blast, the increased immune infiltration may allow FLASH radiotherapy to be just as effective as conventional radiation therapy. Some studies20,21 have shown that tumors that have undergone FLASH therapy tend to be filled with more immune cells compared to tumors that underwent conventional radiation therapy, but the connection still needs to be fully clarified. Another potential explanation for the FLASH effect is that the rapid burst of radiation causes a reduction in the amount of oxygen in normal tissue. Since oxygen particles that absorb radiation are one of the major causes of DNA damage in radiation therapy, the reduction in oxygen levels would reduce the amount of DNA damage. However, since cancer cells tend to already have lower oxygen levels, this effect would not shield the cancer cells22.
More research needs to be done before FLASH radiation therapy can be translated to the clinic. The ideal dosing protocol for FLASH therapy still needs to be found23. Furthermore, many of the FLASH therapy studies have been conducted on animals. The human trials that have been conducted so far have been small24. Larger, high-quality human clinical trials need to be conducted before FLASH therapy can be deemed safe and effective for humans.
The landscape of cancer treatment is constantly shifting, and it is hard to predict what it will look like in 20 years. But it seems like there is a good chance radiation therapy will still play a big role in cancer treatment. With promising ideas like FLASH therapy on the horizon, radiation therapy will continue to become a safer and more effective route to combating cancer.
Edited by Melanie Padalino
References
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2. Marie Curie the Scientist: Biography, Facts & Quotes. Marie Curie Foundation.
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4. Hanahan, Douglas, and Robert A. Weinberg. “Hallmarks of cancer: the next generation.” cell 144.5 (2011): 646-674
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6. Falzone, Tessa. “Palliative Radiation Treatment.” OncoLink, 26 Aug. 2021.
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11. Durante, Marco, and Jay S. Loeffler. “Charged particles in radiation oncology.” Nature reviews Clinical oncology 7.1 (2010): 37-43.
12. “NSRL User Guide.” BNL, https://www.bnl.gov/nsrl/userguide/bragg-curves-and-peaks.php.
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14.“External Beam Radiation Therapy for Cancer.” National Cancer Institute, 1 May 2018
15. Kavanagh, J. N., et al. “Antiproton induced DNA damage: proton like in flight, carbon-ion like near rest.” Scientific reports 3.1 (2013): 1-10.
16. Felder, Gary. “Annihilation and Creation: The Story of Matter and Antimatter.” Wondrium Daily, 5 Jan. 2022, https://www.wondriumdaily.com/annihilation-and-creation-the-story-of-matter-and-antimatter/.
17. Knudsen, Helge V., et al. “Antiproton therapy.” Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms 266.3 (2008): 530-534.
18. Bittner, Martin-Immanuel, et al. “A systematic review of antiproton radiotherapy.” Frontiers in Physics 1 (2014): 37.
19. Lin, Binwei, et al. “FLASH radiotherapy: history and future.” Frontiers in oncology (2021): 1890.
20. Kim, Young-Eun, et al. “Effects of ultra-high doserate FLASH irradiation on the tumor microenvironment in Lewis lung carcinoma: role of myosin light chain.” International Journal of Radiation Oncology* Biology* Physics 109.5 (2021): 1440-1453.
21. Rama, N., et al. “Improved tumor control through t-cell infiltration modulated by ultra-high dose rate proton FLASH using a clinical pencil beam scanning proton system.” International Journal of Radiation Oncology, Biology, Physics 105.1 (2019): S164-S165.
22. Friedl, Anna A., et al. “Radiobiology of the FLASH effect.” Medical Physics 49.3 (2022): 1993-2013.
23. Lin, Binwei, et al. “FLASH radiotherapy: history and future.” Frontiers in oncology (2021): 1890.
24. Vozenin, MC., Bourhis, J. & Durante, M. Towards clinical translation of FLASH radiotherapy. Nat Rev Clin Oncol 19, 791–803 (2022). https://doi.org/10.1038/s41571-022-00697-z
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