Physics and radiobiology of radiosurgery
Article information
Abstract
Radiosurgery, a high-precision, high-dose modality, has revolutionized the field of radiation treatment. The physics of radiosurgery is integral to its design and commissioning. The technology relies on three-dimensional imaging, immobilization, setup, and patient positioning to maintain accuracy within the sub-millimeter range. However, it is particularly important to understand the physical processes causing biological effects. Stereotactic radiosurgery (SRS) currently plays a major role in the treatment of brain tumors due to its ability to precisely and accurately deliver a high dose of radiation to a target, effectively ablating viable tumors while minimizing the dose and preventing damage in surrounding normal tissue. The biological mechanisms underlying these new modalities have not been fully elucidated. Evidence now indicates that SRS with doses higher than about 10 Gy per fraction induces vascular damage in tumors, subsequently causing secondary and additional tumor cell death. The ensuing degradation of tumor cells then releases massive amounts of tumor-specific antigens, thereby elevating the antitumor immune response and suppressing the recurrence of tumors and metastasis. The radiobiology of radiosurgery is thus a complex interplay of physical precision and biological responses, making it a powerful tool in the fight against cancer.
INTRODUCTION
Everything around us has energy. The interaction between a particular object and the human body depends on the type of object and the energy it has. When an object has high enough energy to enter the body and knock electrons out of the atoms that make up the body, we call it ionizing radiation. When electrically neutral atoms are ionized, the electrons that are knocked off have a negative charge, so the remaining ions have a positive charge, which changes the electrical bonds between atoms and causes molecules to break apart. When this molecular breakdown occurs in DNA, the DNA becomes deformed, which in many cases is repaired, but sometimes leads to cell death. Understanding the biological effects of radiation means understanding how ionization occurs and the process of repairing the deformed DNA. Calculating how much ionization occurs and in what form is radiation physics, and understanding the process of repairing DNA damage caused by ionization is radiation biology. This article describes the physics of gamma rays (X-rays) and particle rays used in radiosurgery and the biology of radiosurgery, which distinguishes it from radiation therapy.
PHYSICS OF GAMMA RAYS
Gamma rays are light (photons) like visible light. While visible light is blocked by our skin, gamma rays have a high enough energy to penetrate the human body and cause ionization, which is why they are often used for diagnosis and treatment with radiation. Gamma rays used in radiotherapy are often referred to as X-rays, but since X-rays are photons in a slightly lower energy range than gamma rays and there is no physically meaningful difference between the two, we will only use the word gamma rays in this article. In the medical field, the energy of gamma rays is expressed in units called MeV (Mega-Electron Volt), and gamma rays with energies of 0.6 to 6.0 MeV are commonly used in radiation therapy and radiosurgery. Gamma rays with this energy interact with atoms in the body primarily through Compton scattering, where the gamma rays knock off one of the atom’s electrons (Fig. 1A). The energy of the gamma-ray that knocks out the electron is reduced by the energy that it delivers to the electron and the energy that the electron was bound to the atom, and the gamma-ray travels in a direction that preserves the total momentum of the scattering process. Most of the time, the scattered gamma ray escapes from the body without reacting again. In other words, gamma rays for radiosurgery usually cause one, or in rare cases two, Compton scatterings in the body, and the electron that bounces out of the atom due to Compton scattering is called a Compton electron.

The process of ionization that occurs when a gamma ray with energy between 0.6 and 6.0 MeV enters the human body (ellipse). (A) In Compton scattering, an incident gamma ray with wavelength λ bounces off an electron (Compton electron) and travels in the other direction. The wavelength, λ*, of the scattered photon is longer than λ because the energy was reduced by the transferred energy to the Compton electron and the electron binding energy. The scattered photon usually leaves the body without causing any further reaction. (B) The Compton electron ionizes other atoms, and the electrons that pop out in the process are called secondary electrons. (C) The secondary electron also ionizes other nearby atoms, and because the energy of the secondary electron is usually less than 100 eV, in water it usually stops within 4 nm and causes approximately three ionizations before stopping; this narrow range of clustered ionization is called a spur.
As such, gamma rays rarely cause more than one or two ionizations, the ionizations that have radiobiological effects are mostly related to the ionizations caused by the Compton electrons moving around until they stop inside the body. The electrons that result from the Compton electrons moving around and ionizing other atoms are called secondary electrons (Fig. 1B). The average kinetic energy of secondary electrons in water is around 70 eV, with most having values less than 100 eV. On the other hand, the average ionization energy in water is about 22 eV, so one secondary electron causes about three ionizations, and the average distance a secondary electron travels before it stops is about 4 nm [1]. In radiobiology, a group of three ionizations within a 4 nm diameter is called a “spur,” (Fig. 1C) and about 95% of the energy absorbed by water from medical gamma rays is through the spur [2]. Given that the DNA double helix is 2 nm wide, one spur can be expected to cause approximately one double-strand break (DSB), and radiation such as gamma rays, which cannot cause many DSBs in such a small space, is called sparsely ionizing radiation.
PHYSICS OF PARTICLE BEAMS
The particles currently used in radiotherapy and radiosurgery are hydrogen and carbon nuclei. The nucleus of a hydrogen atom is a proton. Protons and carbon nuclei have a positive charge and interact with the electrons of atoms in the body primarily through Coulomb scattering. In this process, when the energy transferred to an electron is greater than its binding energy, the electron leaves the atom and ionization occurs. Since protons are more than 1,800 times heavier than electrons, and carbon is more than 12 times heavier than protons, the energy transferred to an electron at a time is very small when they are moving very fast, i.e., when the electrons inside the atom can be assumed to be at rest. For a 1 MeV proton, the energy transfer is very similar to that of a 150 eV electron [1], which is why protons are classified as sparsely ionizing radiation, like gamma rays. Carbon does not show much difference in the distribution of the amount of energy it delivers to an electron at any one time, but it ionizes many times more frequently than protons, which means that it causes much more ionization while traveling a shorter distance. To account for this phenomenon, in radiobiology, an energy transition of 100 to 500 eV within a diameter of 7 nm, resulting in an average of 12 ionizations in a group, is called a “blob,” and carbon is densely ionizing radiation with a high percentage of energy transitions by blobs [2]. In this case, multiple-strand breaks occur simultaneously in a particular region of DNA, which is relatively more difficult to repair compared to breaks caused by sparsely ionizing radiation. When protons and carbon reach the Bragg peak region, i.e., when the movement of electrons inside the atom can no longer be ignored, a number of more complex phenomena occur, which are beyond the scope of this article, and the interested reader is referred to the literature [3,4].
VERIFICATION OF THE ABSORBED DOSE
Because the number of DNA mutations, which is important for radiosurgery, is related to the amount of energy absorbed, it is critical to accurately verify the amount and distribution of energy absorbed. Since radiosurgery targets are three-dimensional objects, it would be ideal to verify the absolute value of the absorbed dose at each point within the target, but in clinical practice, a point within the target is usually chosen and the absolute value of the absorbed dose at this point is verified. The accuracy of the two-dimensional distribution can then be verified by measuring the relative absorbed dose on a straight line through this point, or on a plane containing this point, and then relative to the absolute absorbed dose at the point verified above. The measurement of the absolute value of the absorbed dose at a point requires the use of a unique measurement protocol that varies from radiosurgery machine to machine, with International Atomic Energy Agency (IAEA) TRS-483 [5], a protocol recently published jointly by the IAEA and the American Association of Medical Physicists (AAPM), representing the standard protocol. The AAPM’s report on gamma knife surgery recommends that the error of the absolute absorbed dose measured at a point should be no more than 2–3% [6]. On the other hand, to measure the relative absorbed dose distribution in a plane, a radiochromic film is used, which changes color depending on the absorbed dose.
The accuracy of the actual radiation dose absorbed by the patient depends on various factors, including the accuracy of the imaging used in the radiotherapy procedure, the mechanical accuracy of the radiotherapy device, the accuracy of the radiotherapy planning program, and the patient’s movement during radiation. Therefore, it is necessary to verify the absorbed dose under the circumstances of the radiosurgery procedure by reproducing the radiosurgery procedure as closely as possible. This is called end-to-end validation, which involves acquiring images in an anthropomorphic phantom, creating a radiosurgery treatment plan, placing a film inside the phantom, and then irradiating the phantom according to the treatment plan to measure the amount and distribution of absorbed radiation dose in the film. Finally, the accuracy is measured by comparing the absorbed dose calculated by the treatment planning program with the absorbed dose measured by the film. To compare the accuracy of the absorbed dose, find the difference between the measured absorbed dose at a point and the calculated value, and the distance to the nearest calculated value when the absorbed dose is measured at a point. Combine these two values to calculate a gamma index value, and if it is less than or equal to one, the point passes validation. For every point in the absorbed dose distribution measured in this way, we determine whether it passes the gamma index and define the percentage of points that pass the test as the gamma index pass rate. For radiosurgery, a gamma-index pass rate of more than 95% is typical, based on an absorbed dose difference of 3% or 2% and a distance of 1 mm between points with the same value [7,8].
RADIOBIOLOGY OF RADIOSURGERY
Since conventional radiotherapy and radiosurgery deliver radiation to the body from the outside, normal tissues in the path from the skin to the lesion absorb more radiation than the lesion when radiation is delivered from only one direction. Nevertheless, in order to minimize the risk of side effects in normal tissues while treating the lesion, conventional radiotherapy is based on fractionated treatment, while radiosurgery, which is based on the principle of delivering radiation in a single session, focuses more on minimizing the radiation absorbed by normal tissues while delivering radiation to the lesion. Traditional radiotherapy uses the differences between normal and cancer cells in DNA repair, redistribution of the cell cycle, repopulation of the cells, and reoxygenation of the tumor to achieve therapeutic effects. Since these responses are more pronounced in fast-growing cells such as cancer cells, conventional radiotherapy is mainly indicated for highly malignant tumors such as cancer and glioblastoma. Radiosurgery, on the other hand, delivers a single dose of radiation at a time, so there is no redistribution, repopulation, or reoxygenation, and the dose is so high that not enough DNA repair can occur. Therefore, radiosurgery is more commonly used to target benign tumors, vascular disease, or normal tissue rather than malignant tumors [9].
Radiosurgery delivers high doses of radiation at a time, and it has long been known that damage to the tumor’s blood vessels caused by high-dose irradiation induces tumor cell death. To better understand the potential role of indirect cell death due to vascular injury on tumor response to stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS), Song et al. [10] recently used an in vivo-ex vivo ablation assay to investigate the effect of SBRT and SRS on tumor cell death. These recent observations, along with previous reports, clearly demonstrated that high-dose hypofractionated irradiation to tumors induces dose-dependent indirect cell death by causing vascular disruption, which deteriorates the intratumoral environment [11]. High-dose irradiation, such as in radiosurgery, can directly or indirectly induce ablative cell death leading to massive release of tumor antigens, which can elevate the antitumor immune response, and the elevated antitumor immune response 1–2 weeks after tumor irradiation does not participate in secondary tumor cell death but inhibits the proliferation of surviving tumor cells, thereby inhibiting recurrence and metastasis [11].
CONCLUSION
The physics of radiosurgery is the process of understanding the ionization of atoms by radiation. Radiation absorbed by the body ionizes atoms, and this ionization leads to biological changes. While conventional fractionated radiotherapy is primarily indicated for malignant tumors such as cancer, radiosurgery targets benign tumors, vascular diseases, and sometimes normal tissues. This means that radiosurgery requires a unique understanding of radiobiology, including radiation-induced vascular damage and immune responses.
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CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.