Electromagnetic Radiation

EM radiation is composed of oscillating electric and magnetic fields. The EM spectrum spans a range from infrared waves, through visible light, to high-energy x-rays and gamma rays. As the wavelength of the waves decreases, the energy of the waves increases. In radiation therapy, it is the high-energy x-rays and gamma rays that are used for clinical effect. Because of the small wavelengths and high energy of x-rays and gamma rays, EM radiation exhibits a dual nature: it can be described as waves, and it can also be described in terms of small, discrete packets of energy called photons. High-energy photons are considered to be an indirectly ionizing form of radiation. When interacting with tissue, photons induce the liberation of charged particles (electrons), which then cause the majority of the ionization and, thus, the biologic effect.

X-rays and gamma rays differ only in their manner of production. X-rays are produced either as a result of the interaction between a high-speed electron and a nucleus (bremsstrahlung x-rays) or as a result of electrons in the outer shell of an ionized atom falling from a high- to a low-energy level to fill a vacancy created by an electron that has been ejected (characteristic x-rays). X-rays may be a by-product of radioactive decay or may be created by human intervention. For example, linear accelerators (LINACs) generate x-rays by accelerating electrons and directing them to strike a target composed of a substance with high atomic number. The electrons interact with the target nuclei and generate (primarily) bremsstrahlung and (secondarily) characteristic x-rays.²

In contrast, gamma rays are photons emitted from the recoiling nucleus of a radioactive atom when it decays. An example is cobalt 60 (⁶⁰Co), which as it undergoes beta decay converts a neutron to a proton and in the process emits a beta particle (an electron), an antineutrino, and gamma photons.

High-energy photons (>1 MV) are useful in radiation therapy because they deposit a significant amount of energy at depth in tissue, so they can be used to treat tumors deep within the body. In addition, high-energy photons exhibit a property called the build-up region when they enter tissue because the electrons liberated by the interacting photons near the skin surface are propelled in a mostly forward direction and deposit their energy deeper in tissue. This gives photons an advantage known as the “skin-sparing” effect (Fig. 249-1).

FIGURE 249-1 Comparison of dose deposition for photon beams, electron beams, and proton beams. Notice that photon beams have a “buildup region” that provides a measure of skin sparing at the surface of the patient. Electron beams exhibit less skin sparing and a sharper dose falloff. Proton beams deposit most of the dose at the end of their range, a phenomenon known as a “Bragg peak.” Photons also have a maximum dose range in tissue.

Particle Radiation

Particle radiation differs from photon radiation in that the energy of the radiation is propagated through the kinetic energy of the particle itself. High-energy particle radiation is directly ionizing; it has sufficient kinetic energy to ionize atoms as they interact in tissue. Unlike high-energy photons, which tend to sparsely interact with matter and can travel long distances before being completely attenuated, high-energy particles tend to have shorter, bounded ranges of penetration in tissue before they are completely attenuated. The particles routinely used for therapeutic purposes are electrons and protons, with heavy ions used less frequently. Neutrons, which have also been evaluated for use in radiation therapy, are uncharged particles with very different modes of interaction in tissue and are not described here.

High-energy electrons are usually produced in LINACs by replacing the high–atomic number target (usually tungsten), which results in x-ray production, with a foil that serves to scatter the electrons in a desired pattern. Electrons begin depositing appreciable dose near the surface of tissue, have a predictable range at which they deposit the majority of their energy, and exhibit rapid dose falloff. This gives electron therapy a particular advantage in the treatment of cutaneous or subcutaneous lesions (Fig. 249-1).

High-energy protons are produced in particle accelerators such as cyclotrons. Protons are much more massive particles than electrons. Therefore, at a particular velocity, protons have much greater kinetic energy and do not scatter as easily. Hence, protons can potentially cause less damage to surrounding tissue. In addition, most of the energy absorption from protons occurs at the distal end (over the last few millimeters) of the particle track. The precisely defined area of intense ionization at the end of the track after the passage of protons is called a Bragg peak (Fig. 249-1). After the Bragg peak the deposited energy falls off quickly, so protons have a defined range in tissue with essentially no exit dose. To treat the entire thickness of a tumor, the proton beam may be altered to spread the Bragg peak out to the desired range of depth. By taking advantage of the Bragg peak effect, as well as cross-firing of a number of proton beams, a well-localized volume of high radiation delivery can be produced and has been applied in a radiosurgical setting.^3,4

Free Radicals

When cells are irradiated with ionizing radiation, photons can interact with water molecules by stripping an electron from a hydrogen atom, which results in a fast electron and an ionized water molecule. The resulting fast electrons further interact with water molecules through additional ionizing events. The positively charged water molecule exhibits a short half-life before dissociating into an H⁺ ion and an OH⁻ free hydroxyl radical. The hydroxyl radical is reactive and has sufficient energy to break chemical bonds in nearby molecules. This indirect effect of radiation through a free radical intermediary is responsible for the majority of radiation-induced damage. The chemical reactions are enhanced by the presence of oxygen. Tissue hypoxia (PO₂ <30 mm Hg) will inhibit the production of free radicals and thereby lessen the damaging effects of radiation.

Radiation Injury to DNA

A variety of evidence suggests that DNA is the most important target for cellular damage by ionizing radiation. The reactive water derivative may interact with DNA and create the potential for permanent cell injury or death. Radiation can also interact directly with DNA.

Damage to DNA can take the form of single-strand breaks, where one of the two intertwined helixes are broken, or double-strand breaks, in which both are broken. Single-strand breaks (the more common form of damage) are potentially repaired by DNA repair enzymes because the undamaged strand can be used as a template for repair. Double-strand breaks are more difficult if not impossible to repair; they cause the most serious biologic damage. Double-strand breaks may be the result of a single particle or the interaction of two single-strand breaks caused by separate particles occurring at close temporal and spatial distances.

Studies on synchronously dividing cell cultures have demonstrated that cells in the G₂ and M phases of the cell cycle are most susceptible to double-strand DNA breaks.

Radiobiology of Conventional Radiotherapy

Radiation damages the DNA of tumor cells, as well as the DNA of normal cells in its path. Normal tissue, however, is generally more capable of DNA repair than tumors are, partly because of aberrant cell cycle control mechanism in tumors, as well as differences in genetic features that permit damage to the abnormal tumor phenotype. Abnormal metabolic patterns may also make tumors more susceptible than normal cells to increased oxidative stress.

Cells require time to repair DNA damage, and the normal cell response to irradiation is to delay the cell cycle. The length of the G₂ phase delay correlates with radiation resistance. Therefore, the radiobiology of differential cell repair is of paramount importance for conventional radiotherapy. Repair plays a less critical role as the number of fractions decreases.

The probability of cell survival after single doses of radiation is a function of the absorbed dose, measured in the unit gray (Gy). Typical mammalian cell survival curves obtained after single-dose irradiation in culture have a characteristic shape that includes a low-dose shoulder region followed by a steeply sloped region at higher doses.^5,6 The shoulder region is interpreted as an accumulation of sublethal damage at low doses, with lethality resulting from the interaction of two or more such sublethal events. As noted previously, single-strand breaks in DNA may be repaired and therefore represent sublethal damage to the cell. However, double-strand breaks may result in cellular changes, including cell death. Such a model can be described by the following probabilistic equation in which probability (cure or complication) = exp(−K*exp[−αD − βD²])] (“exp” represents exponential, K equals the number of clonogens, “α“ and “β“ are constants related to single-event cell killing and cell killing through the interaction of sublethal events, respectively, and “D” represents dose). The α/β ratio is the single dose at which overall cell killing is equally attributable to both components of cell killing (αD = βD² or D = α/β).⁷ The validity of the linear quadratic formula for single-dose radiosurgery has been questioned, however.⁸ Nevertheless, it still provides a meaningful method to relate radiosurgery to fractionated radiation schemes.

The α/β ratio varies depending on the tumor and normal tissue type (Fig. 249-2). Late-responding tissues such as the brain or spinal cord have an α/β ratio of approximately 2, whereas many tumors have an α/β ratio of nearly 10. The α/β ratio for skin or mucosa is approximately 5 to 8. Tumors with a low α/β ratio (i.e., a small α or single-hit component for radiation kinetics) will have less of a desired effect when a scheme involving a low radiation dose per fraction is used than when comparable tissues with a high α/β ratio are treated. The dose may be normalized to a scheme of 2 Gy per fraction (NTD2Gy) by using the following equation⁹:

FIGURE 249-2 Comparison of single-dose effect curves (A) and fractionated-dose effect curves (B) for low- and high-α/β tissue. The small advantage seen in the low-dose region in which low-α/β tissue is spared is amplified through dose fractionation.

Conventional fractionated radiation therapy relies on the four R’s of radiobiology: repair of nonlethal injury, reoxygenation of hypoxic tumor cells, repopulation of tumor cells, and reassortment of tumor cells into more susceptible phases of the cell cycle. There are advantages and disadvantages to fractionated radiation therapy and radiosurgery. Depending on the clinical scenario, one may prove superior to the other. Certainly, there seems to be little advantage to fractionation for functional cases (e.g., trigeminal neuralgia) or for the treatment of patients with arteriovenous malformations (AVMs).⁸

As mentioned earlier, hypoxia at a PaO₂ below 30 mm Hg reduces the development of damaging free radicals and thus the degree of radiation damage. Experimental studies and clinical observation have suggested that aerated cells become nonviable after irradiation and that the site of irradiation is dominated by hypoxic cells. From this observation it is thus important to note that substantial dose escalation of a tumor may prove to have diminishing returns because hypoxic cells are not adequately depopulated. However, evidence has demonstrated a phenomenon known as reoxygenation, whereby tumors may reestablish their oxygenated state between sessions if the radiation is delivered in fractions. Through reoxygenation, a higher percentage of tumor cells will be depopulated by fractionated irradiation. A variety of factors are involved in the process of reoxygenation, such as decreased oxygen consumption by dead cells and a reduction in the number of cells in relation to capillary blood supply.

Malignant tumors generally fall into the category of early-responding tissue containing hypoxic cells, whereas normal brain tissue consists primarily of late-responding tissue containing well-aerated cells. In malignant tumors, arguments can be made for and against fractionation. Fractionation increases the cellular depopulation of a tumor for a given total radiation dose because of the phenomenon of reoxygenation. At the same time, fractionation reduces the damage to critical late-responding normal tissue. However, fractionation allows malignant tumor cells to repopulate between fractions. This phenomenon is in contrast to the treatment of many benign tumors and AVMs, in which both targeted abnormal tissue and normal brain tissue consist of late-responding tissue of similar radiologic type. There is little to be gained by fractionation in these situations.

The standard approach to radiotherapy includes daily treatments preceded by a dose delivery simulation in which patient positioning relative to the treatment machine is confirmed to result in appropriate beam entrance and exit sites. The most commonly prescribed absorbed dose is 1.8 to 2 Gy, which has proved to be well tolerated in most areas of the body and can be repeated a specific number of times, depending on the region involved and the therapeutic target. For practical purposes, tolerance of the whole brain is considered to be 45 to 50 Gy in 20 to 25 fractions, although it is recognized that this dose may yield substantial dementia and memory loss with time.

Radiobiology of Radiosurgery

A therapeutic advantage may also be achieved by depositing more radiation dose in the tumor than in surrounding normal tissue. The use of cross-firing beams enables delivery of high doses to the region of the target while minimizing the dose to surrounding tissue. Although a single radiation beam entering a patient begins with a region of high dose (after the initial build-up region) and gradually decreases in dose with increased depth, with cross-firing beams the dose at depth progressively increases as the various beams intersect. Thus, as the dose is deposited along each beam, the total dose absorbed by normal tissue can be kept low while achieving a much higher dose at the intersection of the beams and a steep dose gradient between the low- and high-dose regions. This rapid falloff in radiation dose is the basic principle used to spare normal tissue in radiosurgery. Although cross-firing can also be used in conventional radiotherapy, its practical limits are two to four fields, and accuracy of delivery is on the order of 1 cm or greater in many anatomic sites. However in radiosurgery, because hundreds of beams are added together, the isodose lines begin to take on the configuration of the tumor, thus minimizing dose outside the target. This ability led Lars Leksell to propose the concept of radiosurgery in 1951. He described the use of radiation as a means of replacing the scalpel or electrode for functional neurosurgery. In so doing, the biology of differential repair was discarded, and the main biologic advantage became the ability to destroy focally identified areas and avoid normal brain tissue by physical means.

The initial radiosurgical concept of Leksell was intended for the treatment of functional neurological disorders, but it has now expanded to become a standard treatment option for numerous benign and malignant central nervous system pathologies. In radiosurgery, the surgeon does not attempt to spare some tissues and treat others but to achieve inactivation or destruction within the targeted volume. Obliteration of the vascular supply with accompanying endothelial damage of vessels to the tumors also seems to play a much more significant role in radiosurgery than in radiation therapy.

Conventional Radiotherapy

External beam radiation most commonly uses x-rays, gamma rays, or electrons and is the most common form of therapeutic radiation for cancer treatment. Early external beam units could generate x-rays with only relatively low energy and achieve just a superficial depth of penetration. These devices were not capable of treating deep-seated brain lesions. The introduction of ⁶⁰Co teletherapy machines and LINACs has allowed the routine use of megavoltage (>1 MV) high-energy beams. These beams have penetrating power sufficient to reach intracranial lesions.