Principles of Radiation Therapy

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CHAPTER 248 Principles of Radiation Therapy

Carryn Anderson, John Bayouth, John M. Buatti

Radiation therapy continues to evolve, yet many of the basic principles underlying its application remain constant. In this chapter, we review the basic principles that form the foundation of radiation therapy, including descriptions of basic interactions with matter as well as the critical descriptions of biologic effects. We then review an ever-broadening array of devices that serve as sources for radiation delivery and discuss basic shaping mechanisms that are critical to modern radiation therapy. We include definitions of commonly used techniques such as conventional radiotherapy, conformal three-dimensional radiotherapy, intensity-modulated radiotherapy (IMRT), stereotactic radiosurgery (SRS), and stereotactic radiotherapy (SRT). Each treatment choice requires understanding of the basic principles of radiation therapy, with reference to the specific pathologic entity being treated, as well as of the specific advantages of a vast array of techniques that might be applied to a given case. The interaction of the radiation with normal neuroanatomy, as given by these techniques, provides an additional critical decision-making factor.

Treatment has evolved from low-energy, large-area cobalt or orthovoltage radiation treatment fields determined clinically with the use of plain radiographs or encephalograms to an arena in which high-energy linear accelerators are applied to high-resolution three-dimensional databases (magnetic resonance imaging [MRI] and computed tomography [CT]) that are directly linked to the actual patient (stereotactic or image guided). This evolution has challenged radiation oncologists and neurosurgeons to appropriately choose the best method of treatment for an individual patient among surgery, single-fraction radiosurgery, and a variety of multifraction techniques. To understand these shifts in standard practice recommendations and treatment methods, a working knowledge of the basic principles of radiation therapy is needed. We begin with a review of these basic principles.

Basic Principles of Radiation Therapy

Cellular Effects of Radiation

Radiation therapy uses ionizing radiation, which means that the radiation’s energy is sufficient to remove an electron from the outer shell of an atom (more than 124 electron volts).¹ In clinical therapy, photon radiation is most commonly generated by linear accelerators or gamma-ray sources that produce a range of ionizing photon energies. When a high-energy photon interacts with an atom, the atom becomes unstable and is more apt to react with surrounding atoms. With this simple model of ionizing radiation as background, and remembering that in many ways standard radiation sources or beams act like visible light, we can explain the effects of radiation on cells.

When ionizing radiation interacts with a cell, it can interact with any molecule in that cell, including lipids, proteins, sugars, DNA, RNA, or water; but statistically, the most likely interaction is the ionization of water because this is the most abundant molecule. This ionization creates unstable molecules that are apt to chemically interact with other nearby molecules. The most common of these unstable molecules is a free radical derivative of water (OH).

Although these reactions are inconsequential alone, they give rise to events in which a reactive water radical may interact with DNA. DNA is the critical target for cellular radiation effects. Damage to DNA creates genetic mutation, permanent cell injury, or death. Cellular enzyme complexes attempt to repair this DNA damage. Injury to intracellular molecules other than DNA is increasingly thought to play a role in a lethal cascade of cell activity that may end in cell death through apoptosis, necrosis, or nonlethal cellular events.

Evidence supporting that DNA is the most critical cellular target of radiation includes (1) genetic damage and specific chromosomal abnormalities after irradiation are correlated with cell death, (2) defects in cell DNA repair mechanisms increase radiosensitivity, and (3) selective irradiation of the cell nucleus as opposed to cytoplasm has mimicked the overall effect of radiation on cells.¹ This basic effect of irradiation on DNA and the cell’s subsequent repair underlie the observed biologic effects of conventional fractionated radiotherapy treatment.

There is an active interest in increasing application of particle therapy, specifically protons. As opposed to behaving like a light wave, protons deposit their energy at a specified depth over a more tightly defined area, or Bragg’s peak. The pattern of energy distribution of particle therapy (electrons and protons) compared with photon therapy (x-ray) is shown in Figure 248-1. Particles are charged and have physical properties that cause direct damage to the DNA (rather than through reactive water molecules). Their clinical advantage over photon therapy is in less dose to normal tissues, which may be especially important in children who are at risk for radiation-induced malignancy. Electron therapy is readily available on all linear accelerators and has been used clinically for decades; however, this modality is rarely used in central nervous system (CNS) malignancies. Proton therapy requires a multimillion dollar machine called a cyclotron and thus remains less commonly available and of uncertain, albeit promising, importance in years to come.^2,³

FIGURE 248-1 Energy deposition. The pattern of energy distribution of typical photon (x-ray), electron, and proton beams. The photon beam has a low entrance dose, builds up to a maximal dose at a shallow depth, and then loses energy in a gradual exponential fashion. The electron beam has a high entrance dose, maintains a relatively constant dose for depths of 1 to 6 cm depending on the energy, and then loses energy in a steep linear fashion, with a small residual dose-tail. The proton beam has a low entrance dose that remains low until the end of the particle’s travel, at which point most of the dose is deposited (Bragg’s peak), followed by very little dose beyond the depth of maximal dose. Proton beams with varying energy can be combined to treat objects of increasing thickness. A combination of beams from multiple angles is commonly employed in radiation therapy.

Therapeutic Ratio for Radiation

The cellular effects and molecular interactions of radiation occur in an unbiased way. Radiation ionizes molecules and damages DNA in any cell in its path, whether tumor cell or normal cell. Therefore, to have a therapeutic effect, radiation must gain selectivity to be advantageous. Practically, this is accomplished by biologic differences between tumor cells and normal cells (biologic effect) and by the physical characteristics of irradiation that permit selective deposition of radiation dose in tumor cells rather than the normal surrounding cells (technical selectivity). Both are critical in modern radiotherapy.

Biologic Selectivity

Normal tissue generally repairs DNA damage more efficiently than neoplastic tissue. Reasons may include metabolic differences, aberrant cell cycle control mechanisms, and inherent cellular differences. Cells require time to repair DNA damage, and the normal cell response to irradiation is to delay cell cycle progression in the G₂ phase.^4,⁵ The length of G₂ delay correlates with radiation resistance because the cell has more time to repair radiation damage.⁶

This enhanced repair capacity of normal tissue has been critically exploited by fractionated regimens with low doses of radiation (the total therapeutic dose is broken up into a series of small daily treatments). Because a high percentage of normal cells will repair damage at low doses of radiation and because neoplastic cells are less capable of efficient repair, the concept of fractionation of radiation is supported. Figure 248-2A demonstrates a schematic rendering of the effect of multiple fractions of 2 Gy on both normal tissues and tumor; the more fractions, the greater the therapeutic advantage. These principles were extended to hyperfractionated approaches (two or three small doses per day), although with limited success.⁷^–¹⁰

FIGURE 248-2 Radiation survival curves. A, Note that the early responding tissues (tumors) are relatively more sensitive to low doses of radiation compared with late responding tissues like the normal brain. This concept offers progressive therapeutic advantage with multiple small doses of radiation. B, As radiation dose per fraction increases, late responding tissues are at greater risk for damage than tumor tissues.

Another clinical observation is that more rapidly dividing normal tissues such as skin and oral mucosa are more acutely sensitive to the effects of irradiation than are late-responding or slowly dividing and nondividing tissues such as nerve tissue.^1,^11,¹² In contrast, late-responding tissues are more sensitive to large doses of radiation. Note that in Figure 248-2B, a large single dose of radiation is capable of greater injury to late-responding normal tissue than to the tumor.^11,¹³ Therefore, to take advantage of the inherent differential cellular capacity to repair sublethal doses of irradiation, multiple small doses of radiation have been recommended. This basic principle supports the biologic advantage of fractionation to selectively protect late-responding nerve tissues.

Technical Selectivity

Therapeutic advantage may also be achieved by depositing more radiation dose in the tumor target than in the normal tissue. A single-photon radiation beam entering a patient begins with a region of lower dose, termed the build-up region,¹⁴ and then progressively increases until it reaches the depth of maximal dose (Dmax) that is characteristic of the radiation beam energy (Fig. 248-3). This build-up region spares the skin from the highest doses of radiation. After the radiation beam reaches Dmax, the dose decreases with depth as it is attenuated (see Fig. 248-3). Much like shining a light into a dark field, the light becomes less bright the farther you move away from its origin as it becomes attenuated by air.

FIGURE 248-3 Depth dose curve. Note that the radiation beam dose deposition is lower at shallow depths until it builds up to a maximal dose (D Max). After this point the beam attenuates (falls off) with increasing depth. These characteristics are applicable to all megavoltage radiation beams that are used in clinical radiotherapy for brain tumors.

To achieve technical selectivity, several beams of radiation can be added together from several directions (Fig. 248-4). A single beam of radiation entering a patient is shown in Figure 248-4A. In this figure, a group of same dose, or isodose lines, is labeled as a percentage of maximal dose. The percentage of maximum decreases with depth owing to attenuation. When we put a tumor at the intersection of several beams of radiation oriented at divergent angles, the isodose lines are as shown in Figure 248-4B to D. Note that the tumor receives the highest dose, and areas outside the tumor now receive progressively less dose. As multiple beams are added together, the isodose lines become densely concentrated at higher percentages of maximum, as shown in Figure 248-4D. In considering these physical characteristics of radiation beams, these examples illustrate the capacity of multiple radiation beams to deliver a higher percentage of the radiation dose to the tumor, with progressively smaller areas of normal tissue receiving significant doses.