Principles of Radiation Therapy
Radiotherapy plays an integral role in the care of many gynecologic cancers and can be used for definitive management, adjuvant therapy, or palliation. The principal basis of therapeutic radiation lies in its ability to cause ionization, or the creation of free electrons and free radicals, when absorbed by biologic matter. These highly reactive chemical species interact with critical molecules in a cell (in particular deoxyribonucleic acid [DNA]) and, if unrepaired, lead to loss of cellular reproductive capacity and eventual cell death. Ionizing radiation can be emitted from radioactive isotopes, both naturally occurring and man-made, or created using specialized high-voltage but nonradioactive equipment such as linear accelerators.
Optimal radiation for gynecologic malignancies often combines both teletherapy (external beam radiotherapy) and brachytherapy (internal radiation) with careful clinical judgment required to determine the proper weighting of each component. The challenge in radiation delivery is to deliver intended full dose(s) to selected target(s), while minimizing exposure to adjacent normal tissues. Sophisticated developments in imaging, computer-based treatment planning, and linear accelerator technology provide for ever-greater sophistication and accuracy in radiotherapy. However, such precision in dose delivery has to be accompanied by improvements in patient set-up immobilization, reproducibility, and regular tumor tracking to prevent marginal misses of the intended target volume. Advances in radiotherapy for gynecologic malignancies will be based on further integration with systemic agents (for both spatial cooperation and chemosensitization), as well as developments in targeting, tracking, and adaptive processes, featuring radiation plans that may be modified during a course of therapy to conform to changes in patient and tumor geometry.
FUNDAMENTALS OF RADIATION PHYSICS
Structure of Matter
All matter is composed of individual units called elements. Each element is defined by the physical and chemical properties of its basic component—the atom. The atom consists of a central core, the nucleus, made up of positively charged particles, called protons, and neutrons, which have no charge. The nucleus is surrounded by a “cloud” of negatively charged particles, or electrons, which move in orbits around the nucleus. In the basic “resting” state of an atom, the number of protons in the nucleus is equal to the number of orbiting electrons, making the atom electrically neutral.
The formula is used to identify each atom. X is the chemical symbol for the element, A is the mass number or number of nucleons (the number of neutrons and protons in the nucleus), and Z is the atomic number (the number of protons in the nucleus). The number of protons (Z) in an atom determines its chemical properties and its elemental name. Within the periodic table of elements, as Z increases, the number of accompanying neutrons increases proportionately more (ie, A:Z ratio > 2) to maintain nuclear stability. Atoms with the same Z, but with different numbers of neutrons, share the same element name and chemical properties but are called isotopes. When the A:Z ratio varies from the baseline (or lowest energy) form, these isotopes are often unstable and seek to achieve nuclear stability by giving off excess energy in the form of radiation, and are thus called radioisotopes (or radionuclides).
Hydrogen, carbon, oxygen, and nitrogen are the main elements that make up the human body. Each has a relatively small atomic number and mass number. The neutron-to-proton ratio for each of these elements is unity, and each exists at baseline in an electrically neutral and stable configuration.
The mass of subatomic particles is measured in terms of the atomic mass unit (AMU). An AMU is defined as one-twelfth of the mass of the carbon atom. In metric units of mass, . The mass of a proton is 1.00727 AMU, and that of a neutron is very similar at 1.00866 AMU. Electrons are significantly smaller, with a mass of 0.000548 AMU.
According to the atomic model proposed by Niels Bohr, the negatively charged electrons revolve around the positively charged nucleus, held in place by Coulombic force of attraction, in fixed orbits at specific distances from the nucleus. Electron orbits are referred to as shells, with the K shell being the inner most shell, followed radially by the L, M, N, and O shells. The maximum number of electrons in an orbit is defined as 2n2, where n is the integer specific to each shell and called the principle quantum number. In reality, the actual configuration and location of orbital electrons are rather complex and dynamic; however, this simplified model provides for an understanding of the basic concepts of atomic structure.
Electron orbits can also be considered as energy levels within an atom. When an electron moves to an orbit closer to the nucleus, energy is released. For an electron to move to an orbit farther from the nucleus, energy is required. The energy required to remove an electron completely from an atom (or ionization) is termed the binding energy of the electron. The binding energy of the electron depends on the magnitude of the Coulomb force of attraction between the nucleus and the electron. The binding energy for the higher Z atoms is greater because of the greater nuclear charge. Additionally, the binding energy is greater for electrons closer to the nucleus. However, on average, removal of an electron from an orbit requires 33 to 35 eV, where 1 eV, or electron volt, is defined as the kinetic energy acquired by an electron in passing through a potential difference of 1 V. This 33 to 35 eV range reflects the minimum amount of energy that an incident beam of radiation, or photon, must have to cause ionization.
Types of Radiation
The different forms of radiation are usually categorized into 2 groups: electromagnetic and particulate.
Electromagnetic radiation exists on a spectrum and is defined by its energy, or corresponding wavelength. In general order of increasing energy, the electromagnetic spectrum includes radio waves, microwaves, infrared, visible light, ultraviolet, and x-rays and γ-rays. All radiation within the electromagnetic spectrum has the same velocity (the speed of light, or 3 × 108 m/s). Although electromagnetic radiation has no mass or charge, it exists in a duality that can be considered either as a waveform (expressed as wavelength or frequency) or as packets of energy called photons (expressed as eV). These 2 properties of photons can be readily converted from one form to another using the following equation:
where E is the photon energy (eV), v is the frequency of the radiation (s–1), and h is Planck’s constant (4.1357 × 10–15 eV • s).
The frequency and wavelength of a photon are inversely related, with the correlation given by:
where v is the frequency of the radiation (s–1), c is the speed of light (3 × 108 m/s), and λ is the wavelength (m).
As the wavelength of the photon becomes shorter, the frequency increases in inverse proportion. Hence, electromagnetic radiation of shorter wavelengths has higher energies. For the purposes of radiotherapy, it is only the photons that have sufficient energy to overcome the binding energy of electrons in biologic matter that are of specific interest; these are the ionizing x-rays and the γ-rays that exist in the higher energy portion of the electromagnetic spectrum. The lower energy forms of electromagnetic radiation do not cause ionizations but can result in heat and/or light, which are usually considered less injurious to biologic matter. Typically, electromagnetic radiation is considered to be ionizing when the photon energy exceeds 124 eV (or has a wavelength < 10–8m).
There are no intrinsic differences in characteristics between x-rays and γ-rays—their names refer only to the specific photon source. Gamma rays (γ-rays) arise from within the nuclei of radioactive atoms, whereas x-rays come from extranuclear sources. In general, γ-rays are emitted from radioactive isotopes as they decay, whereas x-rays are produced “artificially” in high-voltage equipment, via bombardment of a target with high-speed electrons. Otherwise, they share the same physical properties and, if of similar energy, result in identical biologic effects.
Particulate radiation can be charged (electrons, protons, helium ions, carbon ions) or uncharged (neutrons). The charged particles have a defined and finite depth of penetration in matter, determined by their incident energy. This characteristic is exploited clinically to limit dose to the target range, sparing tissues beyond a specified depth. Of these particulate types, only electrons are commonly used in clinical radiotherapy for gynecologic cancers, although proton radiotherapy is an emerging technology that holds promise for ultraprecise delivery of radiation.
Radioactive decay is a phenomenon in which radiation is given off by the nuclei of elements. As previously mentioned, certain combinations of protons and neutrons are less stable than others for a given element, with heavier elements requiring a specific neutron-to-proton ratio greater than 1 (or ) for maximal stability. When the A:Z ratio varies from the explicit baseline (or lowest energy) form, these isotopes (whether naturally occurring or artificially created by bombardment with neutrons in a reactor) are often unstable and seek to return to stability by nuclear disintegrations that result in the emission of ionizing radiation. This process is known as radioactive decay, in which a “parent” radioisotope achieves a more stable form by transforming to a lower energy “daughter” isotope of the same atom (same Z), or even to a completely different element (different Z). In general, the elements with high atomic numbers tend to be “naturally” radioactive, and all elements beyond lead (with a Z of 82) are radioactive, even if the decay rate is so slow as to be undetectable except with the most sophisticated equipment. However, any element, if bombarded with neutrons to perturb its baseline A:Z ratio, can be rendered radioactive, such as tritium (hydrogen 3) or carbon 14.
A common concept used in describing radioactive decay is the half-life (T½), which is the time required for half the atoms of a specific parent radioisotope to have transformed into its daughter nuclide. The daughter nuclide, in turn, could be stable or remain unstable with further nuclear disintegrations, resulting in its own subsequent T½ of decay. A related concept is the “activity,” or the number of disintegrations per second of a given amount of a specific radioisotope. The greater the activity, the shorter the T½, as the parent radionuclide is transformed more rapidly. The half-lives of radioisotopes vary tremendously and can range from femtoseconds (10–15 seconds) to billions of years.
There are 3 distinct types of radiation emitted by radioactive decay: α-particles, β-particles, and γ-rays. Each nuclear disintegration of a radioisotope can result in the emission of 1 or more of these types of radiation. Alpha decay occurs when the ratio of neutrons to protons is lower than the stable baseline, particularly in radio-nuclides with atomic numbers above 82. The emitted particle in α decay is a helium nucleus (2 protons and 2 neutrons) with a positive charge. These α-particles are relatively “heavy” and of low kinetic energy, such that their effective range is at most only a few centimeters of air or a few millimeters of tissue. In β decay, a β-particle is emitted; it typically has a negative charge and is also known as an electron. The distance range of electrons from nuclear decay is variable, depending on the kinetic energy with which they are ejected. Sometimes, the β-particle has a positive charge, and is then called a positron. Because positrons are readily attracted to surrounding negatively charged electrons in matter, they travel very short distances (typically < 1 mm) before reacting (or annihilating) with an electron, producing a pair of opposing 511-eV photons that can be detected by specialized scintillators. This forms the basis for positron emission tomography (PET), where fluorine 18, a positron emitter, is used to label glucose uptake in tissues. Finally, γ decay occurs when a nucleus undergoes a transition from a higher to lower energy state and a high-energy photon (or γ-ray) is emitted. The penetration capability of the γ-ray in tissue is dependent on the specific energy of the photon; these γ-rays can be used for diagnostic or therapeutic purposes.
The “hotness” of a radioisotope is a complex function of nuclear activity (disintegrations per second), the type(s) and energy of radiation emitted by that specific isotope, and the distance at which the radioactivity is measured.
Inverse Square Law
The inverse square law is represented as:
where I is the intensity of radiation (or a force such as gravity) and d is the distance from the source of the radiation (or force).
When applied to ionizing radiation, the inverse square law strictly applies only to electromagnetic radiation (not to particulate radiation) and where the origin of radiation is a “relative” point source in relation to the distance at which the radiation is measured. When these conditions are met, it means that an increase in the distance from a radiation source results in a proportionately greater decrease in the radiation exposure. For example, doubling the distance from a radiation point source would result in only one-quarter of the dose at the original distance. When the radiation source is not at a “point” relative to the distance at which dose is measured (eg, when calculating vaginal mucosal and paravaginal doses with brachytherapy using a “line source” in the cylinder), the inverse square law does not hold, and the exposure may then be more proportional to 1/d. Nonetheless, the impact of distance on dose remains, and this concept is critical in helping design shielding for rooms housing linear accelerators and/or brachytherapy radioisotope sources. It also explains why, when handling radioisotopes, that in addition to shielding, long-handled equipment is used where possible to maximize source distance and minimize dose exposure.
Interaction of Radiation With Matter
Electrons carry a negative charge and have mass. As a result, they rapidly interact with other electrons found in matter, resulting in rapid transfer of energy, ionization of atoms, and a relatively short, finite range (typically up to a few centimeters), depending on the energy of the incident electron.
When photon radiation enters matter, it is possible that it will pass through without interaction, or it may interact in 1 of several ways, including photoelectric effect, Compton effect, and pair production. In clinical radiotherapy, with the contemporary clinical use of high-energy, megavoltage photons, Compton effect is the dominant interaction of ionizing radiation with biologic matter.
In Compton interaction, the photon interacts with an orbital electron, where it provides enough energy to overcome the binding energy of the electron to the nucleus and further transfers additional kinetic energy to the “free” electron, which is then emitted from the atom. The photon is likewise deflected but continues with reduced energy and may react with additional electrons in a similar fashion along its new path, as long as it has sufficient residual energy to overcome the binding energies of other electrons. Figure 19-1 depicts the Compton effect, which thus results in ionization of biologic molecules and the production of fast electrons. The electrons produced by the Compton effect can also go on to cause further ionization of additional atoms by interacting with other orbital electrons.
FIGURE 19-1. The Compton effect. (Reproduced, with permission, from Khan FM. The Physics of Radiation Therapy. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:60, Figure 5.7.)
Ultimately, the primary basis of ionizing radiation is the production of these free electrons and ions, which are highly reactive and energetic. These ultimately react with important biologic molecules, especially DNA, and result in disruption of vital chemical bonds that may lead to cellular damage and death.
An important consequence of the Compton effect is that its interaction with matter is nearly independent of the atomic number (Z) of the absorbing matter. This is in contrast to the photoelectric effect, which prevails in lower energy photon–matter interactions, where absorption is proportional to Z3. Diagnostic radiology uses lower energy photons (in the kilovoltage range), where photoelectric effect is significant, such that heavier elements (eg, calcium in bones) absorb much more radiation than soft tissue, giving rise to the characteristic tissue contrasts seen in radiographs. However, for therapeutic radiation, preferential absorption by bone (eg, the pelvic girdle in gynecologic cancers) would be detrimental. The relative independence of radiation absorption with respect to Z for the Compton effect (which predominates in megavoltage radiotherapy) means that although a radiograph taken with higher energy photons has reduced contrast, the absorbed dose is very similar in soft tissue, muscle, fat, and bone and, as such, allows better dose delivery to central pelvic structures.
Units Used in Radiation Oncology
Historically, the unit for radiation exposure has been the roentgen (R), defined as the amount of x-rays or γ-rays required to liberate positive and negative charges of 1 electrostatic unit of charge in 1 cubic centimeter of air. With the advent of Système International d’Unités (SI units), the roentgen is no longer used, and exposure is now expressed as coulomb per kilogram (C/kg), which is equivalent to approximately 3876 R. The SI-based definition for absorbed dose in tissue is measured in joule per kilogram (J/kg), which is also known as gray (Gy). As a unit of energy, 1 J is equal to 6.24 ×1018 eV. Rad had previously been used for absorbed dose and was equivalent to 0.01 J/kg. Hence 1 Gy equals 100 rad, and thus, the units centigray (cGy) and rad are often used interchangeably.
For radioisotopes, activity describes the number of disintegrations per unit of time interval. Curie (Ci) had been the historical unit of activity and was based on the number of nuclear events in 1 g of radium 226 (3.7 ×1010 disintegrations per second). Becquerel (Bq) is the SI unit now used for activity and is equal to 1 nuclear disintegration per second of any given radionuclide .
Radiation Damage in Biologic Matter
Radiation biology is the study of the effects of ionizing radiation on biologic systems. The most important biologic effect of radiation appears to result from DNA damage, which can result in genetic mutations, chromosome aberrations, disturbed cell proliferation patterns, cell death, neoplastic transformation, or teratogenesis.
As previously mentioned, when radiation (in particular photons or electrons) enters a biologic system, it results in creation of kinetically energized free electrons (ionization). These electrons ultimately impact the cell by disrupting vital chemical bonds, either directly or indirectly via a cascade of free radical formation.
In direct action, the free electron (eg, produced via Compton effect) itself results in ionization of the nearby DNA strand, thus leading to DNA molecular damage. For x-rays or γ-rays, this accounts for only about one-third of the DNA damage produced. In indirect action, the electron interacts with water molecules (which comprise the vast majority of a cell volume), which become ionized as follows: . The H2O+ ion radical has a relatively short lifetime, on the order of 10–10 seconds, but can react with surrounding water molecules to form additional free radicals . These added free radicals, particularly the hydroxyl radical (OH·), are highly reactive and have a longer lifetime of about 10–5 seconds, so they can diffuse some distance to the DNA and cause damage. Indirect action is estimated to account for two-thirds of the DNA damage produced by x-ray or γ-rays. Because of its “lengthier” course, indirect action is also the component of biologic effect that can be modified by chemical sensitizers and protectors. Figure 19-2 depicts both direct and indirect action of free electrons produced by ionizing radiation. This DNA damage occurs through physical and chemical processes that occur in fractions of seconds. If unrepaired, it then leads to a cascade of biologic events that may take hours, days, months, years, or even generations to be expressed.
FIGURE 19-2. Direct and indirect action of free electrons created by ionizing radiation. (Reproduced, with permission, from Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:9, Figure 1.8.)
Biologic Effects of Radiation: Repair and Cell Death
There is strong laboratory evidence that DNA is the principal target for the biologic effects of ionizing radiation. DNA is a very large and long molecule, which consists of 2 complementary strands of sequential bases held together by an alternating sugar and phosphate “spine,” entwined in a double helical structure. Primarily, damage from radiation results in strand breaks in the DNA spine or backbone, although the induction of abnormal cross-links between DNA strands or between DNA and nuclear proteins can also play a role in the loss of normal replication and transcription. DNA strand breaks can be either single- or double-stranded. Single-stranded breaks are considered of little biologic consequence because they can be repaired readily using the opposite strand as a template, assuming no disruption of normal cellular repair mechanisms. Additionally, breaks in both strands that are well separated in the nucleotide base sequence are also readily repaired as independent breaks. However, DNA strand breaks that are directly opposite one another or separated by only a few base pairs lead to double-strand breaks, which are more difficult or impossible to repair and can result in the separation of the chromatin into 2 or more pieces.
It may be noted that cells are generally very efficient at repair of DNA damage, even with double-strand breaks, using a variety of repair pathways and enzymes. However, a great number of double-strand breaks can overwhelm a cell’s repair processes. Individuals with defective DNA repair mechanisms, such as in ataxia telangiectasia, are more vulnerable to the effects of ionizing radiation. Cancer cells themselves often have mutations that can impact their DNA repair pathways; this increased susceptibility to unrepaired DNA double-strand breaks, as compared to normal cells, is one of the factors exploited with radiotherapy.
Unrepaired fragmented chromatin ends may reassort and rejoin other broken ends to give rise to grossly distorted structures or may fail to rejoin, ultimately giving rise to chromosomal aberrations. Several of these aberrations are lethal to cells. Others are not lethal but can lead to carcinogenesis and other mutations.
When exposed to a dose of ionizing radiation, a cell may survive or die. For nonsurviving cells, death while attempting to divide, known as mitotic or reproductive death, is the dominant process. In this case, the unrepaired DNA/chromosome damage in the parent cells does not allow creation of viable progeny cells. Other mechanisms of inactivation include apoptosis or programmed cell death (typically seen in lymphoid cells) and cellular senescence. Nevertheless, the most important end point for radiation-induced lethality is mitotic death, or the cell’s loss of reproductive capability. The hallmark of a cancer cell is its immortalization, or the ability to continuously proliferate. Using this definition of cell kill, a tumor cell may remain physically and morphologically intact for some time, but if it ultimately dies at the time of attempted mitosis, it has lost its reproductive integrity and is no longer clonogenic.
Cell death, or conversely, survival, following exposure to ionizing radiation is often described by means of a cell survival curve. For a single cell type population, typically determined in vitro, the cell survival curve is represented on a semi-logarithmic scale, where the x-axis represents radiation dose and the y-axis denotes the log of the proportion of surviving cells (Figure 19-3). This is described as a linear-quadratic model of cell survival. As noted earlier, cell death is linked to the frequency of unrepaired DNA double-strand breaks and chromosomal aberrations. At very low doses, both strand breaks may be caused by the same electron, in which case the probability of chromosomal disruption and cell death is linearly proportional to the dose. However, at higher doses, the 2 double-strand breaks are more likely to result from 2 separate electrons acting independently and stochastically, in which case the probability of an interaction is proportional to the square of the dose. The linear-quadratic cell survival curve is a simplified but useful model for evaluating radiation effects on proliferating cell systems and is described mathematically as:
FIGURE 19-3. Linear-quadratic cell survival curves for tumor and early-responding tissues compared to late-responding tissues.
where S is the surviving fraction of cells, D is the dose of radiation delivered, α is the linear component of ionizing radiation cell kill, and β is the quadratic component of ionizing radiation cell kill.
The α and β values used in the linear-quadratic cell survival curve model vary by cell type and are measures of the DNA repair capacity of that cell. A high α means that for a given dose of radiation, there is less repair compared to cells with a high β. Because these 2 components of repair exist to a variable degree in most cells, this repair capability is often expressed as the ratio α/β. Cellular systems with high α/β ratios have a “steeper” cell survival curve, indicating less repair, and thus greater cell kill, for a given radiation dose than cells with lower α/β ratios. In general, tumors and acute-responding, rapidly cycling normal tissues (eg, hematopoietic cells, skin, hair follicles, and gastrointestinal mucosa) are considered to have high α/β ratios, approximating 10, whereas late-responding normal tissues (eg, visceral parenchyma and stroma) have lower α/β ratios of approximately 3. This difference in α/β ratios, representing the differential repair of tumor and various tissues to the effects of ionizing radiation, is critical and is exploited when using a course of fractionated radiotherapy of multiple lower-dose applications, rather than a single large dose of radiation (Figure 19-4). During fractionated radiotherapy, assuming sufficient time between doses to allow for repair, the initial slope of the cell survival curve is reprised with each subsequent dose of radiation. This allows the relatively small differences in the single-fraction cell survival curves to be magnified over a protracted course of radiation, allowing greater sparing of late-responding, dose-limiting tissues relative to tumor. Although fractionation may provide relatively little sparing of early-responding tissues, acute toxicity in clinical practice is often supported by compensatory proliferation and migration of neighboring cells from outside the radiation field. The linear-quadratic model and α/β ratios can also be used to “convert” one dose fractionation scheme to its biologic equivalent using a different fraction size.
FIGURE 19-4. Effect of dose fractionation on radiation cell survival. As compared with single large doses, fractionation magnifies the difference in survival, or “sparing,” of late-reacting normal tissues relative to tumor.
A similar corollary to radiation dose size on cell survival, and the relative sparing impact of fractionation, can be seen for the effect of radiation dose rate (Figure 19-5). This is particularly germane in the use of brachytherapy sources.
FIGURE 19-5. Effect of dose rate on radiation cell survival. For a given dose, a higher dose rate results in greater cell kill than lower dose rates.
Beyond ionization, DNA double-strand breaks, and cellular repair capacity, several other factors impact on the biologic effects of radiation. All proliferating cells, including tumors, travel through the cell cycle, with phases that have been defined as mitosis (M), gap1 (G1), DNA synthesis (S), and gap2 (G2). The nature of the DNA molecule itself, the presence of cell cycle checkpoints to accommodate repair time, and the relative levels of repair, replicative, and transcriptive enzymes vary during the course of the cell cycle. In general, cells are considered most radiosensitive in M and late G2 phases, but are most resistant during the S phase. The presence of oxygen during radiation has profound impact on the subsequent biologic effects. It has been postulated that oxygen prolongs or perpetuates the free radical process initiated by ionization, leading to an approximately 3-fold increase in radiosensitivity in the presence of oxygen (known as the oxygen enhancement ratio) compared to hypoxic or anoxic conditions. Because many tumors have aberrant vasculature and regions of hypoxia, the study of oxygen effect on ionizing radiation, as well the potential to enhance tumor oxygenation during radiotherapy, has commanded a significant proportion of basic and clinical research efforts over the past few decades.
Much of the biologic effects of ionizing radiation described earlier relate to low linear energy transfer (LET) radiation, which include photons, electrons, and also protons. High-LET radiation, such as neutron and carbon ions, causes very dense ionization trails in biologic matter, which result in decreased DNA repair and reduction of both the cell cycle and oxygen effects. However, the expense, lack of broad clinical benefit, and often unacceptable normal tissue injury (because reduced repair affects both tumor and normal tissues) of high-LET radiation have led to very limited clinical use and applicability.
Genetic Effects of Radiation and Radiation’s Impact on the Human Reproductive Process
In distinction to the reproductive or mitotic cell death in any tissue that can be induced by ionizing radiation, it also has direct impact on the human reproductive system. These effects can take the form of reduction or ablation of fertility or germline mutations that can be transmitted to future, yet unconceived offspring, or they can affect a developing embryo or fetus in a pregnant woman.
In women, the ovarian dose associated with permanent sterility is age-dependent, reflecting the maximum number of oocytes present at birth (with no further production) and accelerated decrease following the onset of menarche. In the prepubertal female, a radiation dose of 12 Gy or more is generally required to cause sterility, whereas a dose of only 2 Gy may cause the same consequence in a premenopausal woman. Unlike in men, ovarian gonadal function is tightly linked to hormonal production, such that the same doses that cause permanent sterility also result in menopause.
If the female is not rendered infertile, radiation can cause nonlethal damage and mutations in oocyte DNA that may be inherited by subsequent generations, resulting in heritable, or genetic, diseases in offspring. It is important to remember that genetic mutations occur with some baseline frequency in the general population, independent of any radiation, and that not all mutations result in clinically apparent disease. Ionizing radiation does not result in unique or bizarre heritable diseases, but rather increases the frequencies of the same genetic mutations that already occur spontaneously. Hereditary diseases can be classified as single gene–based (eg, Huntington chorea and sickle cell anemia), chromosomal (eg, Down syndrome), or multifactorial (eg, neural tube defects, cleft lip). Information on the added hereditary effects of radiation exposure comes almost entirely from animal experiments; based on mouse data, the dose required to double the spontaneous germ cell mutation rate is approximately 1 Gy (100 cGy).1
The effect on ionizing radiation on an existing embryo or fetus depends on its gestational stage. In the first week to 10 days following fertilization and zygote formation (preimplantation phase), doses as low as 10 cGy can result in loss of the embryo. However, if the embryo survives, it may then develop normally, with few consequences (hence termed an “all-or-nothing” effect). Radiation exposure during the period of organogenesis, from approximately weeks 2 to 6, results in the highest likelihood of congenital malformations (teratogenesis), neonatal death, and growth retardation. After approximately week 6 (fetal stage of gestation), radiation can lead to permanent growth retardation and also mental retardation, as the central nervous system matures later in utero. Although the effect of radiation on the embryo and fetus is dose dependent, there is no threshold dose below which ionizing radiation can be stated to have no impact. Thus, the use of medical radiation in a pregnant patient should be avoided whenever possible or, if absolutely required, be given only after a full discussion of risk and informed consent. Although controversial, it has been suggested that 10-cGy in utero exposure, at least during the early first trimester, be used at the cutoff point beyond which a therapeutic termination of pregnancy should be considered.
Beyond 20 to 25 weeks (third trimester), low doses of radiation to the fetus may be “relatively” safe, although some have reported an increase in childhood malignancies. Obviously, pelvic or abdominal radiotherapy, as is used in gynecologic cancers, results in an unacceptably high dose to the fetus and would be associated with spontaneous abortion or require an evacuation. However, there are many case reports and small series of successful and healthy infant deliveries following radiotherapy to other sites during late pregnancy (eg, for breast cancer or supradiaphragmatic lymphomas). Careful blocking and patient set-up to limit scatter dose to the uterus, medical physics consult to optimize shielding and dose monitoring, and patient informed consent are clearly required.
Ionizing radiation has been shown to cause an increased risk of both solid tumors and hematologic malignancies. The induction of secondary cancer is considered to be a stochastic effect, that is, the probably of occurrence increases with dose, but there is no threshold dose, and the severity of the malignancy, once induced, is independent of the dose. The risk is also age dependent; younger patients may have developing tissues that are more susceptible to radiation carcinogenesis and may have a longer life span in which to manifest the secondary malignancy. There is often a long interval between exposure to radiation and the appearance of the induced malignancy. The shortest latencies are seen in leukemias, which may occur 5 to 7 years after radiation, whereas secondary solid cancers may take 10 to 40 years or more to develop. Radiation-induced malignancies also tend to appear at the same age as spontaneous malignancies of the same type.
Risk estimates of secondary malignancy after therapeutic radiation are somewhat controversial because patients undergoing radiation are often already at a higher risk of developing a second cancer based on lifestyle and/or genetic predisposition. However, studies do indicate that there is an increased risk of radiation-induced malignancies in cancer patients, regardless of underlying biases. Fortunately, the absolute risk of secondary malignancy induction by ionizing radiation is very low. In a recent large-population analysis of more than 485,000 irradiated patient survivors from the US Surveillance, Epidemiology, and End Results (SEER) database, it was estimated that therapeutic radiation resulted in a risk of 3 and 5 excess cancers per 1000 individuals at 10 and 15 years, respectively, after diagnosis and treatment. Germane to the field of gynecologic oncology, radiotherapy did result in a small risk of induced secondary malignancies in patients treated for cervical cancer (hazard ratio [HR], 1.34) and endometrial cancer (HR, 1.14), but this risk disappeared in patients radiated when they were 60 years of age or older.2
Up to about 1950, most external beam radiation was primarily carried out with x-rays generated from kilovoltage machines. These low-energy x-rays suffered from poor penetration for deeply seated tumors and resulted in excess dose deposit on the skin surface, as well as in bones (high photoelectric component of photon interaction). Indeed, skin toxicity was often the limiting factor in delivering adequate doses of kilovoltage therapeutic radiation.
The introduction of cobalt 60 (60Co) therapy units in the 1950s represented a big step forward in radiation oncology. 60Co, a radioactive isotope that is artificially created by neutron bombardment of the stable cobalt 59 in a reactor, undergoes nuclear decay with the emission of 2 clinically useful γ-rays of 1.17 MeV and 1.33 MeV and a half-life of 5.3 years. 60Co radiotherapy units allowed the first routine use of megavolt-age photons, with improved depth dose penetration, skin sparing, and abrogation of excessive bone absorption (via high-energy Compton effect). Other advantages of the 60Co units were the relatively constant beam output, lack of day-to-day output fluctuations, well-defined half-life allowing for predictable decay, and introduction of an isocentric gantry system, in which the radiation source rotated about a stationary patient. However, the quest for even higher energy photons, the poor dose homogeneity for large fields, the need to replace the radioactive 60Co isotope every 4 to 5 years, strict Nuclear Regulatory Commission requirements for shielding and securing of a source that cannot be “turned off,” and costly licensing fees have led to its widespread replacement by linear accelerators (at least in developed countries) over the past 2 to 3 decades.
The linear accelerator (linac) has now become the dominant radiotherapy treatment unit (Figure 19-6). It is a megavoltage machine and uses high-frequency electromagnetic waves to accelerate electrons to high energies through a linear tube, with the electron energy determined by the strength of the accelerating electromagnetic field. The units used to determine the energy of the produced radiation are MeV for electrons and MV for photons—both units refer to the millions of volts in electrical potential difference that is created for electron acceleration in a linac. The accelerated high-energy electron beam can be used by itself for treating superficial tumors, or it can be made to strike a metal target (typically tungsten), within the accelerator head, to produce x-rays for treating deeper tumors. This type of machine is often referred to as a multimodal linac because it can provide multiple electron beam energies (6-25 MeV), as well as 2 or 3 x-ray energies (6, 10, and 18 MV). The effective source of radiation in a linac is mounted on a gantry and can rotate 360° around a stationary patient. The point around which the gantry rotates is called the isocenter. It is typically sited in a patient within a tumor volume so that the target can be readily radiated from multiple different directions.
FIGURE 19-6. A contemporary linear accelerator (linac). Note that the gantry is mounted on a rotational mechanism that allows it to completely rotate about an isocentric point. Opposing the gantry is the electronic portal imaging device (EPID), which allows capture of digital radiographic portal images, predominantly emphasizing bony anatomical landmarks. Perpendicular to the gantry/EPID axis is a computed tomography (CT) imager and detector set, which allows for 3-dimensional cone beam CT (CBCT) of specified soft tissue targets for enhanced image-guided radiotherapy.
Within the accelerator tube, electrons are accelerated to extremely high speeds (and energies) via an electromagnetic microwave field. As the high-energy electrons emerge from the accelerator structure, they are monoenergetic and in the form of a pencil beam of about 3 mm in diameter. To produce x-rays, which are the most commonly used form of ionizing radiation, the electrons are directed toward a water-cooled metal target, typically consisting of tungsten. As the electrons “crash into” the tungsten target, they lose energy, resulting in the production of a spectrum of x-rays with a range of different energies, but with the maximum photon energy equal to the incident electron energy. These x-rays are typically referred to as Bremsstralung radiation, which results from the “braking,” or rapid deceleration, of the high-energy electrons on encountering the metal target. The average photon energy of the beam thus created is approximately one-third of the monoenergetic incident electron energy. Photon energy is designated as MV because of its heterogeneous energy; the MV refers to the maximum photon energy. If electrons, rather than x-rays, are selected for clinical use, the tungsten target of the linac is withdrawn. Instead, as the thin electron beam exits the accelerator structure, it is made to strike a scattering foil to widen the beam to a clinically useful dimension and to get a uniform electron fluence across the treatment field. Electron beam energy is designated by MeV because it is monoenergetic.3
The treatment head of a linac also contains the collimation (or aperture) system for defining, or “shaping,” the radiation beam. The primary collimator is created by pairs of heavy metal jaws (or blocks) that move in perpendicular directions, thus determining the length and width of the radiation field. Previously, secondary collimation to further shape the radiation beam into asymmetric shapes was achieved by poured blocks that were then mounted on the outside of the gantry head. New linacs have built-in secondary collimation that consists of multiple thin leaves, which can be designed to achieve the desired geometry of almost any radiation field shape. This system of multiple-leaf collimators (MLCs) now allows near-infinite computer-assigned positions that can remain static during a radiation exposure or can change shape in real time and, when coordinated with gantry and patient couch rotations, produce highly dynamic, conformal dose delivery such as with intensity-modulated radiation therapy techniques.
A treatment simulator is an apparatus that uses diagnostic x-rays to display the treatment fields so that the target volume may be appropriately encompassed without delivering excessive radiation to the surrounding normal tissues. It duplicates the physical set-up characteristics of the linac itself, in terms of isocentricity and the ability to recreate patient and treatment machine alignments. Historically, simulators were based on fluoroscopic units, with plain radiographs obtained of the region to be treated. Areas to be avoided were then defined on the 2-dimensional films, which were then used as a template for cut blocks to shape the radiation beam. Today, computed tomography (CT) scans have almost completely replaced fluoroscopic simulators in developed countries. CT simulation allows the capture of more anatomic information and creation of 3-dimensional volumes that can be used to refine tumor coverage and normal tissue shielding.
Treatment of gynecologic cancer with radioactive material inserted against, or into, the tumor, has been used effectively for many decades. With rare exceptions, the radiation sources are not placed directly into the patient, but rather are contained indirectly within hollow, specialized applicators that are positioned within the target volume. Early applicators were preloaded with the radiation sources and were thus inserted “hot” into the patient, raising concerns for operator safety. Today, all gynecologic applicators are first inserted without radioactivity, allowing the clinician to take time to achieve optimal geometrical positioning. These hollow applicators are then “after-loaded” with the appropriate radioisotope, either manually (using long-handled equipment) or, increasingly, remotely by specialized machines.
The original radiation source used for gynecologic implants was radium 226 (226Ra). 226Ra itself does not produce any γ-rays appropriate for treatment. However, 226Ra undergoes nuclear decay and transforms into radon gas (radon 222 [222Rn]). The daughter products of the 222Rn actually produce the higher energy γ-rays necessary for effective treatment. Due to these properties, the radium, along with the radon, had to be encapsulated and sealed to produce a suitable brachy-therapy source. 226Ra is a rare, naturally occurring isotope with an extremely long half-life. Several tons of ore material have to be refined to obtain enough 226Ra for a single clinically useful source.
The typical activity for a 226Ra source is 10 to 20 mCi. This corresponds to a mass of 10 to 20 mg of radium by definition (because 1 Ci is defined as the activity, or number of disintegrations per second, of 1 g of 226Ra). Most treatments used between 2 and 5 sources, lasted about 48 hours, and were defined as low dose rate (LDR) brachytherapy. These 226Ra sources had to be hand loaded into the applicators, and the patient was confined to bed during the entire treatment.
Much of our understanding regarding radiation implants, from applicator geometry, dose and dose rate, tumor control probably, and normal tissue tolerance, is based on the historical use of 226Ra. However, the hazards of securing 226Ra and 222Rn and the disastrous consequences if the integrity of a source capsule is compromised became large-scale problems for institutions and regulators. Other radioisotopes were investigated as replacements, but with the intention of mimicking the geometry and dose distribution of 226Ra. With the advent of nuclear reactors, a good clinical substitute was found in cesium 137 (137Cs). This was a readily available reactor by-product refined from spent fuel rods. The sealed 137Cs sources, without a gaseous daughter molecule, were much safer than the 226Ra capsules. To recapitulate the size, shape, and activity of the 226Ra sources, 137Cs sources were calibrated in milligram-Ra-equivalent units (mgRaEq). For example, a 20-mgRaEq 137Cs source did not specifically detail the amount of 137Cs itself in the source; it was simply the amount of 137Cs that gave the same amount of dose and activity, at a specified distance, as the previously used 226Ra source. Because the size, shape, and activity of the 137Cs sources reprised those of its corresponding 226Ra capsule, the applicators generally were unchanged, and source loading and duration of treatment remained the same (ie, continued LDR brachytherapy).
The 137Cs supply has now become increasingly restricted due to decreased reactor production. Additionally, techniques have been developed, using remote afterloading equipment, to effectively treat patients in a much shorter time, removing the necessity of a prolonged hospital stay. This required a very high activity source and a shielded procedure suite. This method of implant radiation delivery has become known as high dose rate (HDR) brachytherapy. The source developed for HDR brachytherapy was iridium 192 (192Ir). 192Ir is activated inside a nuclear reactor, without having to disturb the fuel core or spent fuel rods. To accommodate outpatient-based HDR brachytherapy, a source would have to be highly radioactive, as well as suitably small, such that it could fit in small-diameter tubes. This combination of source attributes is defined by an isotope’s specific activity, which is the maximum achievable activity of an isotope per gram of material. The specific activity of 192Ir is 100 and 10,000 times that of 226Ra and 137Cs, respectively, allowing it to have a very compact size while maintaining high activity. For HDR brachytherapy delivery, the 192Ir source activity typically ranges between 4 and 10 Ci. For this activity range, 226Ra or 137Cs sources would have to be the size of grapes or larger, but 192Ir, with its high specific activity, can be constructed into sources that measure 4 to 5 mm in length and < 1 mm in width, making it eminently suitable for HDR systems. A comparison of the physical properties of the 3 radioisotopes historically and currently used for gynecologic brachy-therapy is provided in Table 19-1.
Table 19-1 Properties of Brachytherapy Isotopes Used in Gynecologic Cancer