Principles of radiation therapy and chemotherapy in gynecologic cancer: Basic Principles, Uses, and Complications

Radiation therapy principles

Radiation therapy is the safe clinical application of radiation for the local treatment of abnormally proliferating benign or malignant tumors. The principles of radiation physics and radiobiology underlying treatment are discussed, but several key therapeutic goals deserve mentioning first. The dose response of tumor cells after radiation treatment follows a sigmoid curve, with increasingly effective tumor cell kill or arrest of division associated with increasing dose ( Fig. 28.1 ). A similar treatment response exists for normal tissues, and the ability of radiation therapy to control malignancy depends on the greater tolerance of normal tissues to radiation exposure and a diminished capacity of cancer cells to recover from radiation-induced damage. Thus if one were to treat up to the total radiation dose that causes no normal tissue damage, only a small proportion of a tumor would be controlled by radiation-induced damage. Conversely, if one were to treat to a total dose that could eradicate almost the entire tumor, irreparable damage to normal tissue would often occur. This would lead to an unacceptable series of complications or even patient death after radiation treatment. The therapeutic goal of radiation therapy is to balance attempts at maximum local tumor control while minimizing adverse symptoms of treatment and normal tissue damage. Basic radiation therapy principles are detailed throughout the chapter but briefly include the following ( ):

• Fractional cell kill: Each radiation dose kills a constant fraction of the tumor cell population. Tumor cell kill follows a linear-quadratic relationship with the potential for cell-mediated repair of radiation-induced damage between radiation dose fractions.

• Radiation dose rate: Large radiation doses per fraction produce the greatest number of tumor cell kills; these same large radiation doses also produce the greatest damage burden on normal tissues, leading to early and late adverse complications.

• Radiation resistance: Although all tumor cells are sensitive to the effects of radiation, select malignant tumor cells show reduced radiosensitivity, resulting in slow tumor regression or renewed tumor repopulation during or after radiation treatment. Radiation resistance is associated with (1) enhanced cell-mediated repair of radiation-induced damage, (2) active concentration of chemical radioprotectors, or (3) cellular hypoxia or nutritional deficiency.

• Cell cycle dependency of cell kill: Actively proliferating tumor cells are most often killed by radiation therapy. Ionizing radiation imparts its greatest cell kill effect during the mitotic phase (M phase) and, to a lesser extent, during the late Gap1 phase and early DNA synthesis phase (G ₁ /S). Radiation has little effect during the late synthetic phase (S phase). Before each phase of the cell cycle, genomic integrity is monitored; if found intact, a cell then progresses through the next phase. If, however, genomic damage is detected, a cell arrests the cell cycle so that the damage may be repaired. If the normal monitors of genomic integrity are faulty, as in the case of most cancers, then a cell traverses the cell cycle with radiation-induced damage, leading to mitotic cell death or loss of critical genomic information vital to future cell survival.

With these basic fundamental principles of radiation therapy discussed, it is important to examine in depth the effects of electromagnetic radiation on biologic systems as they pertain to the treatment of gynecologic malignancies.

Basic radiation physics

Matter is made up of subatomic particles bound together by energy to form atoms. The simplest representation of the atom consists of a central core of one or more positively charged protons (+1; 933 MeV [mega electron volt]) and zero or more uncharged neutrons (±0; 933 MeV) surrounded by a cloud of negatively charged orbital electrons (−1; 0.511 MeV). As Bowland described, four fundamental forces hold these subatomic particles together: the strong force (10 ¹ N), electromagnetic or coulomb force (10 ^–2 N), weak force (10 ^–13 N), and gravitational force (10 ^–42 N). The strong nuclear force acts over a short range (10 ^–14 m), keeping an atom’s protons from repelling one another because of the similar electrostatic charge. The coulomb force of attraction binds orbital electrons to the nucleus so that the closer an electron is to the nucleus, the higher the binding energy of the electron. As described later, the strength of the binding energy of orbital electrons relates to the interaction of radiation on matter and its subsequent biologic effects. The chemical identity of an atom relates to its number of protons, and this number identifies the atom’s atomic number (Z). The neutron number (N) varies among atoms and increases as the atomic number increases to stabilize the nucleus. An atom’s atomic mass number (A) is approximately the sum of the proton number and the neutron number (A = Z + N). Radionuclides are represented by the following notation: ^A X.

When an atom is neutral, it has no electric charge, meaning that the number of protons equals the number of electrons. If incident energy is transferred to an atom, an ionization event can occur whereby the atom acquires a positive or negative charge. When a charge is acquired, an atom is said to be ionized. Removal of an orbital electron results in an atom with a positive charge; the energy required to strip an electron off an atom must exceed the binding energy of that particular electron. Addition of an orbital electron results in an atom with a negative charge. This can occur when an electron passes close enough to an atom to experience a strong attractive force from the nucleus. Atoms can also undergo excitation, a process whereby an incident particle’s energy is not sufficient to eject an atom’s orbital electron but rather raises one or more electrons to a higher orbital energy state. It is through these types of interactions in atoms that radiation therapy elicits biologic consequences within tissues.

Radiation itself can be defined as the emission and propagation of energy through space or a physical medium. Radiation can be particulate, meaning that units of matter with discrete mass and momentum propagate energy (e.g., alpha particles, protons, neutrons, electrons), or it can be electromagnetic (photons), meaning that energy travels in oscillating electric and magnetic fields that have no mass and no charge, with a velocity of the speed of light ( c = 3.8 × 10 ⁸ m/sec). Both particulate radiation and electromagnetic radiation can ionize atoms, events that occur randomly throughout the medium.

In the treatment of gynecologic malignancies, the most common source of radiation is electromagnetic (photon) radiation. Photons are generally referred to as x-rays (extranuclear or from the atom) or gamma rays (from the nucleus) based on their origin. Important properties of a photon include its wavelength (λ), frequency (ν), speed c = (λν), and energy E = (hν), where h is Planck’s constant. A photon’s energy (E) is proportional to its frequency—that is, higher energies are transmitted at a higher frequency. Because the frequency of a photon is inversely proportional to the wavelength, electromagnetic radiation with a shorter wavelength has a higher frequency and thus a higher energy. As Kahn described in his textbook on the physics of radiation therapy, the energy that is produced is measured in electron volts, 1 eV = 1.6 × 10 ^-19 J, and it takes approximately 34 eV to generate one ion pair in water. The photons used to treat gynecologic malignancies can be generated externally at a distance from the woman’s tumor (teletherapy) or internally, close to the woman’s tumor (brachytherapy). Teletherapy x-ray radiotherapy units can deliver a range of photon energies from 50,000 eV (50 keV) to more than 30 MeV, depending on their radiation source or linear accelerator design. Nuclear decay of radioactive isotopes generates the gamma ray photons used in brachytherapy; such decay or disintegration was measured historically in a unit called a curie (Ci). One Ci is defined as 3.7 × 10 ¹⁰ disintegrations/sec, which is equivalent to the rate of disintegration of 1 g of radium. The modern standard unit for activity is the becquerel (Bq), which is 1 disintegration/sec, or 2.7 × 10 ^–11 Ci.

Regardless of the source of electromagnetic or photon radiation, the transmitted energy diverges as the distance it travels from the source increases. This divergence causes a decrease in energy, a relationship described by the inverse square law. The inverse square law states that the energy dose of radiation per unit area decreases proportionately to the square of the distance from the site to the source (1/r ² ). For example, the dose of radiation 3 cm from a point source is only one ninth of the value of the dose at 1 cm ( Fig. 28.2 ) ( ; ).

Therapeutic radiation production

In general, two techniques are used in radiation therapy treatment: teletherapy (external) and brachytherapy (internal). Teletherapy in the form of external beam radiation treatment produces ionizing radiation through radioactive decay of unstable radionuclides such as cobalt ( ⁶⁰ Co) or, more commonly, through acceleration of electrons. In a typical linear accelerator teletherapy unit, electrons are “boiled” off a filament and accelerated under vacuum along an accelerating waveguide using alternating microwave fields. These accelerated electrons can be used to treat the patients themselves or can hit a high Z material transmission target to produce photons of various energies by an interaction known as bremsstrahlung, which means braking radiation. Most treatment machines generate photon energies of 4 to 20 MeV and, similar to ⁶⁰ Co teletherapy units, have 360-degree gantry rotation around a patient. Typical linear accelerator dose rates are 3 Gy/min at 100 cm from the source. Alternate forms of teletherapy treatment are available, but they are rarely used to treat gynecologic malignancies. A teletherapy radiation dose can be delivered using alpha particles (helium nucleus), neutrons, or protons. Alpha particles produce a large number of ionizations over a short distance, but they have limited use as a mode of therapy because of their short range in tissue. Neutrons are highly penetrating into tissue because of their lack of charge; they cause high-energy collisions with atomic nuclei, principally of hydrogen, to produce recoil protons that then lose energy in surrounding tissues by ionization. Accelerated protons, as positively charged particles, used as therapy deposit a radiation dose sparingly along their path until near the end of their range, where the peak dose is delivered, the so-called Bragg peak. Neutron and proton therapies are used to treat cancer but are not used routinely in the treatment of gynecologic malignancies.

To produce a consequential radiobiologic effect in tissues or tumor, incident photons or other forms of radiation must interact with matter. Kahn has noted that there are five possible electromagnetic (photon) interactions with matter ( ):

• 1.

  Coherent scattering (<10 keV) occurs when an incident photon scatters off an atom’s outer orbital electron without losing energy. This produces no radiobiologic effect.

• 2.

  Photoelectric effect (10 to 60 keV) occurs when an incident photon interacts with an inner orbital electron and the photon’s energy is completely absorbed by that electron. If enough energy is transferred to the orbital electron to exceed the binding energy of the inner orbital electron, it is ejected, leaving a vacancy that an outer orbital electron fills. When an outer orbital electron fills the vacancy, a characteristic x-ray is produced with energy equal to the difference in binding energy between the two electron orbitals. The probability of a photoelectric effect event happening is proportional to Z ³ /E ³ . Diagnostic radiographic or computed tomography (CT) images that are acquired at relatively low photon energies have high tissue–bone contrast detail because the Z ³ /E ³ ratio is maximized.

• 3.

  Compton effect (60 keV to 10 MeV) occurs when an incident photon (Eγ) loses some or all of its energy to an outer orbital electron. The photon, if it remains, is scattered at some angle away from the atom. An electron that has acquired energy exceeding its binding energy (E _BE ) leaves the atom with sufficient kinetic energy (E _KE = Eγ − E _BE ) to penetrate tissue and produce molecular damage through downstream ionizations. For simplicity, at common therapeutic photon energies (4 to 18 MeV), the Compton effect is biologically most important in that incident photons interact predominantly with cellular water. Human and mammalian tissues are principally composed of water (90%) and functional biomolecules such as proteins and DNA ( Fig. 28.3 ). Incident photons ionize water to produce an ion radical (H ₂ O ⁺ ) and a free electron (e ⁻ ). The ion radical is highly reactive (half-life of 10 ⁻¹⁰ second) and can interact with another molecule of water to form a hydroxyl radical (c. OH). Hydroxyl radicals are also highly reactive (half-life of 10 ^–9 second) and can break chemical bonds in target molecules such as proteins and DNA (c. R). Breaks in the chemical bonds of DNA can lead to DNA base damage, DNA cross-links, DNA single-strand breaks, and DNA double-strand breaks. As discussed later, DNA strand breaks can result in the loss of vital genomic material during subsequent cell divisions, potentially leading to mitotic death of the damaged cell. In this way, therapeutic radiation leads to significant radiobiologic effects by functionally modifying cellular proteins and damaging DNA.

  

• 4.

  Pair production (>10 MeV) occurs when an incident photon has an energy greater than 1.022 MeV. This threshold is required because the photon disappears to form an electron-positron pair, with each particle having an energy of 0.511 MeV. Once formed, free electrons slow by nuclear attraction and are quickly stopped in tissue; however, the formed positron is highly reactive and short lived in that it is annihilated with surrounding electrons to create two photons of 0.511 MeV, each traveling 180 degrees apart from one another. Positron emission tomography (PET) scanners build images based on the coincident detection of photons formed by this process.

• 5.

  Photodisintegration (>10 MeV) occurs when an energetic photon penetrates the nucleus of an atom and dislodges a neutron. Emitted neutrons cannot ionize tissue themselves because they have no charge; rather they collide with surrounding atomic nuclei to produce recoil, positively charged protons that elicit radiobiologic effects through subsequent ionizations.

Radiation biology

Munro has shown that nuclear DNA is unquestionably one essential target of therapeutic radiation ( ). In his textbook on radiobiology, Hall reported that one-third of radiation-induced DNA damage is from the direct interaction of incident photons ionizing atoms within DNA itself ( ). Two-thirds of radiation-induced DNA damage is a consequence of the indirect damage done by freely diffusing hydroxyl radicals (ċOH); however, Hall and Hei described a bystander effect whereby lethal damage to cellular proteins, organelles, or the cell membrane in an irradiated cell can lead to neighboring cell death in cells that would not have died on their own ( ). The bystander effect suggests that damage to cellular proteins or organelles in one cell may also result in cell lethality. Note that not all radiation damage is lethal to the cell; some damage to DNA can undergo repair—namely, sublethal DNA damage repair. Sublethal DNA damage repair occurs in normal cells and malignant cells, but it occurs much less so in malignant cells because these often have abnormal DNA repair mechanisms. A variety of complex and redundant repair mechanisms have been identified, including base excision repair and nucleotide excision repair for damage to the DNA base and deoxyribose backbone, homologous recombination repair for DNA single-strand breaks, and nonhomologous end-joining repair for DNA double-strand breaks. As the time interval between radiation doses lengthens, cell survival increases because of the prompt repair of radiation-induced damage. The repair process is usually complete within 1 to 2 hours, although this period may be longer in some slowly renewing cellular tissues. Before discussing the consequences of DNA damage, it is important to understand key factors that can modify the rate at which DNA damage accumulates.

Intracellular molecular oxygen importantly modifies radiation-induced DNA damage as it fixes damage done by free hydroxyl radicals. Palcic and Skarsgard reported that molecular oxygen, when present during or within microseconds of photon-induced ionization events, reacts with the altered chemical bonds of ionized molecules (ċR) to produce organic peroxides (RO ₂ ), a nonrepairable form of the target molecule ( ). Molecules fixed in this manner are permanently altered and may function abnormally. Thus tumor and tissue oxygenation have practical implications in radiation therapy insofar as a rapidly proliferating gynecologic malignancy may have a poor blood supply, which decreases tumor cell oxygenation, particularly at the center of large tumors. Tumor tissue hypoxia leads to radiation resistance, as reflected by increased cell survival after radiation treatment ( ). Laboratory experiments have shown that the radiation dose necessary to kill the same proportion of hypoxic cells compared with aerated cells approaches 3:1 ( ). This ratio is commonly referred to the oxygen enhancement ratio. For oxygen to have its maximal effect, the dissolved oxygen concentration in a tumor must be approximately 3 mm Hg (venous blood is 30 to 40 mm Hg), according to . In the treatment of gynecologic malignancies, Dunst and coworkers found that cervical cancer patients undergoing radiation therapy with a serum hemoglobin level greater than 10 mg/dL have improved tumor oxygenation, resulting in superior local control and superior clinical outcomes compared with patients whose hemoglobin level is less than 10 mg/dL ( ). Also, hypoxic cell sensitizers such as the nitroimidazoles, as studied by Adams and colleagues, and the bioreductive drug tirapazamine, as reported by Goldberg and coworkers, improve the radiosensitivity of hypoxic cells within tumors ( ; ). The potential benefit of these agents in the treatment of gynecologic cancers has been explored in clinical trials.

The rate at which energy is lost per unit path length of medium, or linear energy transfer (LET), also has an effect on the accumulation of radiation-induced DNA damage. For photons, energy loss is infrequent along its path length, typical of low-LET radiation. Sparsely ionizing, low-LET radiation produces one or more sublethal events, and thus multiple hits are needed to kill the cell. Heavy particulate radiation from alpha particles or protons is densely ionizing because energy is deposited more diffusely along its path length. This is typical of high-LET radiation. Because the probability of producing a lethal event in a cell is much higher with high- LET radiation, cell death in this case is independent of tumor oxygenation. Thus research efforts have been directed toward the development of heavy particle generators that can overcome the limitation of poor oxygenation of cancer cells.

Within the cell, molecules that have sulfhydryl moieties at one end and a strong base such as an amine at the other end are capable of scavenging free radicals produced by radiation-induced ionization events. These molecules can also donate hydrogen atoms to ionized molecules before molecular oxygen can fix the damage done by radiation-induced hydroxyl radicals. As Utley and associates reported, amifostine is a nonreactive phosphorothioate that accumulates (1) readily in normal tissues by active transport to be metabolized into an active compound to scavenge free radicals and (2) slowly in tumors by passive diffusion, with limited or no conversion to the active compound ( ). It is reasonable to conclude that the presence of a radioprotector such as amifostine would decrease radiation-induced DNA damage and limit normal tissue radiation-related side effects. Clinical trials have been investigating the radioprotective effect of amifostine in gynecologic malignancies but, at present, amifostine has shown the most promise as a chemoprotectant and has been approved to reduce the renal toxicity associated with repeated administration of cisplatin chemotherapy in women with advanced ovarian cancer.

What constitutes cell death in the traditional sense—cessation of cellular respiration and vital function—is not the same in radiation biology. Death in radiation biology is the loss of reproductive integrity or the inability to maintain uninterrupted cellular proliferation with high fidelity. Thus radiation kills without the actual physical disappearance of malignant cells, although body macrophages often remove the dead cells, causing tumors to shrink in size. Malignant cells may remain a part of a tumor but have discontinued cellular metabolism and proliferation. Most cells, when exposed to radiation, die a mitotic death, meaning that cells die at the next or a subsequent cell division, with all progeny also dying. Inflammation can accompany mitotic cell death, potentially resulting in local adverse side effects. Jonathan and associates noted that alternative forms of loss in reproductive capacity caused by radiation include terminal differentiation, senescence, and apoptosis ( ). In apoptosis, cells undergo a complex process of programmed cellular involution and phagocytosis by neighboring cells. There is no inflammatory response resulting from apoptosis. One remarkable example of apoptosis is the formation of the spaces between the digits of the hand during human fetal development.

Returning to radiation-induced DNA damage, electromagnetic radiation (x-ray or gamma) deposits energy in cells, which may damage DNA directly or indirectly through hydroxyl radicals (OH). In relative terms, more than 1000 DNA base-damaging events, 1000 DNA single-strand breaks, and 40 DNA double-strand breaks occur with each typical radiation dose fraction. Although base and DNA single-strand breaks must be repaired so that mutations are not propagated, DNA double-strand breaks are believed to be the most crucial radiobiologic effect of radiation therapy. There is an increased statistical probability that a cell will be unable to repair a DNA double-strand break, resulting in the loss of genetic material at cell division. Also, attempts by cells to repair the DNA double-strand breaks often result in bizarre chromosome arrangements that interfere with the normal division of the cell. Cell death ensues through loss of critical genes or impaired cell division.

Cell death after radiation therapy is modeled by a linear-quadratic relationship ( Fig. 28.4 ). The initial slope of the cell survival curve is shallow and curvilinear, whereas the terminal slope is more linear. In the low-dose region of the survival curve typical of daily dose fractions used in radiation therapy, the fraction of cells surviving is high because of the repair of single-event sublethal damage (e.g., multiple base damage or DNA single-strand breaks). In the high-dose region of the survival curve, the fraction of cells surviving is low because of multiple event damage in the form of DNA double-strand breaks or the accumulation of too many sublethal events that can be repaired before the next cell division. Capacity to repair sublethal damage depends on radiation quality (LET), tissue oxygenation, and cell cycle time.

As shown in Fig. 28.5 and as described by Deshpande and associates and Pawlik and Keyomarsi, there are four highly regulated phases of the cell cycle ( ; ). After completing mitosis, cells enter a gap phase (G ₁ ), variable in time span, in which the cell performs protein synthesis and other functional metabolic and biologic processes. Under the influence of complex, finely regulated intercellular and intracellular signaling, cells then enter the DNA replication phase (S phase) in which the cell must exactly replicate its DNA to produce an identical set of chromosomes. Entry into the S phase is controlled by sequentially activated, highly regulated cyclin-dependent kinases (CDKs) responsible for differentially recruiting and amplifying specific gene products necessary for DNA replication. Moreover, there are corresponding cell cycle inhibitory proteins (cyclin-dependent kinase inhibitor proteins [CDKIs]) that negatively regulate cell cycle progression. After DNA replication, the cell enters a second gap phase (G ₂ ), in part to ensure high DNA replication fidelity in the newly formed chromosomes. At the completion of the G ₂ phase, cells undergo mitosis, whereby two identical daughter cells are produced.

To maintain genetic integrity through the cell cycle, the cell has multiple checkpoints through which it must pass, notably at the G ₁ -S and G ₂ -M transitions, as described by Pawlik and Keyomarsi ( ). The G ₁ -S checkpoint prevents the replication of damaged DNA, as in the case of radiation therapy. Malumbres and Barbacid have reported that proteins critical to the G ₁ -S checkpoint include p53, p21, and the retinoblastoma protein (Rb), all of which modulate the activity of CDKs responsible for the transition to S phase ( ). Briefly, Rb lacks phosphorylated subunits in its active form, binding to the E2F transcription factors and preventing E2F translocation to the nucleus to recruit genes needed for the S phase. Sequential phosphorylation of RB by CDK 4/6–cyclin D and CDK2–cyclin E complexes releases the E2F transcription factors. Radiation-induced DNA damage results in the accumulation of the G ₁ checkpoint regulatory protein p53, which in turn activates the CDKI p21; p21 inhibits the phosphorylation of RB, delaying the G ₁ -S transition. The G2/M checkpoint prevents the segregation of aberrant chromosomes at mitosis. Two molecularly distinct checkpoints have been identified, one that is regulated by the ataxia-telangiectasia mutated gene product (ATM) and one that is ATM independent. ATM has multiple phosphorylation products that modulate CDKs at the G ₂ -M transition (Chk1 and Chk2) and p3 expression through modification of its degradation pathway. According to Xu and associates, phosphorylation of Chk1 and Chk2 inhibits the cdc2 protein kinase, blocking cells at the G ₂ -M transition ( ). ATM’s essential role in DNA damage recognition is highlighted by the extreme radiosensitivity of patients with mutated ATM. Malignant cells that often have mutated cell cycle checkpoint proteins have an impaired ability to repair damage done to nuclear DNA and thus accumulate lethal DNA-damaging events that lead to cell kill in a few cell cycles.

Cells show different radiosensitivities during the cell cycle. M-phase cells are particularly radiosensitive because the DNA is packaged tightly into chromosomes, so ionization events have a high likelihood of causing lethal DNA double-strand breaks. S-phase cells are particularly radioresistant because enzymes responsible for ensuring high-fidelity DNA replication are relatively overexpressed and recognize altered DNA bases or inappropriate strand breaks. Cells in the G ₁ or G ₂ phase of the cell cycle are relatively radiosensitive compared with the S phase. Chemotherapies that inhibit cell cycle–dependent pathways or impede DNA repair enhance the radiobiologic effect of radiation ( ; ).

Radiation treatment: Brachytherapy and teletherapy

In general, two techniques are used in radiation treatment: brachytherapy (internal) and teletherapy (external). Brachytherapy involves the placement of radioactive sources within an existing body cavity (e.g., the vagina) in close proximity to the tumor. In the treatment of gynecologic malignant tumors, radioactive sources can be placed within hollow needles that are implanted directly into the tissue to be irradiated (interstitial implant) or within a hollow cylinder, or they can be inserted in tandem into the uterus through the cervical os, respectively. For the treatment of cervical cancer, two vaginal ovoids are positioned in the vaginal fornices (intracavitary therapy). One of the most widely used intracavitary applicator is the Fletcher-Suit applicator, which is useful for the treatment of a cervical tumor or a tumor located near the cervix ( Fig. 28.6 ). For interstitial and intracavitary brachytherapy, the radiation dose delivery to the tumor and surrounding tissues follows the inverse square law as modified by source and tissue photon attenuation. With the increased use of high-dose rate brachytherapy, a tandem and ring may be used where the ring replaces the ovoids (see Fig. 28.6 ). In the past, interstitial or intracavitary brachytherapy needles or applicators without radioactive sources are placed first in the operating room with the patient under anesthesia. After postanesthesia patient recovery, the position of the needles or applicators is confirmed by radiographic imaging. These radiographic images help guide radiotherapy planning. With the increased use of high-dose brachytherapy described later, the majority of patients are just sedated or spinal anesthesia is used during the procedure. The instruments are placed and then the patient undergoes imaging, usually a CT or magnetic resonance imaging (MRI) scans, and planning is done on these images instead of plain films. Once the plan is completed, the patient is treated in the radiation oncology department and then released to go home. The approximately time for the entire procedure varies from 3 to 5 hours. The entire procedure is done on an outpatient basis and is usually repeated three to six times, usually twice a week.

Several radioisotopes with various photon energies and half-lives are used in gynecologic brachytherapy. Although uncommon, radioisotopes with a short half-life (e.g., ¹⁹⁸ Au [gold]) may be placed within the woman and left permanently. Radioisotopes with a long half-life (e.g., ¹³⁷ Cs [cesium]) are placed temporarily within interstitial or intracavitary needles or applicators and are removed after a prescribed radiation dose has been administered. Historically, brachytherapy for most gynecologic malignancies consisted of temporary low-dose rate (40 to 70 centigray [cGy]/hr) sources in place for 1 to 3 days. A low-dose rate requires that the woman be in a shielded hospital room with medical personnel supervision, on bed rest, with prolonged analgesia and prophylactic anticoagulation, and limited family contact during radiation dose administration. High-dose rate, catheter-based brachytherapy has become popular because the procedure can be performed in 1 day on an outpatient basis. The high-dose rate uses a thin wire tipped with iridium ( ¹⁹² Ir) to deliver radiation doses at rates exceeding 200 cGy/min. Unlike low-dose rate therapy, high-dose rate therapy is performed in a shielded treatment room requiring patient immobilization for a short period and minimal patient analgesia and anesthesia. Table 28.1 indicates the half-lives of some of the isotopes commonly used in treating gynecologic cancers. It is also important that a uniform distribution of radiation be achieved in the adjacent tissues to avoid hot spots, which can damage normal tissue, as well as cold spots, which can lead to reduced dose delivery to the tumor.

Teletherapy in the form of external beam radiotherapy means that the source of radiation is at a distance from the woman, sometimes located at a distance 5 to 10 times more than the depth of the tumor being irradiated. This distance is referred to as the source-to-surface distance (SSD) and is used to calculate dose using the inverse square law. When using an SSD patient treatment setup, the SSD is used along with tumor depth, radiation beam energy, depth of the point of maximum dose, and output parameters for a given treatment field size to determine the daily radiation dose. Alternatively, with the use of different angles and ports of treatment, the concept of source-axis distance has been introduced; it denotes the distance from the radiation source to the central axis of machine rotation. The woman is positioned so that this axis passes through the center of the tumor, and treatment ports are arranged around this axis to optimize tumor dose. When using a source-axis distance patient treatment setup, the daily radiation dose is calculated using machine output and beam attenuation at the depth for a given treatment field size.

Conventional external beam radiation is delivered with beams of uniform intensity. Advances in computer-guided planning and treatment have made the use of beams of varying intensity more commonplace. This approach of planned dose intensification allows the high-dose region to be conformed precisely to the shape of the planned treatment volume, a technique called intensity-modulated radiotherapy (IMRT). The advantage of this technique is that there may be more sparing of normal tissue, especially small bowel, and therefore hopefully decrease both short-term and long-term toxicity ( Fig. 28.7 ). Advances in radiotherapy delivery systems have allowed linear accelerators to be coupled with helical CT scanners. Image-guided radiation therapy using this type of device is called helical tomotherapy. In conventional therapy, and in IMRT and helical tomotherapy, beams from the external radiation source can be sculpted using high electron-dense material collimators. Collimators limit scatter radiation and block portions of the treatment beam from delivering an intolerant radiation dose to critical tissues ( Fig. 28.8 ). In general, the higher the energy source of the radiation, the deeper the beam can penetrate into tissue. Thus high-energy radiation has its predominant effect in deeper tissues and spares the surface of the skin of a radiation effect.

An isodose curve is a line that connects points in the tissue that receive equivalent doses of irradiation. Fig. 28.8 contrasts the isodose curves for 6- and 22-MeV machines. For the 6-MeV machine, the maximum dose is near the surface, with a more rapid falloff in the deeper tissues. For the 22-MeV machine, the maximum dose is deep to the surface, sparing the effects of radiation on the overlying skin. In addition to the energy of the beam, the energy of radiation absorbed at various depths is affected by the size of the field being treated. Larger fields contain more scattered radiation, which leads to a greater dose at a given depth. Fig. 28.8 shows the effect of increasing the size of the field with an increasing dose at a given depth for three different types of energy sources.

Thus the radiation dose delivered to the tumor is affected by the energy of the source, depth of the tumor beneath the surface, and size of the field undergoing irradiation. With external therapy, usually 180 to 200 cGy/day is given five times per week.

Tissue tolerance and radiation complications

Adverse radiation effects are commonly divided into two broad categories, early and late, which demonstrate markedly different patterns of response to radiation dose fractionation. It is important for the treating physician to understand critical tissues and organ systems at risk of radiation damage. Table 28.2 presents the approximate tolerance of tissues to radiation therapy.

Early or acute effects manifest as the result of death in a large population of cells and can occur within days to weeks after the initiation of radiation therapy. For early effects, the total dose of radiation and, to a lesser extent, the dose per fraction determine the severity of the side effect. Radiation acutely affects tissues undergoing rapid cell division to replace lost normal functioning cells. This is most pronounced in areas such as the skin, intestinal mucosa, mucosa of the vagina and bladder, and hematopoietic system, in which precursor stem cells are renewing functional mature cells. The radiation dose given in multiple small fractions reduces the untoward adverse effects of cell damage on normal tissue and allows normal healing to occur between treatment fractions through sublethal DNA damage repair (the shallow curvilinear portion of the cell survival curve). During the treatment of gynecologic malignancies, most adverse early treatment-related toxicities can be managed with medication. It is preferred practice that radiation treatment not be interrupted for treatment-related toxicities caused by radiation-induced tumor accelerated repopulation. Only rarely does a treatment program have to be temporarily discontinued for treatment-related toxicities.

Late effects occur after a delay of months or years after radiation therapy. Late effects are often the product of parenchymal connective tissue cell loss and vascular damage. Late effects may be seen in slowly renewing tissues such as the lung, kidney, heart, and liver and in the central nervous system. In the treatment of gynecologic malignancies, late adverse effects include tissue necrosis and fibrosis, as well as fistula formation and ulceration. In contrast to early effects, late effects depend primarily on the dose per fraction. Fractionated radiation therapy using a daily radiation dose of 180 to 200 cGy minimizes the risk of late effects. Second cancers (mostly sarcomas) induced after radiation are rare (1 in 500 to 1000 cases) and do not usually appear until 15 to 20 years after radiation exposure. Arai and associates noted an excess of rectal cancer, bladder cancer, and leukemia in women with carcinoma of the cervix treated by radiation compared with those treated by surgery ( ).

The skin overlying the tumor being treated visibly reveals the effects of radiation-induced normal tissue damage. Skin effects are manifest by reddening of the skin and loss of hair where the radiation treatment beam enters the body. Erythema may progress to dry or moist skin breakdown or desquamation caused by loss of the actively proliferating basal layer of the epidermis that renews the overlying epithelium. This is less common now than in prior years because higher-energy radiation beams, which spare the surface, are used; however, during the treatment of vulvar malignancies, the skin surface and superficial groin nodes are the radiotherapeutic target, so desquamation is more commonly observed. Medical treatments consisting of non–metal-containing creams and emollients during therapy reduce discomfort and allow healing within 2 to 4 weeks after completion of radiation therapy. Late skin fibrosis may produce a rough, leathery texture to the skin in the irradiated field. Chiao and Lee as well as Gothard and coworkers have reported on the use of pentoxifylline and vitamin E to promote healing of late subcutaneous and deep tissue fibrosis after radiation ( ; ).

In the treatment of gynecologic malignancies, other sites at risk of radiation-induced normal tissue damage are the bladder, rectum, and large and small bowel. Risk factors for late complications include a history of smoking and body habitus. The bladder epithelium consists of a basal layer of small diploid cells covered by large transitional cells. Radiation damage to the diploid cells results in slow renewal of the overlying transitional cells that are periodically sloughed off during urination. Radiation cystitis manifested as dysuria and urinary frequency results in bladder irritation. Treatment with analgesics such as phenazopyridine (Pyridium) can alleviate symptoms. Hematuria may also occur. Therapy with sclerosing solutions or fulguration through a cystoscope may be necessary. McIntyre and colleagues noted that ureteral stricture after radiation for stage I carcinoma of the cervix is 1% at 5 years and 2.5% at 20 years, a rare but important complication ( ). In rare cases, urinary diversion may be required. Bladder fibrosis and reduced bladder capacity are late effects of pelvic radiation therapy.

In the intestine, the renewing stem cells are found at the bottom of the crypts of Lieberkuhn. Within 2 to 4 days after the start of radiation, these cells can become depleted, leading to atrophy of intestinal mucosa. Damage to the bowel usually occurs in the form of inflammation (sigmoiditis or enteritis), which commonly results in increased bowel motility or diarrhea but also, rarely, may be associated with severe bleeding and cramping pain. Less severe cases can often be controlled with a low-roughage diet and antispasmodic medications. Although uncommon, severe cases may require bowel resection or permanent bowel diversion through a colostomy. Covens and coworkers noted that those who require operation for radiation damage to the bowel have an approximately 25% risk of dying in 2 years, with ileal damage being the most risky ( ). Those with complications not requiring surgery often have decreased vitamin B ₁₂ and bile acid absorption. Late bowel toxicities include radiation proctitis caused by small vessel vascular damage in the epithelium, which may progress to intermittent rectal bleeding. Bowel stenosis or obstructions resulting from fibrosis and adhesion formation may occur, especially in patients who have had previous pelvic or abdominal surgery. Occasionally, enteric fistulas can develop, and bowel perforation may occur. In the latter case, surgical therapy is required, usually to bypass the affected area of the intestine. As a rule, extensive dissection of irradiated tissue is avoided. Montana and Fowler have shown that the risks of proctitis and cystitis are dose related ( ). For example, they found severe proctitis and cystitis at doses of 6750 and 6900 cGy, respectively, whereas such complications were not observed in patients whose median dose was 6300 and 6500 cGy. Extensive work looking at dose response and late toxicity is presently being done through a large multiinstitutional study (EMBRACE).

A lowering of circulating lymphocytes, granulocytes, platelets, and red blood cells can be seen with pelvic radiation therapy for gynecologic malignancies. The stem cells of the bone marrow in an adult reside in the axial skeleton (vertebrae, ribs, and pelvis). Usual external beam radiation therapy treatment fields for gynecologic malignancies encompass the sacrum and lower vertebrae and pelvis, thereby reducing precursor stem cells for circulating blood cells. This is an important consideration if the woman is to receive concurrent radiosensitizing chemotherapy or subsequent cytotoxic chemotherapy. Growth factor support with synthetic erythropoietin or granulocyte colony-stimulating factor (G-CSF) is often required for patients receiving multiagent chemotherapy after treatment with pelvic radiation therapy.

Finally, fistulas between the vagina and bladder or between the vagina and rectum may develop when there has been extensive radiation damage to the intervening tissues. As a rule, such complications generally occur 6 to 24 months after treatment, although they may develop many years after primary therapy. Diverting surgery or resection of the fistulas is often needed to correct these serious complications.

Chemotherapy principles and guidelines

Some of the concepts used in antibiotic therapy for infections have been applied to the chemotherapeutic approach to cancer management; however, major differences exist. Infections are often caused by a single virus or even multiple types of bacteria with specific growth patterns and sensitivities to antibiotics. Although it is believed that a cancer can originate from a single cell, clinically evident disease is composed of a heterogeneous population of cells with different cell cycle durations, varying growth fractions, and diverse expression of genes, potential mutations, and proteins responsible for cell proliferation and metastasis. Intrinsic and acquired drug resistance remains one of the daunting challenges in the treatment of gynecologic cancers.

Basic principles for cancer chemotherapy arose from experiments in murine tumor models, notably mice leukemias, conducted by Skipper and colleagues at the Southern Research Institute ( ). These principles include the following:

• Fractional cell kill: Each dose of chemotherapy kills a constant fraction of the tumor cell population. Tumor cell kill usually correlates in a linear relationship with the pharmacokinetic parameter of the area under the curve (AUC) for drug concentration.

• Dose intensity: High chemotherapy doses interspersed with short rest periods produce the greatest tumor cell kill in rapidly proliferating malignancies.

• Drug resistance: Single-agent chemotherapy administration selectively isolates drug-resistant tumor cells, leading to an outgrowth of hardy, resistant malignant cells. Chemotherapy drug resistance has been associated with the following: (1) cell-mediated modification of drug targets, (2) active drug transport out of the cell, and (3) alteration of drug activation or targeting.

• Cell cycle dependency of cell kill: Actively proliferating tumor cells are most often killed by chemotherapy agents; drugs inhibiting DNA processing act during the S phase and those impairing cell division act during the M phase. If the normal monitors of genomic integrity are intact, a cell may suspend the cell cycle to repair any detected damage. If, however, these monitors are abnormal, a cell may continue progression through the cell cycle, which may lead to unrecoverable cell cycle arrest or irreparable damage to critical genes vital for future cell survival. Malignant cancer cells often demonstrate abnormal monitors of genomic integrity, in part permitting their rapid proliferation but also increasing their sensitivity to chemotherapies.