Wafic M. ElMasri, MD
Oliver Dorigo, MD, PhD
Two European discoveries in the late 1800s led to future radiation treatment of human malignancies. While studying the penetrating power of cathode ray emission in Germany, Wilhelm Roentgen discovered x-rays on November 8, 1895. In France, the Curies isolated radium from uranium ore in 1898. Soon thereafter, Robert Abbe of New York City introduced radium for medical therapy, and Howard Kelly of Baltimore pioneered radium treatment of cervical cancer. Since then, radiation therapy has evolved to become a major modality in the treatment of many cancers, particularly those of the female reproductive tract.
RADIATION PRINCIPLES
Radiation therapy is used for definitive or palliative treatment of cancer and may be defined as therapeutic delivery of radiation to a target tissue, which results in tissue damage. Radiation causes breaks in DNA and generates free radicals from cell water that may damage cell membranes, proteins, and organelles. Such radiation may be electromagnetic or particulate, both of which transfer energy to the electrons or nuclei of the target atoms.
Electromagnetic radiation is energy that is transmitted at the speed of light through oscillating electric and magnetic fields. The energy contained in these fields can be described as discrete units known as photons. The energy of each photon is proportional to the frequency of the wave associated with that photon. Because radiation with a shorter wavelength has greater frequency, it carries greater energy per photon, allowing deeper tissue penetration. The most clinically relevant forms of electromagnetic radiation are x-rays and gamma rays. For therapeutic applications, x-rays are mechanically produced by linear accelerators that accelerate electrons to very high energies. These electrons then strike a target within the accelerator, usually tungsten, to produce a beam of x-rays that is targeted at the patient. Gamma rays are produced by the decay of radioactive substances. Currently, the most commonly used radioisotopes for gynecologic cancer treatments are cesium-137 and iridium-192.
Particulate radiation uses subatomic particles (electrons, neutrons, protons), instead of photons, to deliver the dose of radiation. Compared with electromagnetic radiation, particle-beam therapy enables more precise dose localization and better depth-dose distribution.
Interaction of Photons with Matter
The first step in the absorption of an incident photon with matter is the conversion of the energy of that photon into the kinetic energy of an electron, or electron–positron pair. Depending on the energy of the photon, this conversion takes place either through the photoelectric effect, the Compton effect, or pair production. In the lower range of energy transfer, the photoelectric effect predominates, whereas in the transfer of higher levels of energy, the Compton effect and pair production are more prevalent.
Photoelectric effect: an incident low-energy photon (0.5–100 kV) interacts with a tightly bound inner shell electron of the target tissue. The energy is completely absorbed by this electron, which is ejected from the atomic orbit with kinetic energy equal to the photon energy. The product electron then ionizes the surrounding tissue. The lower the energy of the incoming photon and the higher the atomic number of the tissue, the more likely photoelectric effect will occur. Absorption is directly proportional to the atomic number of the target. Tissues bearing elements of higher atomic numbers (eg, calcium in bone) absorb proportionately higher levels of radiation, which may lead to toxicity.
Compton effect: an incident mid-energy photon (100 kV–20 MV) transfers energy to an outer-shell electron in the target tissue, causing ejection of this electron. The photon’s energy is incompletely absorbed; instead, the photon is scattered at an angle to its original path. Both the product electron and the scattered incoming photon (which now has lower energy) continue with ionizing interactions (Fig. 52–1). The Compton effect is inversely proportional to the energy of the incoming photon and is independent of atomic number (ie, all tissue absorbs the same amount of energy). The Compton effect accounts for the biologic effects on tissues seen in radiation therapy.
Figure 52–1. Absorption of an x-ray photon by the Compton process. The photon interacts with a loosely bound planetary electron of an atom of the absorbing material. Part of the photon energy is given to the electron as kinetic energy. The photon, deflected from its original direction, proceeds with reduced energy. e–, electron; p+, proton; n, neutron. (Reproduced, with permission, from Hall EJ. Radiobiology for the Radiologist. 4th ed. Philadelphia, PA: JB Lippincott; 1994, p. 7.)
Pair production: refers to a complex interaction between an incident high-energy photon (>1.02 MV) with the nucleus of a target atom resulting in formation of a pair of electron–positron (e+) and negatively charged electron (e–) that scatters in the opposite direction. Because the pair production interaction typically predominates at energy levels above the range that is usually used in therapy, it plays a small role in most clinical settings.
Interaction of Photons with Tissue
As a radiation beam travels through a patient, it deposits energy in the tissue through interactions such as the Compton effect. The depth of tissue penetration is dependent on the energy. At 100% depth dose, 250 KeV will be reached at the skin level, 1.25 MeV at 5 mm, 6 MeV at 1.2 cm, and 20 MeV at 10 cm.
These interactions set secondary electrons in motion, which result in further ionizations. These ionizations lead to the breakage of chemical bonds and subsequent damage to DNA and cellular structures. The result is reproductive cell death and apoptosis in case of excessive damage.
The most critical target for damage within the cell is DNA. Direct damage occurs when a photon becomes absorbed by an atom in the DNA resulting in DNA breaks that are beyond the cell’s repair machinery. More commonly, however, DNA breaks are indirect. The water surrounding the DNA is ionized by the radiation, creating oxygen radicals, hydroxyl radicals, peroxide, and hydrated electrons. These highly reactive species then interact with the DNA to cause damage.
Dosage Theory
Normal tissues as well as malignant cells are susceptible to toxicity induced by radiation therapy, the extent of which depends on total dose, fractionization, and tumor volume.
After exposure to radiation, tissue survival follows a predictable curve that essentially constitutes the number of viable clone cells (Fig. 52–2). The shoulder represents the cell’s enzymatic ability to reverse radiation-induced damage. As radiation increases, cells become incapable of self-repair, and a logarithmic pattern of cell destruction occurs. Importantly, for every increase in dosage that occurs beyond the shoulder, a constant fraction of cells is eliminated (log-kill hypothesis).
The implications of these observations provide some of the rationale for dividing (fractionating) the total dose of radiation therapy administered in the clinical setting. It is helpful to consider the so-called 4 Rs of radiobiology to understand the effects of fractionated doses at the cellular level:
A. Repair
Fractionation into small doses allows for sublethal injury repair (shoulder repetition) and results in the higher total dose necessary to achieve the same biologic effect. When a specified radiation dose is divided into ≥2 doses given at separate times, the number of cells surviving is higher than that seen when the same total dose is given at 1 time. However, fractionation allows the administration of a divided radiation dose that would not be tolerated by surrounding normal tissue if the specified dose were to be given in only 1 treatment.
B. Repopulation
The reactivation of stem cells that occurs when radiation is stopped is necessary for further tissue growth. Repopulation is cellular proliferation during delivery of a radiation therapy course. If the cancer repopulates slower than acutely responding normal tissue, fractionated radiation will be successful in eliminating tumor cells. The shorter the doubling time of tumor cells, the higher total dose of radiation will have to be delivered. Prolonged and unnecessary delays between radiation fractions decrease the effectiveness of the total radiation dose delivered.
C. Reoxygenation
Hypoxic cells are known to be relatively resistant to radiation. Oxygenated cells are 3 times more sensitive than cells irradiated under anoxic conditions (Fig. 52–2). Malignant cells located farther than 100 mm from capillary flow are at risk for hypoxia and may not be killed by radiation therapy. For this reason, it is important to correct anemia in patients undergoing radiation treatment so that tissue oxygen perfusion will be enhanced and tissues will become more radiosensitive. Fractionated radiation results in better oxygenation of initially hypoxic tumor cells. As tumor shrinks with radiation treatments, the percentage of hypoxic cells decrease and the percentage of radiation sensitive cells is increased.
Figure 52–2. Typical radiation survival curve for mammalian cells. These cells have been irradiated and then plated out in culture, and the number of survivors has been determined by measuring the colonies (clones) of cells that survive. The curve is characterized by an initial shoulder followed by a log-linear region. Cells irradiated in air are considerably more sensitive than those irradiated in nitrogen (hypoxic), and the difference between the levels of killing is frequently about 3-fold. It is believed that most clinically demonstrable tumors have areas of hypoxia that lead to radioresistance. (Reproduced, with permission, from Morrow CP, Curtin JP, Townsend DE (eds). Synopsis of Gynecologic Oncology. 4th ed. New York: Churchill Livingstone; 1993, p. 449.)
D. Redistribution
Radiation-induced synchrony allows for cellular progression into a more radiosensitive part of the cell cycle during interfraction intervals. Within an asynchronous tumor cell population, fractionated radiation kills radiosensitive cells (late G2 and M phase), leaving radioresistant cells (early G1 and mid-late S phase) with little damage. Interfraction intervals allow for cell-cycle synchronization (progression to G2 and M phase) and leads to higher overall cell death with each subsequent fraction. Cell killing is more effective with shorter cell-cycles.
Dosimetry
Dosimetry is the measurement of the amount of radiation absorbed by target tissue. The unit of absorbed dose is the Gray (Gy), which is defined as the joules of energy absorbed in a kilogram of tissue (J/kg). One Gy is equal to 100 rads. External pelvic irradiation is expressed in those terms, whereas internal irradiation (intracavitary) is also described in milligram-radium-equivalent hours (mgRaEq-hr). This latter unit is calculated by multiplying the mgRaEq of cesium or radium in the system by the number of hours the radioactive sources are left in place during treatment.
The amount of radiation used in radiation therapy varies depending on the type and stage of cancer. The typical dose for the primary treatment of solid epithelial tumors including advanced cervical cancer ranges from 60 to 85 Gy, whereas the lower doses between 20 and 40 Gy are used for lymphomas.
Adjuvant radiation therapy is used in selected cases after surgery for cervical and endometrial cancer. The radiation doses are typically lower compared with primary treatment, ranging between 45 and 60 Gy in 1.8- to 2-Gy fractions. Factors to be considered when planning radiation and selection of a dose include concurrent chemotherapy and patient comorbidities.
Planning of radiation treatment involves specialized treatment planning software that incorporates the radiation delivery method and several angles or sources to optimize the dose to the tumor and minimize the radiation effect on the surrounding healthy tissues. Computer-directed dosimetry permits the calculation of isodose curves, points of equal dose surrounding a radioactive source that permit critical considerations in avoiding overdose to the bladder and rectum. Unfortunately, the radiation tolerance of the bladder and rectum is close to the dosage levels required for curative radiation therapy of common pelvic cancers.
Fractionation
Fractionation is an important principle of radiation biology and treatment. The total radiation dose is given over a period of time at approximately 1.8–2 Gy per day over 5 days a week. Fractionation allows time for normal cells to recover and repair radiation-induced DNA damage. Tumor cells usually have dysfunctional repair mechanisms and are therefore preferentially effected by the radiation. In addition, fractionation allows tumor cells that were relatively radiation resistant during one treatment to enter a radiation sensitive phase of the cell cycle before the next fraction is given. Another tumor cell selective killing mechanism relates to hypoxia-induced radiation resistance. Hypoxic tumor cells might reoxygenate between fractions, therefore improving the effect of radiation during the next treatment.
TREATMENT METHODS
For gynecologic cancers, therapeutic radiation is delivered as external radiation (teletherapy), internal radiation (brachytherapy), or a combination of both.
External Irradiation (Teletherapy)
Early radiation therapists used electric x-ray sources that were basically modifications of Roentgen’s experimental apparatus. Electrons were accelerated across a vacuum tube to strike a tungsten target with the subsequent liberation of photons. These orthovoltage (140–400 keV) units were limited in their power to penetrate tissue effectively because of their relatively low energy output. Consequently, pronounced fibrotic skin changes and high absorbed bone radiation levels limited their usefulness in some patients.
As units generating higher levels of energy were developed, the penetrating power of the x-rays produced was enhanced, and less scattering of radiation was seen at the margins of the treatment area. The surface skin dose was also diminished, of particular importance in the treatment of obese patients, and less toxic bone radiation was achieved (Fig. 52–3).
Figure 52–3. Typical isodose curves for orthovoltage (250 keV), cobalt 60, and a 6-MeV linear accelerator (LINAC). The most important difference between the megavoltage (cobalt 60 and LINAC) beams in comparison with the 250-keV beam is the movement of the 100% isodose line several millimeters beneath the surface. This results in elimination of the severe skin reactions characteristic of earlier radiation sources. In addition, the higher energy leads to deeper penetration as the energy of the beam increases.
The goal of external radiation treatment is to ensure that radiation is delivered to the target tissue without affecting uninvolved tissues and that the amount of radiation received is as uniform as possible. Traditionally, the planning of radiation treatment has been done in 2 dimensions (height and width). Today, this is achieved by optimized 3-dimensional conformal planning to more precisely target a tumor with radiation beams (height, width, and depth). Patients undergo computed tomography (CT) scanning in the treatment position, and the volume of abnormal tissue, that is, the gross tumor volume (GTV), is delineated. Given the possibility of microscopic extension along tissue planes, a margin of tissue is added to the GTV. This larger volume, the clinical tumor volume, is the volume of tissue to be irradiated. Using information from these images, special computer programs design radiation beams that “conform” to the shape of the tumor.
Internal Irradiation (Brachytherapy)
Brachytherapy is radiation therapy in which the source of therapeutic ionizing radiation is placed close to the treatment area. The chief advantage of local irradiation is that a relatively high dose of radiation can be applied to a limited anatomic region. The inverse square law has critical implications in clinical applications. The principle of the inverse square law states that the intensity of radiation is inversely proportional to the square of the distance from the source. An important implication is that the rapid falloff of radiant energy supplied by a central source precludes the achievement of cancerocidal doses at the margins of the pelvis. Consequently, external therapy must be used to provide adequate radiation to eliminate tumor at the periphery of large lesions and at the pelvic side walls, where metastatic disease may be present.
Brachytherapy can be delivered using an intracavitary approach with a variety of applicators, or via an interstitial approach using needles or catheters. Most applicators for intracavitary brachytherapy consist of an intrauterine tandem and paired colpostats or ovoids, which are placed in the lateral vaginal fornices. Interstitial applicators consist of multiple needles that are inserted into the tissue at or near the target site. Radioactive isotopes are then loaded into the applicators at the beginning of the treatment.
Several isotopes are available for brachytherapy. The most commonly used in the United States is a low-dose rate (LDR) approach employing cesium-137. However, acceptance of a high-dose rate (HDR) therapy, usually with iridium-192, is quickly gaining acceptance. HDR brachy-therapy offers some significant advantages over LDR, as it can be used on an outpatient basis, eliminates radiation exposure to medical personnel, and has shorter treatment times.
TREATMENT OF GYNECOLOGIC CANCER
Cervical Cancer
Treatment of cervical cancer is considered a prime example of the successful application of radiation therapy. The relative accessibility of a central cervical lesion, a predictable metastatic and local spread pattern, and the radiation tolerance of the cervix and surrounding tissues often permit the administration of curative therapy in cases of cervical carcinoma.
Radiation therapy with curative intent uses both external-beam and intracavitary radiation. Palliative radiation for advanced or recurrent cervical cancer may use either modality for control of bleeding, management of disease in the pelvis, and relief of pain.
The size of the radiation field used to treat a patient with carcinoma of the cervix must be carefully designed to encompass those structures at risk for regional spread of the cancer. The goal of external irradiation in is to sterilize metastatic disease to pelvic lymph nodes and the parametria and/or to decrease the size of the cervical lesion to allow optimal placement of intracavitary radioactive sources. A standard radiation field for external-beam radiation therapy extends inferiorly to the midpubis or 3–4 cm below the most distal disease, superiorly to the interface between the fourth and fifth interlumbar vertebrae, and lateral at least 1cm lateral to the bony pelvic markings. The dose for external-beam radiation therapy is approximately 40–45 Gy.
The rationale for external-beam radiation therapy is the treatment of the lymphatic lymph node chain along the pelvic side walls, but it also induces shrinkage of the primary cervical tumor. However, in order to deliver a curative dose to the tumor, brachytherapy needs to follow external-beam radiation therapy. This is done mainly by HDR radiation therapy applied directly to the tumor via a vaginal applicator. The doses of radiation are commonly calculated based on 2 reference points. Point A defines a point 2 cm lateral and 2 cm superior to the external cervical os in the plane of the implant. Point B is located 3 cm lateral to point A. The total dose for the primary treatment of cervical cancer ranges between 75 and 90 Gy when external and brachytherapy doses are combined.
Definitive radiation therapy is an acceptable alternative to radical surgery for women with early-stage disease (stages IA, IB1, and nonbulky IIA) and is the treatment of choice in more advanced stages. Concurrent cisplatin-based chemotherapy is synergistic and leads to better tumor control and clinical response. Numerous studies show that concomitant radiation therapy and chemotherapy (chemoradiation) improves overall and progression-free survival in patients with cervical cancer.
Concurrent chemotherapy does not generally lead to treatment delays, and it sensitizes cervical cancer cells to the effects of radiation therapy. Its proposed mechanisms of action include interference with and modification of sublethal injury repair, cell phase distribution, tumor vascularity, hypoxic cells, repopulation, cell survival curve, and apoptosis all culminating in maximal cellular lethal damage.
The treatment volume for women undergoing external-beam radiation therapy after radical surgery usually involves the whole pelvis. Patients with known or suspected metastatic disease to periaortic lymph nodes may be considered for extended-field irradiation that includes a para-aortic radiation field.
Endometrial Cancer
The decision to use radiation treatment for endometrial cancer is often made after comprehensive surgical staging has been performed and is dependent on the estimated risk of recurrent disease. Patients have been traditionally divided into different risk groups for adjuvant treatment decisions based on the likelihood of recurrence.
In general, low-risk patients have disease confined to the endometrium. Adjuvant radiation should be considered in patients over 60 years of age and patients with poorly differentiated tumors (grade 3), lower uterine segment involvement, or large tumor size. However, these criteria are controversial, and the decision to administer adjuvant radiation in early-stage disease is made at the physician’s discretion.
Intermediate-risk patients have cancers that are confined to the uterus but invade the myometrium or demonstrate occult cervical involvement. Other adverse prognostic factors that increase the risk for recurrence include invasion of the outer one-third of the myometrium, poor histologic differentiation, and the presence of lymphovascular invasion. The presence of these risk factors might prompt the administration of adjuvant pelvic radiation to reduce the rates of local recurrence.
Patients with high risk of recurrence have tumors with stromal cervical involvement (stage II), extrauterine disease (stage III and IV), or high-risk histologies (papillary serous or clear cell tumors). High-risk histologies have a propensity for lymphovascular and upper abdominal spread and are associated with a worse outcome than the hormone-dependent, more frequent endometrioid adenocarcinomas. When high-risk disease is present and confined to the pelvis, whole-pelvis radiation with or without vaginal brachytherapy should be considered. In the presence of distant disease, a combination of radiation and chemotherapy will be necessary to achieve tumor control.
Primary radiation therapy may be used in women who are considered to be at high surgical risk, such as the elderly and those with significant comorbidities. Patients with well-differentiated adenocarcinoma may be managed with tandem and ovoids or intrauterine Simon capsules. Patients with moderately or poorly differentiated cancers or those with involvement of the cervix are at risk for parametrial and pelvic lymph node spread and should receive whole-pelvic irradiation before brachytherapy.
Ovarian Cancer
The role of radiation therapy in the management of ovarian cancer is minor. There are no well-structured trials that demonstrate the benefit of external-beam radiation in the treatment of ovarian cancer. Several studies have compared the use of intraperitoneal chromic phosphate (32P) with platinum-based chemotherapy in early-stage ovarian cancer. None of these trials showed a difference in 5-year survival rates, but the gastrointestinal complication rate was significant in the radiation group. Local radiation therapy is occasionally used for the treatment of isolated recurrences in ovarian cancer.
Vaginal Cancer
Radiotherapy remains the primary treatment for vaginal cancer, which is one of the rarest human malignancies and historically one of the gravest. A 1954 review of a published series of 992 patients reported an overall 5-year survival rate of 18%. More recent studies, however, have shown overall 5-year cure rates of 40–50%. Such improvement in survival rates is attributed to megavoltage external-beam therapy along with physical and technical advances in local irradiation. Despite radiation therapy being the primary treatment modality for vaginal cancers, there are no standardized treatment protocols. With squamous cell carcinoma comprising the most common form of vaginal cancer, most of these patients undergo whole-pelvic radiation therapy followed by intracavitary or interstitial brachytherapy. Patients with lesions involving the lower third of the vagina should have the inguinal and femoral lymph nodes included in the external-beam treatment field. Extended-field radiation to include periaortic lymph nodes may be needed if imaging studies reveal bulky pelvic or periaortic disease.
Vulvar Cancer
Slightly more common than vaginal cancer (5% vs. 2% of female malignancies), vulvar cancer is usually squamous cell in origin. The mainstay of treatment of stages I and II vulvar cancer is surgical, often consisting of radical vulvectomy plus inguinofemoral lymphadenectomy. Adjuvant pelvic radiation therapy benefits patients with close or positive surgical margins, as well as patients with positive inguinofemoral lymph nodes. In patients with more advanced vulvar squamous cancer (stage III or IV), chemoradiation may reduce the need for more radical surgery, including primary pelvic exenteration.
Complications of Radiation Therapy
Radiation therapy regimens are formulated to maximize the chances for cure while incurring the smallest amount of damage to normal tissues. The effects of radiation on normal tissue are what limit the doses of therapeutic radiation that can be administered. In gynecologic cancers, the most serious complications are those involving the gastrointestinal or genitourinary systems.
Planning of radiation dosimetry takes in account the sensitivity of the pelvic organs, which varies greatly between the different tissues. The vaginal mucosa tolerates 20,000–25,000 cGy in the area of the vaginal vault, whereas the bladder mucosa only tolerates 7000 cGy of total radiation. The rectum mucosa is even more sensitive, with 5000–6000 cGy as the maximum-tolerated dose. The most sensitive pelvic organs are the ovaries, which will cease all hormone production when a dose of 2000 cGy is reached. However, approximately 50% of all ovaries stop hormone production when about half of this dose is delivered.
Complications of radiation therapy are classified as early or delayed. Early radiation reactions result from direct damage of parenchymal cells in organs that are sensitive to radiation. These include enteritis, proctosigmoiditis, cystitis, vulvitis, and, occasionally, depression of bone marrow elements. Bowel side effects usually comprise cramping and diarrhea that require dietary adjustments and the judicious use of antidiarrheal agents. Such problems usually respond to appropriate medication, but occasionally radiation therapy must be interrupted or curtailed because of fulminant acute reactions.
Delayed radiation reactions are believed to be caused by slow vascular damage along with direct damage of parenchymal cells. Such injury may be manifested by chronic proctosigmoiditis, hemorrhagic cystitis, small- and large-bowel strictures, and the formation of rectovaginal and vesicovaginal fistulas. Pelvic fibrosis and loss of ovarian function may affect sexual activity in younger patients.
In order to protect the pelvic organs from radiation injury, isodose curves have to be calculated very carefully to minimize the radiation to the bladder and rectum. In young, fertile patients who require radiation therapy to the pelvis, the ovaries can surgically be moved from their location within the radiation field and area along the paracolic gutters (oophoropexy). In many cases, this will preserve ovarian function after radiation. When brachytherapy is administered using a vaginal applicator, the vagina is packed with gauze around the applicator, therefore creating a greater distance between the radiation source and the bladder and rectum.
NEW DIRECTIONS IN RADIATION THERAPY
Novel, improved radiation treatment strategies are under development. These include more effective radiation sensitizers, neutron beam therapy, and altered fractionation schemes. Intensity-modulated radiotherapy (IMRT) has emerged as a new teletherapy technique. IMRT improves the ability to conform the treatment volume to the 3-dimensional tumor shapes. The radiation beam’s intensity varies according to the shape of the tumor. The radiation dose intensity is increased in areas of gross tumor volume, whereas radiation to the surrounding tissue is significantly decreased. This tumor tailored radiation dose is intended to maximize tumor dose while protecting the surrounding normal tissue. As newer computer-imaging technologies continue to improve, further advances in anatomic contouring for planning and treatment are expected to translate into better local control rates, as well as improved survival with a wider margin of safety.
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