Deborah Citrin
As one of the three widely accepted modalities in the management of cancer, radiotherapy (RT) maintains perhaps the most “alternative” form; it is neither chemical nor invasive. Indeed, because of the general lack of understanding of the physics and biology underlying the principle and practice of RT, many clinicians and patients remain perplexed by its ability to cure disease and the constant evolution in its delivery to maintain the therapeutic window, ultimately designed to preserve quality of life and functionality while eradicating disease.
RADIATION BIOLOGY AND PHYSICS
Although radiobiology and physics are clearly separable in theory, and many textbooks have been written to focus on one or the other, a practical understanding of one subject cannot be easily delineated from the other.
Prior to discussing the biology and antineoplastic activity of RT, it is important to understand the basic physical properties of contemporary RT, in terms of both its activity and its production by a modern linear accelerator. The most common form of RT used today is a photon, or packet of x-rays. Discovered by Wilhelm Röntgen in 1895, photons were found to blacken photographic film; as these “new kinds of ray” were unable to be measured at the time, they were called “x-rays.” Shortly following their discovery, Wilhelm Freund treated a mole with the x-rays, giving birth in 1897 to the field of therapeutic radiology or radiation oncology. The following year, in 1898, Antoine Bequerel discovered radioactivity and the Curie family isolated radium. Indeed, because of the transportability and ease of administration, radioactive elements such as radium remained the preferred route of RT until only recently. Subsequent experiments demonstrated that the energy released by the radioactive decay of an element, so-called γ-ray, was identical to that artificially produced by a gas tube, an x-ray. Today, most modern RT consists of photons produced by linear accelerators, though there are many effective and curative applications from radioactive decay, generally termed brachytherapy.
Mechanism of Action
RT, in any of its forms, represents ionizing radiation because the energy passed from RT to the tissues is sufficient to cause an outer orbital electron to be released, thus ionizing or charging the tissue’s atom. Specifically, x-rays and γ-rays are forms of electromagnetic radiation, while the less commonly used forms of RT (protons, neutrons, mesons, carbon ions) are generally termed particulate radiation because they have mass. Despite the fact that RT “excites” or ionizes tissue particles, and thus can be measured by calories, it does not increase the temperature of the recipient or induce a thermal effect. So-called radiation burns are not thermal; the erythema of the skin is a reflection of the denudement of the superficial layers of the skin, caused by the increased cellular turnover induced by RT, leaving behind the better-vascularized deeper dermal tissues to show through as red.
When RT is delivered it is either directly or indirectly ionizing. Particulate, charged, or heavy ions deliver their energy to the tissue by direct effect; that is, these particles have enough kinetic energy to directly alter the genetic material with which they make contact. On the other hand, electromagnetic RT (γ- and x-rays) affect cells by indirectly ionizing them. These rays give up their energy to the absorbed tissues, thus causing the formation of fast-moving charged particles. Typically, the energy of an x-ray or γ-ray is passed to many circulating electrons (often called free radicals), which then go on to interact with various host tissues, including the genetic material of cancer cells. It is this interaction with the DNA of cancer cells that underlies the biology of RT.
Linear Accelerator
Modern RT is manufactured by a complex machine called a linear accelerator. The basic premise of this technology is that electrons are accelerated to a frequency of 3,000 megacycles per second and then are shot at a tungsten steel target. The negatively charged electrons are then repelled by the orbiting electrons of the steel target and, as they are deflected away and change direction, they lose some energy. In the observation of Newton’s laws regarding conservation of energy, the energy lost by the deflection of the electron interaction is gathered into a form, called an x-ray. The gathered x-rays (photons) are then shot out of the head of the linear accelerator into the patient. There are many beam-modifying devices (wedges, compensators, and blocks, among others) that can be placed between the accelerator and patient to conform the radiation to accomplish its goal of sparing normal tissues while targeting tumors.
Treatment Planning
In order to determine the methods and specifics by which the beam should be modified to accomplish its goals, the radiation oncologist works closely with several specialists. In fact, because of the complexity and ever-changing landscape of the field of radiation oncology, the days when the single clinician could consult a patient, set them up for treatment, calculate the physical parameters of the RT, and actually deliver the treatment are extinct. Many clinicians have been trained to operate all elements of the department, but this remains inefficient and the increasing volume of patients for whom radiation therapy is a necessary modality has relegated the clinician to consultation of the patient, delineation of the treatment target, prescription of the RT, and oversight of the various affiliated healthcare professionals responsible for the myriad of treatment responsibilities.
In today’s modern department, a simulator technologist sets the patient on a fluoroscopy unit or CT simulator to determine the site to be treated. The medical dosimetrist then takes the clinician’s prescription and assists in determining the most appropriate beam arrangement to accomplish the goals of therapy. The medical physicist, whose main responsibility is to ensure the machines are properly referenced and operating without any problems on a daily basis, calculates the dose delivered by the machine to coincide with the prescription without error. The radiation technologists then actually deliver the radiation therapy, closely following all set-up data provided to them by the physician, dosimetrist, and simulator technologist. The radiation technologist may also be responsible for performing ultrasounds, x-rays, or CT scans of the patient prior to each treatment fraction to ensure that the location receiving treatment is without error. The radiation oncology nursing team then evaluates the patient every few days of treatment to ensure there are no concerning side effects that require attention and they, along with the physician, initiate the appropriate clinical response. Furthermore, with the increasing realization that RT is often improved by sensitizing tumors with targeted agents and cytotoxic and cytostatic chemotherapeutics, the nurse and physician need to be more aware of potential interactions, toxicities, and tumor-response parameters than previously encountered when RT alone was delivered. Because of the evolving combined- or multimodality approach to many cancers, it is important to mention the pure biologic characteristics of tumors and normal tissues, to appreciate how and why RT alone has become less commonly used in the definitive and curative treatment of cancer.
FUNDAMENTALS OF RADIOBIOLOGIC PRINCIPLES
There are four fundamental radiobiologic principles that are considered by a radiation oncologist when determining the course of RT to be delivered: cellular repair, repopulation, redistribution, and reoxygenation.
Cellular Repair
The ability of a cell to repair potentially lethal damage induced by RT remains one of the basic differences between malignant and normal tissues. Normal cells maintain an enhanced ability to repair RT damage, while malignant cells generally do not have that capacity. However, at a certain threshold dose of RT even normal, nonmalignant tissues lose the capacity to recover and therefore attention to dose is critically important to avoid permanent damage to uninvolved tissues. Estimates and guidelines have been published to guide clinicians on total doses, daily doses, and volumes of tissue irradiated, beyond which normal tissue toxicities will be encountered.
Cellular Repopulation
Cellular repopulation is a phenomenon often observed following the initiation of RT. The often-recited theory to explain this event is that as a percentage of cells are destroyed by RT, the remaining living cells have access to greater relative blood supply and nutrients, among other probable growth-related cytokines, resulting in greater growth of the remaining fraction of cells. Indeed, this is observed clinically in head and neck cancers, cervical cancers, and lung cancers prompting the standard that definitive RT be completed as soon as possible and without avoidable treatment breaks.
Cellular Redistribution
Cellular redistribution refers to the portion of the cell cycle within which a cell resides at a specific time. Tumors divide at varying rates and portions of the cell cycle are inherently more sensitive to antineoplastic agents. Notably, RT most effectively eradicates cells in the G2-M junction, while cells in the S1 portion of the cell cycle are relatively unresponsive. The benefits and purpose of exploiting cellular redistribution underlie the concept of fractionated RT. By dividing the RT dose daily over many weeks, there is a greater chance that RT delivery will coincide with cells in the responsive portion of the cell cycle, resulting in greater cell kill. As a corollary, cellular cytostatic agents thought to cause cellular arrest in a certain portion of the cell cycle (i.e., tamoxifen) have been theorized to potentially reduce the benefits of RT, though recent studies have demonstrated the absence of a clinical decrement.
Cellular Reoxygenation
Cellular reoxygenation remains one of the most critical elements of RT effect. The indirect ionization occurs when electromagnetic radiation (x-rays) enter target tissues and excite electrons, typically from cellular water, to free radical status. These free radicals then directly alter the tumor’s DNA, inflicting a potentially lethal injury. If the damaged DNA interacts with oxygen, the damage is no longer reversible and is said to be “fixed.” In vitro and clinical data clearly demonstrate that relative tissue hypoxia reduces the killing effect of RT. In many tumor sites, including cervix and head and neck, low oxygen levels or relatively low hemoglobin levels significantly reduce the benefits of RT. Further evidence that electron free radicals are the “smart bombs” formed by RT is the clinical loss of local control when antioxidants (namely, megadoses of vitamin C and E) are ingested concurrent with RT.
Clinical Radiation Oncology
Radiation is used to treat a variety of malignancies with curative intent. Radiation can be used alone, or in combination with surgery and/or chemotherapy. Often, the use of radiation in combination with chemotherapy or surgery can be used for a strategy of reducing morbidity of therapy or improving functional outcomes. For example, the use of limited surgery and radiation to the breast has been used as an alternative to mastectomy. Similarly, the use of chemotherapy combined with radiation has been found to be a successful method to preserve the larynx in patients with advanced laryngeal tumors.
RT may also be used to palliate symptoms of advanced cancer. Malignant spinal cord compression, superior vena cava syndrome due to tumor, and airway compromise are all oncologic emergencies that may be treated with RT. Radiation may also be used to palliate symptoms of bone pain, to treat brain metastases, and to treat other symptoms caused by mass effect from tumors.
With the exception of fatigue, the side effects of radiation are dependent on the area of the body being treated. For example, alopecia and skin irritation and redness may occur in the area being treated. Patients receiving radiation to the chest may experience cough, dysphagia, and odynophagia during treatment, while patients treated to the pelvis may experience loose bowel movements or urinary frequency. Most side effects of radiation resolve within a few weeks to months after treatment is completed. Less frequently, patients may experience long-term side effects after treatment. Included in the rare late toxicities is a risk of a cancer caused by radiation in the site treated.
RADIOSENSITIZATION
Sensitization refers to the increased clinical response of a tumor to a combination of any agent delivered concurrently with RT. Almost every cytotoxic systemic agent has the ability to sensitize tumors to RT. Many targeted and biologic drugs also have this ability, especially if they inhibit DNA repair or pathways associated with survival after radiation (such as EGFR) are inhibited. Most potent in their ability to sensitize are the anthracyclines and platinum agents, though the newer taxanes and gemcitabine have clearly demonstrated an ability to increase both tumor and normal tissue response to RT. The mechanism behind chemotherapy-induced cellular sensitization to RT appears to be a result of the incorporation of halogenated pyrimidines into the tumor’s DNA. The new analog weakens and damages the DNA, rendering it incapable of repairing RT-induced injury. Experiments have shown that only several generations of substitutions can inflict this type of DNA injury; thus the most effective sensitization occurs when the systemic agent is delivered concurrently with RT, or for several cycles prior to the RT. Because of the increased normal tissue effect of concurrent therapies, they are considered only when a significant survival benefit has been proven in randomized trials. Combined modality therapy is currently the accepted standard for patients with a range of malignancies, such as cervical cancer, advanced head and neck cancer, glioblastoma, and gastrointestinal malignancies. For other cancers, such as breast cancer, RT is typically given without concurrent chemotherapy.
INTENSITY-MODULATED RADIOTHERAPY
Intensity-modulated radiotherapy (IMRT) refers to any technology wherein dose is modified to differentially treat target tumor and uninvolved normal tissues. Several different techniques are currently in use to accomplish IMRT, including customized brass-based tissue compensators and multileaf collimation, the latter of which is used in a dose delivery system that is either dynamic or static. The dynamic system arcs around the patient, delivering different beamlets from each beam’s-eye view of the tumor, accomplishing this dose delivery from an almost limitless number of angles. The static systems aim and shoot x-rays from each angle and then the machine stops and rotates before targeting the tumor from a new angle; this dose delivery is usually accomplished from four to eight different angles. IMRT allows the delivery of radiation in a more conformal nature than was provided by other techniques used previously, thereby sparing normal tissues from higher doses.
STEREOTACTIC THERAPIES
New techniques have been developed to increase the conformality of treatment with the goals of minimizing the amount of tissue receiving high doses of irradiation and allowing delivery of larger fractional doses. An example is stereotactic radiation which is usually accomplished by immobilizing the patient with specialized equipment that provides a high degree of accuracy and precision. This allows treatments to be delivered to a smaller area since less margin for patient movement is given. Often, these treatments are given in one to five large fractions instead of the typical daily fractionation used for conventional treatments. These treatments can be used for tumors in many locations, including the brain and are also commonly used for patients with oligometastatic disease.
PARTIAL-BREAST IRRADIATION
Partial-breast irradiation (PBI) refers to any technique used to irradiate a portion of the breast. The most commonly used technique includes intracavitary methods (Mammosite, Contura, Savi), wherein a balloon with one to eight catheters jointly housed are postoperatively placed within the surgical tumor bed. High-dose–rate brachytherapy is then delivered remotely and directly to the tumor bed, typically twice daily for 1 week. A prospective phase 3 Intergroup trial comparing PBI to standard whole-breast RT is currently accruing patients to determine whether PBI is equal. Other forms of PBI include three-dimensional conformal RT (using external beam RT directed at the tumor bed with a noncoplanar beam arrangement of generally three to four beams), intraoperative electron beam teletherapy (mostly used in Europe where the exposed tumor bed is irradiated with a single high-dose beam), and low- or high-dose rate interstitial brachytherapy (where intraoperative catheters are placed within and surrounding the tumor bed cavity). Interstitial brachytherapy has the longest experience of PBI, though the operating room time, potential need for an inpatient admission, and risk of developing a pneumothorax has made this technique less favorable for patient and clinician.
PROTONS
The most commonly used form of electromagnetic radiation in the field of radiation oncology is photons, or x-rays. These particles are uncharged and their energy slowly dissipates when they enter the body. Depending upon the location of the tumor and the angle or beam perspective, other uninvolved structures receive radiation and this leads to side effects. Most photon beams require between 1 and 1.5 cm of normal tissue to traverse before enough dose has built up to achieve maximum dose effect, and the dose then regresses over a 2 to 5 cm length of tissue beyond the target tumor.
Protons are charged particles with very different physical characteristics than x-rays or photons. Protons enter the body at a very low energy level and can rapidly escalate to maximum energy over a few millimeters, deep within the body. This effect, called a Bragg peak, allows the length over which maximum dose is delivered to be minimized and thus less normal tissue receives a high dose. Protons have been shown to be effective when tumors are closely situated adjacent to critical structures, where any considerable radiation dose could be devastating, such as the spinal cord, brain, retina, or developing tissues in a child.
Because of the extraordinary expense associated with the creation of protons, their use has been limited to very few malignancies and few centers have maintained any degree of expertise with their use. Because of increasing pressure to maximize economic advantages, however, more centers have recently begun to develop their own proton beam facilities and the use of this special particle beam has started to evolve, with the more common prostate and lung cancers now being treated. Much data have been generated comparing the normal tissue dosing and side effects of protons, but direct randomized comparisons with other types of RT delivery in regard to side effects and outcomes are not available.
REVIEW QUESTIONS
A 43-year-old woman is diagnosed with breast cancer. She was found to have disease amenable to breast conservation, in which she will receive lumpectomy and radiation. It is felt that she will require chemotherapy based on the tumor characteristics.
1.Which type of radiation is NOT appropriate for delivering treatment as part of breast-conserving therapy for breast cancer patients?
A.Brachytherapy
B.Whole-breast RT
C.Radionuclide therapy
D.PBI
2.The patient undergoes RT to the breast. She can expect which of the following side effects?
A.Nausea
B.Skin redness on the breast
C.Alopecia
D.Urinary frequency
3.Dividing radiation treatment into several doses or fractions is used for which reason?
A.To decrease oxygen delivery to tumors
B.To increase the likelihood of damaging tumor cells in a sensitive phase of the cell cycle
C.To increase the number of DNA single-strand breaks in tumor cells
D.To decrease the vasculature of tumors
4.The lethality of radiation to tumors occurs primarily through interactions with which cellular components?
A.Carbohydrates
B.Exosomes
C.Lipid bilayer
D.DNA
5.IMRT is used to treat the patient with breast cancer. Which of the following is a benefit of using IMRT compared to other external beam radiation approaches?
A.More damage to DNA
B.More conformal treatment
C.Higher dose given to the tumor
D.Shorter overall treatment time
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