Veterinary Radiation Therapy: Review and Current State of the Art
Veterinary radiation oncology became a recognized specialty in 1994. Radiation therapy is an important component of a multimodality approach to treating cancer in companion animals. It is important to understand the many aspects of radiation, including the equipment used in external beam radiation therapy, the basic mechanism of action of ionizing radiation, the results of irradiating various histopathological types of tumors, as well as the associated potential acute and late side effects of radiation. A comprehensive review of radiation therapy is timely and provides information for clients on cancers that may benefit from external beam radiation therapy.
Introduction
Radiation therapy is becoming increasingly available and in demand following greater awareness of radiotherapy as a treatment option for pets with cancer.1 Veterinary oncologists have recognized the utility of radiation therapy in a field where a multimodal approach is imperative if cancer is going to be controlled and potentially cured. Significant advances are being made in clinical veterinary radiation oncology, such as the utilization of megavoltage (high energy) radiotherapy, daily radiation therapy protocols with administration of higher total doses of radiation, and the use of computed tomography (CT) for both tumor imaging and radiation treatment planning. The purpose of this paper is to review various aspects of radiation therapy, including the equipment, mechanism of action, radiation treatment planning, response to radiation therapy, acute and late radiation side effects, and recent advancements in radiation oncology.
External Beam Radiation Equipment
External beam radiation sources include beams of X-rays, gamma rays, or electrons delivered by either orthovoltage or megavoltage (e.g., cobalt 60 and linear accelerators) radiation therapy equipment. Megavoltage refers to the use of higher energy radiation, which is defined as 1 million volts (MV). 2 Teletherapy refers to the use of radiation applied from a distance to the patient. Orthovoltage equipment is now used only on a limited basis in veterinary radiation oncology. The trend over the past 20 years was toward the installation of cobalt 60 units, and now many veterinary radiation facilities have converted to linear accelerators.1
Orthovoltage
Orthovoltage radiotherapy entails the use of X-rays that are generated by bombarding a metallic target (i.e., tungsten) with high-energy electrons. Orthovoltage machines produce X-rays with an energy range of 150 to 500 kilovolt (peak; kVp), and most operate at 200 to 300 kVp.2 This is relatively low energy radiation, with the maximum radiation dose deposited at the skin surface. The dose falls to 90% at approximately 2 cm of depth in tissues, thereby limiting the use of orthovoltage to lesions 2 to 3 cm in depth. 2,3 It is difficult to deliver an adequate dose to deep-seated tumors with orthovoltage, because the skin dose becomes prohibitively large. With orthovoltage, there is a differential absorption of radiation dose in bone compared to soft tissue (greater in bone by a factor of 2 to 4 times) that results in the risk of bone damage or necrosis when irradiating tumors surrounding or involving bone.3
Orthovoltage units are operated at a relatively short source-to-skin distance (usually 50 cm), which limits the size of the radiation treatment field.2 The size and shape of the radiation treatment field are defined by cones of various shapes (e.g., circular, square) that attach to the radiation unit and extend down to the surface of the animal in order to direct the radiation. Orthovoltage irradiation is primarily suited for the treatment of superficial tumors that do not involve adjacent bone.
Cobalt 60
Cobalt 60 teletherapy radiation units emit gamma rays from a radioactive source with a 5.26-year half-life (the half-life is the time required for a radioactive isotope to decay to half of its original strength).3 The average energy of cobalt 60 is 1.25 MV, which places it in the category of megavoltage radiation therapy.3 With megavoltage radiotherapy units there is a “skin-sparing” effect, because the maximum radiation dose is not deposited at the skin surface. Rather, the maximum dose is deposited at a depth of 0.5 cm below the skin surface.2 As a result of this “skin-sparing” effect, there is less skin reaction than with orthovoltage radiation. Treatment of superficial tumors and cancer cells that may be located along a surgical incision requires that material with a tissue-equivalent depth be placed over the site to allow the radiation dose to build up so that maximal deposition starts at the skin surface.
Cobalt 60 units are typically isocentric units; the animal is positioned on the treatment couch, and the radiation source located in the head of the machine is rotated around the animal to deliver radiation from multiple angles. Greater penetration of the radiation beam occurs because of the higher energy, which is advantageous for the treatment of more deeply seated tumors.2 Additionally, uniform deposition of the radiation dose occurs in bone and soft tissue. The source-to-skin distance is typically 80 cm, so larger field sizes are possible than with orthovoltage radiation units.2 The radiation field size is altered by changing the position of collimators (i.e., two pairs of thick metal blocks that can be moved to form either rectangular or square fields). Additional radiation field shaping is done through the use of lead blocks (preformed or custom made) that are placed on a tray located near the head of the machine (between the machine and the animal).
Cobalt 60 is indicated for tumors at many different sites and is effective against many tumors in companion animals.4 The primary limitation of cobalt 60 teletherapy is the difficulty encountered in irradiating large fields located over critical, normal tissues. For example, the treatment of tumors that overlie the thorax or abdomen may result in unacceptable toxicity and higher morbidity from the delivery of a radiation dose at the depth of critical tissues. In these instances, a linear accelerator with electron capability is preferable.
Linear Accelerator
Linear accelerators utilize X-rays (also referred to as photons) or electron beams and provide greater flexibility in treating both deep and superficial tumors.2 Linear accelerators use high-frequency electromagnetic waves to accelerate charged particles (i.e., electrons) to high energies through a tube. The electrons can be extracted from the unit and used for the treatment of superficial lesions, or they can be directed to a target to produce high-energy X-rays for treatment of deep-seated tumors.2 The photon energy is higher and variable (range 4 to 25 MV), depending on the machine’s specifications. Some units have dual photon energies (e.g., 6 and 10 MV photons).2
Electron capability is available with >6 MV energy photon machines.2 Linear accelerators with electron capability have a range of different electron energies, from 4 to 22 million electron volts (MeV), depending on the manufacturer and specifications.2 There is a skin-sparing effect with photon radiation, and the depth at which the maximum dose is deposited increases with increasing energy [Table 1].5
Collimation of the photon beam and field shaping are accomplished by two sets of jaws that can move independently to form square or rectangular fields. Further modification of the field requires the use of lead blocks (preformed or custom made). Some linear accelerators are equipped with a multileaf collimator, which consists of a large number of pairs of narrow rods with individual motors that drive the rods in or out of the treatment field, thus creating the desired field shape. The source-to-skin (or axis) distance is typically 100 cm, and this relatively large source-to-skin distance allows treatment of larger fields than with either orthovoltage or cobalt 60 units.2 Additionally, linear accelerators have a higher radiation output so that treatment times are shorter.
For electron beam therapy, a cone is attached to the head of the machine that collimates the beam [Figure 1]. Electrons scatter in air, so beam collimation is extended close to the body surface (5-cm offset). Electron cones are available in a number of sizes (e.g., 5-cm circular cones and 10-, 15-, 20-, and 25-cm square cones), with secondary beam shaping accomplished by lead cutouts placed at the end of the cone closest to the animal.3 Electron cutouts are typically custom made.
Electron beams are used to treat superficial lesions and are particularly useful for treating lesions that overlie critical, normal tissues such as the heart, lungs, kidneys, liver, and gastrointestinal tract. Electron beam dosimetry is notably different from photon dosimetry. The dose falls off rapidly in tissues [Table 2], and a comparison of Tables 1 and 2 demonstrates the extent to which this attenuation of dose allows safe delivery of radiation to tumors overlying critical structures.5 The penetration (in cm) of electrons in tissue is approximately 0.5 × their energy in MeV. For example, 12 MeV electrons penetrate to a depth of approximately 6 cm, and dose at this depth is <10%. Electrons lose approximately 2 MeV of energy for each centimeter traversed in tissue.6 Normally the 80% or 90% depth isodose curve is used to encompass the target volume. The 80% isodose curve lies at a depth (in cm) of tissue that is about 0.33 × the MeV.6 In general, higher energy electron beams deliver a higher surface dose than lower energy electron beams. With lower energy electron beams (<15 MeV), there is a significant skin-sparing effect, and if tumors involve the skin, it may be necessary to add tissue-equivalent material to the site to increase the skin dose.6
Quality Assurance for Radiation Therapy
The requirements for quality assurance are greater with linear accelerators than with either cobalt 60 or orthovoltage radiation.7 Daily inspections such as safety (e.g., door interlocks, audiovisual monitors) and mechanical checks (e.g., lasers, distance indicator) are performed for both cobalt 60 and linear accelerators. Linear accelerators additionally require daily assessments of X-ray output constancy and electron output. Linear accelerators are complex pieces of equipment requiring frequent and higher levels of technical support (provided by a medical physicist) and appropriate dosimetry equipment for daily, monthly, and yearly checks.
Mechanism of Action of Ionizing Radiation
Electromagnetic radiation, which includes X-rays and gamma rays (both also referred to as photons), is indirectly ionizing.8 Ionizing radiation is radiation that has sufficient energy to dislodge electrons from a stable orbit. X-rays and gamma rays do not directly cause damage, but rather they give up their energy when they are absorbed in tissue and produce fast-moving charged particles that, in turn, cause chemical and biological damage.8 When X-rays or gamma rays interact with an orbital electron, the electron may be shifted to a higher energy orbit (i.e., excitation) or, more commonly, be ejected from the atom (i.e., ionization; called a fast electron). The fast electrons ionize other atoms, break chemical bonds, and initiate the chain of events that ultimately is expressed as biological damage.8
The process by which X-ray photons are absorbed depends on the energy of the photons and the chemical composition of the tissue. For cobalt 60 and linear accelerators, the Compton process dominates.8 For photon energies characteristic of diagnostic radiology and orthovoltage X-rays, both the Compton and photoelectric absorption processes occur.8 In the Compton process, the photon interacts with an electron having a binding energy that is negligibly small compared with the photon energy.8 Part of the energy of the photon is given to the electron as kinetic energy. The photon, with whatever energy remains, continues on its way but is deflected from its original path. The result is a fast electron and a photon of reduced energy that may participate in additional interactions. The mass absorption coefficient for the Compton process is independent of the atomic number of the absorbing material, so no differential absorption of dose occurs in bone versus soft tissue with megavoltage (i.e., cobalt 60 and linear accelerators) radiotherapy as compared to orthovoltage radiotherapy.8
In the photoelectric process, the photon interacts with a bound electron.8 The photon gives up all of its energy to the electron. Some of the energy is used to overcome the binding energy of the electron and release it from its orbit, while the remainder is given to the electron as kinetic energy of motion. The mass absorption coefficient for photoelectric absorption varies with atomic number (Z) and is approximately proportional to Z3.8 Because the mass absorption coefficient varies with Z, X-rays are absorbed to a greater extent by bone (calcium has a high atomic number) with orthovoltage X-rays and in diagnostic radiology. For radiotherapy, high-energy photons are preferred, because the Compton process is of primary importance, and the absorbed dose is approximately the same in soft tissues and bone.
In terms of radiation damage, deoxyribonucleic acid (DNA) is the most critical target, although there are a number of other events that result in perturbation of cellular homeostasis and contribute to cell death.8 Although electromagnetic radiation is an indirectly ionizing radiation, direct and indirect mechanisms of action also exist.8 In the direct action, a secondary electron resulting from absorption of an X-ray photon interacts with DNA to produce an effect. In the indirect action, the secondary electron usually interacts with a water molecule to produce free radicals (i.e., hydroxyl radical) that, in turn, damage DNA.8 A free radical is an atom or molecule carrying an unpaired orbital electron in the outer shell, which is a state associated with a high degree of chemical reactivity. Free radicals can damage DNA or can revert back to a stable form. Approximately two-thirds of the biological damage of X-rays arises from indirect actions.
Cells typically die after irradiation when they attempt to divide at the next or a later mitosis, referred to as mitotic death. Some cells die by apoptosis (i.e., programmed cell death); an example of this is the lymphocyte.8 Oxygen is very important in radiation therapy. Free radicals are the primary cause of damage to DNA. If oxygen is present, it will react with the free radical, producing an organic peroxide that is a nonrestorable form of the target material.8 In other words, the reaction results in a change in the chemical composition of the material exposed to radiation. This particular reaction cannot take place in the absence of oxygen. If oxygen is not present, then many of the ionized target molecules can potentially repair themselves and recover the ability to function normally. Cells that are not well oxygenated (i.e., hypoxic cells) are two to three times more resistant to the effects of radiation because of this oxygen-related effect.
Fractionation of Radiation Therapy
In external beam radiation therapy, the total radiation dose is typically delivered as a number of smaller doses or fractions. The rationale for fractionation of radiation therapy lies in the potential of a differential response of tumor cells as opposed to normal tissue.8 Tumors frequently have a subset of cells that are not well oxygenated, and fractionating the dose allows for reoxygenation of tumor cells and subsequent killing of more tumor cells. Cells that normally turn over or renew themselves, such as oral mucosa, undergo accelerated repopulation and result in a differential recovery of normal tissue as opposed to the tumor cells. Tumor cells that are irradiated redistribute in the cell cycle with movement of the cells into a more radiosensitive phase of the cell cycle (i.e., G2M). It is also possible for normal cells to repair radiation damage between fractions, although repair may also occur in tumor cells.
External Beam Radiation Therapy
Patient Evaluation
A number of steps are involved in radiation therapy, starting with a thorough patient evaluation. It is important to determine the ability of the animal to undergo radiation therapy, specifically the ability to undergo multiple episodes of general anesthesia. The initial evaluation may include, but is not limited to, a complete blood count (CBC), biochemical profile, urinalysis, and thoracic radiography. It is imperative to be cognizant of any concurrent conditions that may limit longevity and impact the decision to proceed with a full course of radiation therapy. The presence of regional and distant metastases must be evaluated, possibly through regional lymph node aspiration, three views of thoracic radiographs, and abdominal ultrasonography. Aspiration cytology or biopsy of a regional lymph node is performed as indicated, based on the expected biological behavior of the primary tumor, not just on the basis of detectable lymphadenopathy.
Tumor Imaging
Tumor imaging and localization are important parts of radiation treatment planning. A number of different modalities are used to identify tumor location, as well as the extent of disease. The most commonly used imaging tools are radiography and CT. Other imaging tools include ultrasonography, nuclear scintigraphy, and magnetic resonance imaging. Computed tomography is also a critical component of computer-assisted radiation treatment planning. Based on a CT scan, it is possible to make an initial assessment of the extent of disease; determine the potential inclusion of critical, normal tissues in the treatment field; and make a risk versus benefit determination.3
Tumor Diagnosis and Selection of Therapy
Histopathology of the tumor and tumor grading can assist in determining the potential usefulness of radiation therapy and the expected prognosis. For example, postoperative irradiation of an incompletely resected, low-grade soft-tissue sarcoma would likely improve long-term local control, but treatment of a high-grade and potentially metastatic soft-tissue sarcoma would carry a poorer prognosis. Animals with radiosensitive tumors and localized disease are considered good candidates for radiation therapy.4 Animals with distant metastases or radioresistant tumors may still potentially benefit from radiation therapy, but the procedure may involve palliative radiotherapy or a combination of radiotherapy and cytoreductive surgery. In addition to the decision of whether to pursue radiation therapy, a decision must be made as to whether to recommend a full course of therapy or more coarsely fractionated (i.e., fewer treatments but larger dose per fraction), palliative radiation therapy.
Postradiation Evaluations
After completion of radiation therapy, it is important to evaluate the animal for both tumor response and side effects induced in normal tissues. A typical recheck schedule includes an evaluation 2 and 4 weeks after the end of radiation therapy. Subsequent rechecks are recommended at 2, 3, 5, 7, 9, and 12 months, and then every 3 to 6 months thereafter, depending on the tumor type, expected behavior, and anticipated local and/or distant failure rate.
Portal Radiography
The first time an animal is to be irradiated, it is anesthetized and positioned for radiation, and the treatment field is designed. The actual location of the field and position of the animal are checked with a port film (also referred to as a localization film).9 The radiation source is used to expose the film, a process called portal radiography. Special film and screen combinations are used for taking radiographs using the high-energy X-rays from radiation units. One exposure is made that delineates the radiation treatment field; then the collimators are opened, and a second exposure allows visualization of the surrounding normal tissues [Figure 2]. The central region that outlines the treatment field is exposed twice and is darker.
Port films are made on the first day of treatment and then repeated at least one other time, once weekly, or as necessary to check both the animal and field positions. Port films are an important part of radiation quality assurance. The port film is used to confirm the location of the treatment field, both in terms of assessing inclusion of tumor and in documenting normal tissues irradiated. The port films are also used to assess whether any blocks that are being used to protect normal tissues are appropriately placed. Port films can be compared to the digitally reconstructed radiograph of the treatment field for CT-based, computer-generated treatment fields [Figure 3].10,11 Port films are an important and permanent part of the animal’s medical record. They can be referenced to determine if a tumor recurrence is within or outside the irradiated field, if the animal develops a secondary problem in the irradiated field, or if another tumor arises in close proximity to the original tumor where subsequent overlap of the radiation fields is a concern.
Verification films are also acquired on a limited basis to verify the extent of the treatment field.10 The film is left in place for the full delivery of one fraction of the radiation dose. The standard of care in human radiation facilities is CT simulation prior to the beginning of radiation therapy. Treatment simulation is only done at a limited number of veterinary radiation facilities, so portal radiography has been the standard of care for setting up radiation treatment fields in animals.
Radiation Therapy Protocols
The radiation dose is the absorbed dose of energy deposited in the tissue. The unit of dose is the Gy (gray), which is defined as 1 joule/kg. One Gy is equivalent to 100 cGy (centigray).12 One cGy is the same as 0.01 Gy. Older terminology used units in rads, with 1 rad being equivalent to 1 cGy.
A standard radiation protocol for a full course of definitive radiation therapy involves the delivery of 2.25 to 3.2 Gy/fraction, given daily on Monday through Friday for a total of 16 to 25 treatments and a total dose of 48 to 63 Gy.1 A palliative radiation protocol entails the use of a larger dose per fraction and a lower total dose of radiation, such as 8 Gy/fraction, given once weekly for 4 consecutive weeks, for a total dose of 32 Gy.1 Other palliative radiation protocols include twice-weekly treatments for 3 weeks (e.g., 6 Gy/fraction for six treatments) and daily (Monday through Friday) treatments for 1 week (e.g., 4 Gy/fraction for five treatments). Radiation protocols can vary based on the tumor type, stage, and site, as well as from one facility to another. It is important to discuss the specific aspects of treatment with the oncologist(s) at the facility that will be delivering the radiation therapy.
Radiation therapy requires anesthesia. The radiation beam is collimated, but there is some level of radiation in the radiation vault while the beam is on, so personnel cannot be in the room during the procedure. Most radiation facilities induce anesthesia with propofol or mask delivery of sevoflurane and then intubate and maintain the animal on gas anesthesia (i.e., isoflurane or sevoflurane).1 Injectable drugs alone are used at some facilities (e.g., propofol infusion, medetomidine, and butorphanol, etc.).
Radiation Treatment Planning Options
Treatment planning can be done manually or by computer. Manual treatment planning entails calculations done by hand based on the field size, depth of treatment, and beam characteristics of the radiation unit. The types of setups that are typically done with manual treatment planning are either single treatment fields or bilateral, parallel-opposed fields.3 Complex treatment fields necessitate CT-based, computer-generated treatment planning. There are a number of considerations and indications for CT-based treatment planning.3 When imaging a patient for radiation treatment planning, it is important that the animal be positioned exactly as it will be for radiation therapy. A table-top insert may be necessary, as CT couches are typically concave, and a flat surface is required to reproduce the same positioning as the flat treatment couch for radiation therapy. Repositioning devices such as alpha cradles, vaclok positioners, thermoplastic masks, and bite blocks aid in accurately repositioning the animal for a fractionated course of radiation therapy, and they are also used at the time of treatment planning.13–15
It is important to maximize the amount of information obtained from the initial CT. Enhanced tumor imaging is possible through the use of intravenous contrast medium, placement of radiopaque catheters in hollow viscera, and the use of barium paste or other markers (small BBs or wire) on the skin to identify surgical incisions or other pertinent anatomical landmarks. Computed tomography images are then directly downloaded to the treatment planning computer. Computer-assisted radiation treatment planning systems vary in their level of sophistication and can range from two- to three-dimensional conformal or intensity-modulated plans.16,17
Three-dimensional radiation treatment planning systems provide information regarding radiation dose to both the tumor and normal tissues in three dimensions. Dose-volume histograms provide information on the dose to tumor and normal tissues in both graphical [Figure 4] and tabular forms.11 Dose-volume histograms are useful for evaluating and comparing radiation treatment plans.
Definitive Versus Palliative Therapy
A definitive course of radiation therapy involves daily treatments Monday through Friday under general anesthesia. In prescribing a definitive course of therapy, the assumption is made that the potential exists for long-term control of the tumor. In general, it is anticipated that the animal will live on average for 1 year after radiation therapy. The acute side effects that are seen with a full course of radiation therapy are likely to cause a temporary decrease in the quality of life for a variable period of time (on the order of 3 to 6 weeks).
Palliative radiation therapy is used for animals that have a decreased quality of life from the presence of a tumor but are not expected to have a good response to a full course of radiation therapy. Animals treated with palliative therapy typically live for 2 to 6 months, although there are exceptions.4 Acute radiation side effects are substantially less with palliative therapy, so there is minimal degradation and hopefully improvement in the quality of life. The goals of palliative therapy are to alleviate pain associated with the tumor, decrease the size of any mass obstructing an airway or the gastrointestinal tract, and to otherwise alleviate debilitating signs of cancer.18 Palliative radiation therapy is not intended to prolong survival but to improve the quality of life for the time remaining.
Radiation therapy alone has some efficacy in the treatment of a limited subset of tumors. Tumors that are considered radioresponsive include the transmissible venereal tumor, extramedullary plasmacytoma, basal cell tumor, acanthomatous epulis, and perianal gland adenoma.4 In some instances, a lower-than-standard radiation dose can achieve local control of such tumors (e.g., transmissible venereal tumor).19 Tumors that are often treated with radiation therapy alone include nasal tumors, brain tumors, and pituitary macroadenomas and macroadenocarcinomas.4
Radiation is commonly combined with surgery and can be administered either pre- or postoperatively. Pros and cons exist for both preoperative and postoperative radiation therapy.20 The most common scenario is that an animal is presented after incomplete surgical excision of a tumor, and postoperative radiotherapy is performed. Hemoclips used to outline the tumor bed at the surgical site facilitate the establishment of the radiation treatment field, because surgical incisions alone may not adequately delineate the region that contains residual microscopic disease [Figure 5].21 Preoperative radiotherapy should be considered for large tumors in an attempt to kill microscopic extensions of the tumor. With preoperative radiation therapy, the size of the radiation treatment field may be smaller than what would be required in the postoperative setting where the entire surgical bed, incision, and drain sites need to be included to ensure treatment of residual microscopic disease. Potential wound-healing complications can arise with preoperative radiation therapy, and when considering such an approach, input should be sought from all involved parties, including the radiation and surgical oncologists.
Radiation and chemotherapy are often used for tumors that have metastasized or have a high risk of metastasis.4 Examples of tumors that may be treated with full-dose chemotherapy in conjunction with radiation therapy include, but are not limited to, appendicular osteosarcoma, tonsillar squamous cell carcinoma (SCC), anal sac adenocarcinoma, feline vaccine-associated sarcoma, and oral melanoma.22–26 Chemotherapy in this setting may impact local tumor control, but it is primarily given for its systemic effect on gross or microscopic metastatic disease. Chemotherapy is also used as a radiation sensitizer when administered at lower, more frequent doses, but its efficacy in this capacity has not been extensively or adequately investigated.27 Administration of full-dose chemotherapy may yield more complications, such as bone marrow suppression and sepsis, and cause delays in radiation therapy, which could negatively impact tumor control.
Radiation therapy has been successfully combined with hyperthermia in the management of soft-tissue sarcomas in dogs; however, accessibility to hyperthermia is very limited in the United States.28,29
Results of Radiation Therapy
The responses of tumors to radiation therapy can vary based on the species, tumor histology, tumor location, histopathological grade, stage of disease (e.g., local disease only, involvement of regional lymph nodes, distant metastases), age of patient, as well as other factors.4 It is important to be familiar with the response of a specific histopathological type of tumor based on tumor grade, stage, location, and species. For example, the response of SCC to radiation can vary substantially depending on tumor location and species. A SCC on the nasal planum of a cat will typically have an excellent response, whereas the same tumor on the nasal planum of a dog may respond initially, but regrowth is usually evident within a few months.30,31 Management of oral SCC in cats requires a combination of radiation therapy and aggressive local resection (e.g., hemimandibulectomy), whereas radiation alone may effect long-term local control of a rostral oral SCC in a dog.32,33 Tumors in young animals are often more aggressive and difficult to treat, but there are exceptions. The papillary variant of SCC that occurs in young dogs (between 2 and 5 months of age) is locally aggressive and causes extensive osteolysis, but it is considered to be radioresponsive with reportedly good long-term survival.34 Table 3 provides some of the reported results of the more commonly irradiated tumors in dogs and cats.
Acute and Late Effects
Acute radiation side effects [Table 4] occur primarily in tissues with rapidly proliferating cells, including the oropharyngeal mucosa, nasal mucosa, skin, small intestines, and bladder mucosa.80–82 The response of tissues to radiation is determined by the inherent radiosensitivity of stem cells, duration of the cell cycle, and the ability to adapt to damage.8 Acute effects typically start during the course of radiation therapy and can take a number of weeks after the end of radiation to resolve. Treatment options include (but are not limited to) topical aloe vera-based lotions or silver sulfadiazine creama for skin reactions (e.g., moist desquamation); a combination of oral corticosteroids (at an antiinflammatory dose) and antibiotics for oral mucositis; and mouth flushes (e.g., one part viscous lidocaine, one part liquid diphenhydramine, and one part aluminum hydroxide and magnesium hydroxide suspension) for oral mucositis (i.e., local inflammation and ulceration of the mucous membranes of the oral cavity). A combination steroid (hydrocortisone acetate 1%) and topical anesthetic (pramoxine hydrochloride 1%) foamb can be used for radiation proctitis when the rectum is included in the radiation treatment field.
Treatment recommendations for acute radiation side effects vary between facilities. It is important to remember that although acute effects can cause temporary discomfort, they are usually self-limiting and resolve within 3 to 6 weeks. For animals with oral mucositis, a soft diet that is less abrasive than dry food is recommended. Nutritional support in the form of a feeding tube may be considered in those animals not eating well prior to radiation and for those that develop local radiation side effects that limit food intake. It is also important to perform a dental prophylaxis prior to radiotherapy of the oral cavity. Deep buccal mucosal ulcers can develop that persist after resolution of oral mucositis secondary to the macerating effect of bacteria in dental tartar and plaque.
Late radiation side effects [Table 5] typically occur in tissues where the cells do not undergo mitosis, such as nerves and bone. Late side effects may also occur in the skin and can arise secondary to severe acute reactions (referred to as consequential late effects).80–82 Late effects are primarily changes that occur in the connective tissues, stroma, and the vasculature. These effects are dependent on total dose and dose per fraction.80 The higher the dose per fraction, the higher the probability of late effects. Late effects are more likely to occur in animals after palliative radiation therapy with a larger dose per fraction; however, these animals typically do not live long enough to develop late effects. For some late effects, there is no effective treatment. For other late effects, possible treatments include surgery to remove cataracts, surgical debridement for bone necrosis, and bougienage or resection for strictures of hollow viscera.81,82
Advances in Radiation Oncology
Stereotactic radiosurgery involves the use of multiple, non-coplanar beams of radiation in a series of arcs to deliver a single, high-radiation dose precisely to the target. This modality is available on a very limited basis but has been used in the treatment of brain tumors and canine appendicular osteosarcoma.78,83 Helical tomotherapy represents a notable advancement in the delivery of radiation that was first used clinically in dogs.84,85 In dogs with nasal tumors treated with tomotherapy, ocular side effects from radiation have been limited and of minor consequence when compared to the high rate of ocular side effects typically seen in dogs irradiated for nasal tumors.86,87 Tomotherapy involves the use of CT imaging to plan, deliver, and provide verification of treatment delivery. Tomotherapy is intensity-modulated radiation therapy that uses a fan beam that rotates around the animal while the animal is moved through the bore of the gantry.85
Several radiation facilities now exist in the United States that have linear accelerators with multileaf collimators and the potential to perform intensity-modulated radiotherapy.88 In this setting, multiple beams are utilized, the beam is shaped to conform to the region to be irradiated, and the intensity of the radiation beam is modified dynamically as the leaves are moved in and out during treatment, which results in a variable radiation dose across the radiation field.88 A more common practice is the use of forward treatment planning with three-dimensional, conformal radiation therapy utilizing cone-down fields to sculpt the radiation dose.89
Other applications of radiation therapy that are under investigation include sequential half-body radiation for canine multicentric lymphoma and total skin electron irradiation for canine cutaneous lymphoma.90–92
Conclusion
Radiation therapy plays an important role in the management of a number of different histopathological types of cancer in companion animals. It is important to have a basic understanding of the various aspects of external beam radiation therapy, ranging from mechanism of action to associated normal tissue side effects. The field of veterinary radiation oncology is growing, and many exciting advancements are being made. As radiation therapy is further explored in the management of cancer, it is hoped that the ability to control and potentially cure cancer in companion animals will be enhanced.
Silvadene; Monarch Pharmaceuticals, Inc., Bristol, TN 37620
Proctofoam-HC; Duchesnay, Inc., Quebec, Canada
Citation: Journal of the American Animal Hospital Association 42, 2; 10.5326/0420094
Citation: Journal of the American Animal Hospital Association 42, 2; 10.5326/0420094
Citation: Journal of the American Animal Hospital Association 42, 2; 10.5326/0420094
Citation: Journal of the American Animal Hospital Association 42, 2; 10.5326/0420094
Citation: Journal of the American Animal Hospital Association 42, 2; 10.5326/0420094
An 8-year-old, castrated male, mixed-breed dog in a repositioning device, being treated with electrons for an incompletely resected mast cell tumor of the right lateral thorax. A square cone has been attached to the head of the radiation machine to collimate the electron beam.
Lateral port film of a 12-year-old, castrated male, mixed-breed dog treated with a palliative course of radiation therapy for metastatic anal sac adenocarcinoma. The linear accelerator is equipped with a multileaf collimator that allows sculpting of the radiation field to match the tumor sites (e.g., primary site and metastatic sublumbar lymph nodes) while minimizing delivery of the radiation dose to the surrounding normal tissues.
Dose-volume histogram (DVH) for an 8-year-old, castrated male Labrador retriever with an incompletely resected, undifferentiated sarcoma in the dorsal cervical region. The DVH graphically depicts normalized tissue volumes (tumor and normal tissues) on the Y axis and the respective radiation dose in cGy that these tissues are receiving on the X axis. The DVH allows assessment of the radiation treatment plan to determine whether or not the entire tumor volume (red line) is receiving the prescribed dose (48 Gy or 4800 cGy), and it depicts the radiation dose to the critical normal tissues included in the radiation treatment field. It can be seen that the spinal cord (green line) is the only critical normal tissue that is receiving over 50 Gy (although to <30% of the tissue).
Plain radiograph of a 10-year-old, spayed female, mixed-breed dog with an incompletely resected hemangiopericytoma of the right caudal thigh. Wire has been placed on the incisions. A pedicle flap was utilized to provide closure at the site. In this instance, the surgical incisions would overestimate the appropriate radiation treatment field. The hemoclips were placed during surgery to outline the tumor bed and provide guidance for establishing the radiation treatment field.
