Indications for Radiation Therapy in Veterinary Medicine

Radiation therapy (RT) is not a well-established subject in veterinary school, meaning that many general practitioners may be hesitant to refer patients for RT. This article outlines the clinical indications, mechanisms of action, types of treatment, decision-making factors, and side effects associated with RT and provides a few brief case examples.

Overview of Veterinary Radiation Therapy

A fundamental tenet of oncologic treatment is “local disease requires local treatment(s).” RT delivers radiation to a targeted area; therefore, patients with microscopic or macroscopic locally aggressive/invasive tumors can be good candidates for RT. RT can be used as a sole treatment or can be combined with surgery, chemotherapy, or immunotherapy.

Intent of Treatment

RT is performed with either definitive or palliative intent. Definitive intent has the goal of achieving durable long-term control of the patient’s tumor. Palliative-intent has the goals of relieving clinical signs associated with the tumor and decreasing the size of the tumor while avoiding treatment-related side effects, without as much emphasis on prolonged survival. Palliative RT can work well for 3 to 6 months, depending on the patient’s condition and cancer type. Most RT in veterinary medicine is palliative.

Cancer Staging and Treatment Simulation

Patients should be extensively staged prior to initiating RT. Imaging of both the abdomen and chest with modalities such as computed tomography (CT), abdominal ultrasonography, and thoracic radiography is important to detect metastasis as well as concurrent cancers. Because RT is expensive and time consuming, complete staging helps to confirm if the benefit, risk, and cost of treatment are likely to be worthwhile.

If, after staging as well as histological or cytological confirmation of cancer, the patient is deemed a good candidate for RT, a CT study (CT simulation) is performed. In many cases, if CT is used as a staging modality, then both the staging study and the CT simulation are performed at the same time. During this simulation, the patient is positioned as it would be for RT. In some cases (e.g., 20 fractions prescribed), a vascular access port may be implanted at this time to aid in anesthesia during RT.

Treatment Planning

After the CT simulation is complete, a treatment plan is made. A computer program uses the CT study to simulate the beam angles and distribution of the RT dose in the patient, and this simulation is quality assured by the radiation oncologist and a medical physicist. Under nonemergent circumstances, this entire process takes approximately 1 week to produce a final RT plan.

In some cases, RT can be administered without a CT simulation, and dose calculations can be made using measurements of the thickness of the anatomic area being treated. This can be done to save on cost; for patients with tumors that are very superficial or in a distal extremity; or in cases with an emergency need for RT, such as tumors that block the airway (e.g., tracheal tumors, laryngeal tumors).

Once the RT treatment plan is ready, the patient is treated. Most RT patients can be treated as outpatients and are dropped off in the morning and recovered/discharged by late morning. If a vascular access port has not been placed, an IV catheter is placed, locked with heparin, and maintained for the week. The IV catheter is removed on the weekends or if there are problems maintaining it during the week.

Veterinary Radiation Therapy Mechanisms of Action

RT works by damaging the DNA of cancer cells to cause cell death. Normal cells can also sustain reversible or irreversible DNA damage from radiation, but cancer cells have deficiencies in DNA repair compared with normal cells, which creates a therapeutic window that RT can exploit.¹

Fractionated therapy (breaking up a large dose into multiple small doses) allows normal tissues that are included in the treatment field to be treated to relatively high doses. Radiation is measured in Grays (Gy), and the RT prescription is described as the number of fractions (treatment sessions) times the dose per fraction (e.g., 3 Gy × 19 or 19 × 3 Gy). Each fractional dose is small enough to allow slowly proliferating normal tissues to recover from radiation injury and minimize the risk of late radiation side effects. Conventional fractionation delivers the total RT dose over a period of several days or weeks, depending on the type of RT being used. RT prescriptions may be described as hyperfractionated or hypofractionated. These terms refer to the relative number of fractions and relative dose of administered RT. In veterinary medicine, an RT prescription of 2.5 Gy × 20 fractions would be hyperfractionated, while 10 Gy × 3 fractions administered on consecutive weekdays would be an example of hypofractionation.

Technology has developed such that large, ablative doses of radiation can be administered to a grossly visible tumor in a short period of time. Beam shaping and image guidance are used to avoid normal tissues as much as possible while only treating the grossly visible tumor, allowing the same dose that would be administered over the course of 10 days using traditional fractionation to be administered over 3 consecutive weekdays. This type of radiation therapy may be referred to as stereotactic radiation therapy (SRT), stereotactic body radiotherapy (SBRT), stereotactic ablative radiotherapy (SABR), or stereotactic radiosurgery (SRS). While DNA damage is an important player in this modality in terms of biological effect, immunomodulation caused by release of vast amounts of tumor antigen and vascular damage to the tumor microenvironment may also account for clinical responses to SRT.²

Side Effects of Veterinary Radiation Therapy

Side effects of RT in normal tissues may be late or acute. Late radiation side effects are irreversible effects that may occur in slowly proliferating tissues such as bone, smooth muscle, or the central nervous system many months to years after RT. Characteristic lesions attributed to late radiation side effects include bone necrosis, strictures, fibrosis, and fistula formation. The incidence of late radiation side effects in sensitive normal tissues increases exponentially with increasing dose per fraction, as in hypofractionated RT prescriptions (e.g., 8 Gy × 4, 10 Gy × 3). The potential for these side effects is minimized by careful treatment planning as well as using technology such as image guidance and specialized treatment planning to avoid normal tissues.

Acute side effects of RT occur in rapidly proliferating tissues such as the skin, oral mucosa, or gastrointestinal tract during or shortly after treatment. Acute side effects are reversible, and their occurrence depends on the anatomic area and volume of normal tissue irradiated. Characteristic sunburn-like lesions in an irradiated area of skin (desquamation) are a commonly observed acute side effect.

Acute side effects are more likely to occur with hyperfractionated treatments and treatments administered to superficial areas such as a distal extremity or the gums/lips and mouth. These side effects, although uncomfortable for a few weeks, are completely reversible. The patient is managed with multimodal pain medications such as a nonsteroidal anti-inflammatory drug, gabapentin, and amantadine. If the mouth is affected, nerve blocks can also be used.

Clients can be assured that with appropriate pain management, most patients recover from acute side effects without complications.

Types of Veterinary Radiation Therapy

The decision of which type of RT would be best for each patient is fundamentally based on the underlying clinical biology of the cancer present. Different cancers have different sensitivities to RT, and this affects the treatment strategy pursued as well as the indication for multimodal treatment (e.g., surgery followed by RT).

Conventionally Fractionated Definitive Radiation Therapy

Because normal cells can repair DNA damage more efficiently than tumor cells, durable local control may be possible depending on the type of cancer being treated.¹ This strategy works well in situations where microscopic cancer is left behind as part of a multimodal treatment strategy with surgery. This radiation prescription, called conventionally fractionated definitive RT, typically consists of 10 to 20 fractions administered on consecutive weekdays.

Tumors such as acanthomatous ameloblastoma (formerly known as an epulis) and infiltrative lipoma are inherently radiation sensitive, and gross bulky disease can be treated to high doses with conventionally fractionated definitive RT as sole therapy with the goal of achieving durable long-term control of the tumor (CASE 1).^3,4

CASE 1: Acanthomatous Ameloblastoma

A 5-year-old female spayed Shih Tzu had a macroscopic acanthomatous ameloblastoma (an invasive but benign oral tumor) in the left rostral mandible (FIGURE 1A). Radical resection as a curative-intent surgery with partial rostral mandibulectomy was discussed. The client elected not to pursue surgery due to concerns with cosmesis and morbidity following surgery. Conventionally fractionated definitive radiation therapy (RT) (3 Gy × 19 fractions) was elected due to the patient’s relatively young age and the radiosensitivity of the tumor.

This patient achieved almost complete clinical remission 10 days after completion of the course of RT (FIGURE 1B)and survived to the age of 12 years without tumor recurrence or clinically significant late RT morbidity. This is an example of a case where conventionally fractionated definitive RT as the sole treatment modality resulted in excellent outcomes for the patient and met the client’s goals.

Figure 1. Left rostral mandibular acanthomatous ameloblastoma. (A) Prior to starting conventionally fractionated definitive radiation therapy.

Figure 1B. Ten days after completing 3 Gy × 19 fractions. The tumor has dramatically shrunk in size.

Other cancers, such as canine cutaneous soft tissue sarcoma, may require a multimodal approach for durable local tumor control. Canine cutaneous soft tissue sarcoma is best treated with surgical excision with wide margins (up to 2 to 3 cm of normal tissue in addition to a fascial plane). If wide surgical excision is not possible or tumor-free margins are not achieved (“dirty margins”), postoperative conventionally fractionated definitive RT may be indicated.^5,6 Conventionally fractionated definitive RT may result in acute side effects more often than is seen with the other modalities described below, especially if the area treated is superficial (e.g., distal extremity, paw pads, lips, mouth).

Conventional Palliative Radiation Therapy

Palliative RT can be considered for macroscopic disease to shrink or stabilize the tumor for a period of time (normally 3 to 6 months) while limiting or avoiding acute side effects. Palliative RT is helpful to decrease clinical signs of oncologic disease, including bleeding or discomfort and pain. Patients that might be candidates for palliative RT have advanced cancers and are not candidates for more aggressive treatment or multimodal treatment with surgery due to the extent of their disease or comorbidities (CASE 2).

CASE 2: Round Cell Tumor

A 10-year-old male neutered Basenji had a very invasive, erosive round cell tumor in the left caudal mandible (FIGURE 2A). Palliative radiation therapy (RT) was offered given that the location made it challenging to remove the tumor completely and based on the potential radiosensitivity of the tumor. The patient also had significant fear aggression toward veterinary staff and was not a good candidate for intensive daily treatment or inpatient treatment. The client elected palliative RT (8 Gy × 4 fractions, weekly) to maintain the dog’s quality of life, and a complete clinical remission was obtained for 5 months (FIGURE 2B). Treatment fractionation was modified to accommodate the patient’s behavioral disposition, resulting in a favorable outcome.

Figure 2. Left caudal mandibular round cell tumor. (A) Prior to initiating palliative radiation therapy (8 Gy × 4 fractions, weekly).

Figure 2B. After the third fraction of radiation therapy, exudation around the lesion resolved significantly.

Conventional palliative RT is delivered once a day for 5 consecutive days or once a week for 4 to 6 weeks as a course. It can be delivered without a planning CT scan in some instances to save on cost.

Care must be taken in terms of estimating the patient’s overall prognosis when electing palliative RT. The dose per fraction administered with palliative RT is much higher than that for conventionally fractionated definitive RT, increasing the risk of late radiation side effects (CASE 3). A patient that might be expected to survive for a long period of time after treatment or that has microscopic disease is not a candidate for palliative-intent RT due to the risk of causing irreversible late side effects in normal tissue. While acute side effects can occur during and after administration of conventional palliative RT, they are less likely. Rapidly proliferating normal tissues are not as sensitive to the large fraction sizes and the low total doses administered in conventional palliative RT.

CASE 3: Maxillary Osteosarcoma

A 12-year-old female spayed mixed-breed dog had caudal maxillary osteosarcoma that was debulked by the local veterinarian during a dental procedure. Significant disease in the caudal maxilla was evident on computed tomography but not on oral examination. Surgery followed by definitive-intent RT was offered but declined due to concurrent chronic renal failure. A course of palliative radiation therapy (RT) was prescribed (8 Gy × 4 fractions, weekly; FIGURES 3A AND 3B).

The patient is alive 1 year and 8 months after completing RT. Significant dental disease and fistula have developed over time (FIGURE 3C). This is an example of a late side effect of palliative RT when the patient lives longer than expected. Despite this treatment-related morbidity, the patient still has a good quality of life and is treated with pain medications and antibiotics as needed.

The prognosis of oral osteosarcoma treated in the absence of a multimodal approach (surgery and RT) is typically poor. This case highlights how tumors can behave unpredictably in response to palliative treatment.

Figure 3. Right caudal maxillary osteosarcoma. (A) Preoperative mass.

Figure 3B. Area of debulked tumor after completing palliative radiation therapy (8 Gy × 4 fractions, weekly).

Figure 3C. Area of irradiation/debulking 210 days after completion of radiation therapy. The gray area (arrow) is an area of maxillary bone exposure. The molar overlying this lesion is devitalized and loose. This is an example of bone necrosis due to late radiation side effects. There is no evidence of tumor regrowth.

Stereotactic Radiotherapy

As noted, the terminology for this treatment modality—SRT, SBRT, SABR, SRS—can be confusing, and different groups of clinicians use these terms with slightly different definitions. SRS is completed in a single treatment session and is typically administered to the head or neck. SBRT/SABR is administered in 1 to 5 fractions.

SRT may be administered with definitive or palliative intent, depending on the stage and size of the tumor being treated, as well as its biological behavior and radiation sensitivity (CASE 4). SRT may be used with the goal of more durable palliation in some cases. This means that while a complete remission or cure may not be possible, the time to regrowth or progression of the tumor may increase significantly with SRT compared with conventional palliative-intent treatments.

CASE 4: Cystic Meningioma

A 12-year-old female spayed Siberian husky mix had cystic meningioma in the left brainstem diagnosed from magnetic resonance imaging findings. The patient presented to the neurologist for acute onset of right-sided head tilt, loss of balance, and nystagmus. The patient had poor ambulation due to the severe head tilt and nystagmus at the time of diagnosis (FIGURE 4, VIDEO 1).

Figure 4. Severe head tilt caused by brainstem cystic meningioma.

Based on the clinical signs and location of the tumor, stereotactic radiation therapy (SRT) (8 Gy × 3 fractions, daily) was elected. Approximately 1 month after completion of treatment, the head tilt and ambulation difficulties had improved dramatically (VIDEO 2). The patient is alive and without clinically apparent symptoms 9 months after completing SRT. This case is an example of response to radiation therapy that is typically expected in dogs with brain tumors. In many cases, patients can have prolonged survival and resolution of their clinical signs.

Specialized equipment (e.g., advanced machines, image guidance, patient immobilization devices) is required to perform SRT. Patient and case selection is important, and macroscopic disease is required. Image guidance cannot detect microscopic tumor cells, and due to the risk of late side effects from the large doses per fraction used, patients with microscopic cancer are not appropriate candidates for SRT. Similar to conventional palliative RT, acute side effects are less likely to occur since normal tissues are avoided.

Factors in Treatment Decisions and Planning

RT treatment planning involves many factors to tailor therapy to each individual patient.

Tumor Type, Location, and Size

Round cell tumors such as lymphoma, mast cell tumor, plasma cell tumor, histiocytic sarcoma, and transmissible venereal tumor tend to be highly radiosensitive. Even palliative RT in a macroscopic disease setting can dramatically shrink some tumors (CASE 5). Epithelial tumors such as carcinomas can also be radiosensitive. Mesenchymal/spindle cell tumors such as soft tissue sarcoma tend to be less radiosensitive. Melanoma tends to be more sensitive to hypofractionated RT, and in many cases canine oral malignant melanoma may respond dramatically to conventional palliative RT.

CASE 5: Oral Squamous Cell Carcinoma

An 8-year-old female spayed mixed-breed dog had an invasive, erosive oral squamous cell carcinoma in the right caudal maxilla that was invading the right nasal cavity (FIGURE 5A). Palliative radiation therapy (RT) was elected to relieve the discomfort since the tumor was too invasive to remove with surgery based on computed tomography (CT) findings and consultation with an oral surgeon. A radiation dose of 8 Gy × 4 fractions, weekly, was prescribed, resulting in complete remission (FIGURE 5B).

Figure 5. Erosive, invasive squamous cell carcinoma of the right maxilla. (A) Prior to palliative radiation therapy.

Figure 5B. Seven months after completion of palliative radiation therapy.

Two years after completing the first course of RT, the patient presented with epistaxis. CT was performed and a new mass was found in the nose. The biopsy of the mass was consistent with squamous cell carcinoma, and recurrence of the original tumor was suspected. A course of stereotactic radiation therapy (SRT) was prescribed (8 Gy × 3 fractions on consecutive weekdays), and the epistaxis resolved.

One year after completion of SRT, the clinical signs of epistaxis returned with concurrent nasal congestion. A CT scan was repeated, and the mass was progressive in size compared with previous scans. A second course of SRT (8 Gy × 3 fractions on consecutive weekdays) was prescribed. The patient survived for another year before being euthanized due to progressive nasal clinical signs and progression of the tumor on CT. The oronasal fistula never recurred.

This case is an example of the possibility for retreatment with RT. Additionally, cases of advanced cancer can have a dramatic response to treatment. Although this does not happen in every case, aggressive treatment and follow-up can have a positive outcome.

Tumors near normal critical organs such as the brain, eyes, or spinal cord need to be treated with computer-based RT planning to spare these organs from severe radiation side effects.

The larger the tumor, the more complex RT planning is. This is because the dose distribution inside a large tumor tends to be heterogeneous (a mixture of “hot” and “cold” spots), and sparing surrounding normal structures tends to be more challenging.

Patient Comorbidities, Age, and Life Expectancy

Intense RT such as conventionally fractionated definitive RT can be very challenging for human patients with significant comorbidities such as heart disease, chronic renal failure, or diabetes mellitus. It is even more so in veterinary patients, which require general anesthesia for each treatment session. Depending on the intent of RT and technique used, this may mean subjecting the patient to up to 20 sessions of general anesthesia. General anesthesia must therefore be safe enough for these patients at each treatment.

The patient’s whole clinical picture, including behavioral factors, must be considered. For example, some feline patients or patients with fear aggression in the hospital tend to do better on an outpatient basis.

If the patient’s life expectancy is short, conventionally fractionated definitive RT may not be the best treatment option, given the high risk of acute side effects and intense treatment protocol (every day for 2 to 4 weeks).

The risk of late radiation side effects depends on the fractionation/fraction size and the total dose of radiation. Therefore, patient age at the time of RT is extremely important to minimize the risk of late side effects. For example, an older patient with comorbidities may benefit from a hypofractionated definitive-intent protocol (e.g., 4.2 Gy × 10 fractions) rather than a more prolonged definitive-intent protocol (e.g., 2.5 Gy × 20 fractions) because the patient may not live long enough to experience late side effects related to the shorter protocol with a larger dose per fraction. Case selection in humans with breast cancer who may need RT is approached similarly.⁷

Goals and Side Effects of Treatment

RT is delivered with either definitive or palliative intent. When considering definitive RT, clients must decide whether the risks of moderate to severe acute side effects are outweighed by the potential for prolonged survival. The best treatment plan should be based on the balance between benefits and risks of RT for the specific patient.

Summary

RT is a powerful tool for controlling local tumors and can be an alternative to surgery. It is very important to understand different types of RT and side effects for successful patient selection to achieve therapeutic goals. The indication of a specific type of RT for each patient requires a fundamental understanding of radiobiology and clinical cancer biology. Each cancer is a different disease and behaves differently. Radiation oncologists must choose the specific radiation treatment at the right time for the right patient.