Cancer in Companion Animals: How It Happens and How It Is Treated

The word “cancer” ignites fear in many, presumably because of how common it has become among all species as well as its overwhelming complexity that has challenged humans’ ability to understand and cure it. Cancer is not a single disease, but many; the only commonality among cancers is how they originate.¹

The Origin of Cancer

Cancer is generally accepted as a genetic disease that is manifested after a series of events within the body that leads to uncontrolled cell growth. Cancer does not discriminate against any species, breed, age, or anatomic site. As written by Drs. Modiano and Hyuk Kim, “It can be said that simply being alive is the single largest risk factor for cancer.”²

Genetic Mutation of Specific Genes

When a cell divides, the daughter cell is likely to contain a few hundred to a few thousand genetic mutations.² Most mutations, regardless of their cause, are unlikely to cause a problem for the host. However, ongoing research has shown that over 400 mutations are associated with an increased risk for cancer.³ These mutations affect 2 classes of genes: proto-oncogenes and tumor-suppressor genes. Proto-oncogenes are responsible for normal cell growth and proliferation, and tumor-suppressor genes are responsible for controlling the rate of growth. When functioning normally, the 2 types of genes act as a checks-and-balances system: proto-oncogenes promoting growth and tumor-suppressor genes regulating the growth so it does not get out of control. A mutation in one of these classes of genes is not enough to set the stage for cancer; a mutation of both is needed. With mutations in both, proto-oncogenes can lead to out-of-control growth and tumor-suppressor genes can fail to limit cell growth.

A logical subsequent question is, what causes the mutations? They can be caused by intrinsic or extrinsic factors. Possible extrinsic causes include environmental exposures such as ultraviolet radiation from the sun, tobacco smoke, asbestos, pesticides/herbicides/insecticides, or infectious diseases. Other extrinsic causes have been reported, and others likely remain unknown. Possible intrinsic factors include inherited mutations, hormones that influence processes that can cause mutations, or random errors in DNA replication.² Inherited mutations are likely to play a part in cancer types that have a breed predilection. For example, the increased risk for mast cell tumors among boxers suggests that heritable factors could contribute to cancer development. Hormonal carcinogenesis is associated with mammary cancer in dogs, and risk for mammary cancer is greatly reduced in dogs spayed before first estrus; however, research has also shown that risk for several other cancer types may be reduced in reproductively intact animals.² Regardless of the origin of the mutations, they will accumulate with time, which explains why cancer risk increases with age. Mutations in proto-oncogenes give cells the capability to sustain proliferative signaling, and the mutations in tumor-suppressor genes deactivate antigrowth signals.² Together, these mutations make up the first 2 hallmarks of cancer.

Hallmarks of Cancer

A review of 40 years of research indicated that cancer has 10 essential characteristics, the hallmarks of cancer.²

• Sustained proliferative signaling (proto-oncogene) and evasion of growth suppressors (tumor-suppressor gene mutations). These characteristics set the stage for cancer, but they do not act alone.
• Apoptosis resistance. The term “apoptosis” means programmed cell death, which is the imprinted outcome for every cell in the body. Apoptosis is a natural process as cells age or become damaged. For cancer to progress, the ability to resist apoptosis is necessary.
• Replicative immortality. Healthy cells are programmed with a set limit on how many times they can divide. Tumor cells, however, must have replicative immortality, which enables the cell to replicate without limit.
• Angiogenesis. Angiogenesis describes the formation of new blood vessels. To be provided with oxygen and nutrients, tumor cells must be able to induce angiogenesis and use existing vasculature to form new vessels and promote survival.
• Invasion and metastasis. Tumor cells must also be able to invade local tissue and spread to distant sites. Although not completely understood, the invasion–metastasis cascade results from dissemination of cancer cells traveling largely through the blood and lymphatics and seeding various organs.⁴
• Genomic instability and mutation. Cancer cells acquire and maintain genetic alterations that support uncontrolled growth. During the chaotic process of rapid division, DNA replication is subject to increased errors, which provides fertile ground for the continuous evolution of cancer cells.
• Tumor-promoting inflammation. Inflammation is a natural response to injury or infection, activating immune cells to assist in the repair or recovery at the site of injury. For cancer cells, this process leads to nutrient provision, angiogenesis, oxygen, and DNA damage, which further promote cancer development.
• Deregulation of cellular energetics (properties of energy). Because of the high amount of energy required for rapid cell division, cancer cells need to alter their metabolism in a way that promotes survival, which is accomplished by deregulating cellular energetics. Cancer cells need to be efficient glucose scavengers and adapt to situations in which glucose is limited (e.g., hypoxic tumors).
• Avoidance of immune destruction. The immune system identifies and eliminates abnormal cells, including cancer cells. Survival of cancer cells relies on the ability to hide from or suppress the immune system.

Cancer cells use many complex pathways to achieve each of the hallmarks. Understanding these hallmarks has led to the creation of new therapies, often referred to as targeted therapies, which differ from traditional chemotherapy and will be discussed later in this article.

Cancer Treatment

The goals of therapy for veterinary patients differ from that for human patients due to differences in longevity and perception. Companion animals do not live nearly as long as humans and they “live in the moment,” not recognizing that today’s discomfort during treatment may lead to a longer life. Thus, in weighing the pros and cons of treatment for veterinary patients, the goal should focus on maximizing their quality of life more than extending their lifespan.

Surgery

Surgery is a major part of cancer treatment. In dealing with nonhematopoietic (solid) tumors, the best chance of a cure is at the time of the first surgery. The degree of excision is considered debulking, marginal, wide, or radical (TABLE 1).⁵ The goals of surgery are generally to remove the primary tumor with clean margins as well as any metastasis. Because biopsy samples do not necessarily represent the entire tumor, definitive diagnoses may also be obtained by surgery, in which case the primary goal of surgery should be obtaining an appropriate degree of excision.⁶ However, using surgery to obtain a diagnosis may result in the surgeon being conservative and ultimately not obtaining clean margins, which can dramatically affect the patient’s treatment response and outcome, especially with aggressive tumors.

Why is obtaining clean margins so important? The word “cancer” comes from the Latin word for “crab” because it resembles the shape of a crab with a body and finger-like projections, similar to legs. If the body of a tumor is removed while the legs are not, the tumor will usually recur (FIGURE 1).

Figure 1. Various surgical margins of a visible tumor. Vink Fan/shutterstock

Before and after surgery, veterinary nurses can assist surgeons by properly marking the tissue, preparing the samples for submission, and completing the report.

Tissue Demarcation

Tissue demarcation is the process of identifying the surgical margins by either applying surgical ink or placing sutures to help orient the sample in a manner that enables the pathologist to better assess the surgical margin.⁷ Tissue should be marked before the sample is fixed as tissue can shrink after being put in formalin. Surgical inking is generally preferred by pathologists and surgeons because it is easy to apply and provides more detail for the pathologist. The process often requires only surgical ink and cotton-tipped applicators. The ink is easily identified both on gross examination of the sample as well as microscopically (FIGURE 2).

Figure 2. Bladder mass with surgical ink applied to the margins.

Sample Preparation

Before neoplastic samples are submitted for histopathology, specimens should be placed in 10% neutral buffered formalin at a 1:10 ratio (tissue:formalin) no more than 30 minutes after excision.⁷ Very small samples should be placed in a tissue cassette before being submersed in formalin (FIGURE 3). Oversized samples that cannot be easily shipped in formalin can be refrigerated and then shipped overnight with cooling materials. If additional guidance is needed, the receiving laboratory should be contacted.

FIGURE 3. Tissue cassette with small tissue sample.

Report Completion

The accuracy of the pathology report is critical for determining management and prognosis of the cancer patient. Providing adequate information will help the pathologist make an accurate diagnosis. A properly completed pathology request should provide patient signalment and a thorough history that includes lesion-specific information (e.g., anatomic information, growth rate), clinical and treatment history, and results of prior diagnostics performed on the mass.

Radiation Therapy

Radiation therapy is primarily administered by using a radiotherapy unit called a linear accelerator (FIGURE 4). These units are becoming increasingly common at specialty centers offering radiation therapy due to their greater flexibility for treating deep and superficial tumors. The intent of radiation therapy for cancer patients is often classified as either curative or palliative. Irradiation may also be used as adjuvant therapy (administered after the primary treatment) or neoadjuvant therapy (administered before the primary treatment) when combined with surgery⁸ if the goal is to sterilize the margins to make complete excision more feasible (preoperative) or to address microscopic disease when the excision is incomplete (postoperative).

FIGURE 4. A linear accelerator.

Radiation therapy is considered a cytotoxic (cell toxic) therapy for solid tumors and is rarely used as a sole modality, unless for palliative intent. In 90% of cases, radiation causes mitotic cell death by disrupting chromosome separation during cell division.⁹ Disruption relies on oxygen free radicals; thus, the success of radiation therapy depends in part on the oxygen within the cells.⁹ Normoxic cells are 3 times more sensitive to radiation than hypoxic cells.¹⁰ Unfortunately, fast-growing tumors tend to be hypoxic due to their chaotic proliferation and inability to form adequate blood vessels; therefore, these tumors can be inherently radioresistant. However, for tumor types that are not overtly radioresistant, a higher mitotic rate tends to lead to a faster response to irradiation because the rate of tumor response is correlated with the rate of cell division (i.e., growth).

Radiation adverse effects are also correlated with the mitotic rate in the irradiated areas (TABLE 2). In tumor types and tissues with higher mitotic rates (e.g., oral mucosa, epithelial structures of the eye and skin), adverse effects are more acute, whereas in slower-proliferating tissues (e.g., bone, lung, nervous system), adverse effects occur later.⁸

Acute adverse effects after irradiation often include hair loss and moist desquamation (FIGURE 5A); other acute effects vary, depending on the site irradiated. Acute effects occur during and shortly after irradiation and do not tend to be life-limiting. Although they can be distressing to clients, acute effects can be adequately managed with multimodal analgesics (e.g., anti-inflammatories, gabapentinoids, N-methyl-D-aspartate antagonists), and most will resolve with time. Late adverse effects occur months to years after irradiation and can include bone/tissue necrosis and tissue fibrosis, which can be life-threatening (FIGURE 5B); however, appropriate irradiation planning and dosing can greatly reduce the risk.

FIGURE 5. Radiation adverse effects. (A) Moist desquamation, an acute radiation adverse effect.

Figure 5B. Oronasal fistula, a late radiation adverse effect.

Palliative irradiation protocols are used when the primary goal is to improve the quality of life of the patient rather than treat the cancer itself. Because the goal is to manage pain and improve patient comfort, the total radiation dose can be adjusted for most patients to minimize adverse effects.

To spare as much healthy tissue as possible from radiation, patients must be immobilized by general anesthesia during treatment. Patient positioning includes use of body molds and bite blocks to ensure that the patient’s position is repeatable with each treatment (FIGURE 6), which also helps spare healthy tissue. Each radiation session is referred to as a fraction, with protocols ranging from 2 to 20 total fractions. Patient comorbidities should be considered when deciding whether repeated general anesthesia is clinically appropriate.

Figure 6. An anesthetized patient ready to undergo radiation therapy. The patient’s positioning is repeatable with use of a bite block and body mold.

Chemotherapy

In the 1940s, cytotoxic drugs began being used for cancer treatment.¹¹ Drugs were very experimental at the time and often discovered accidentally. Although cancer treatment has advanced over the years, the chemotherapy drugs available are largely unchanged and focus on cytotoxicity to induce a response. Similar to radiation therapy, chemotherapy interferes with various parts of the cell cycle, depending on the drug. The interference leads to cell death, especially of rapidly dividing cells. Chemotherapy cannot distinguish between cancer cells and healthy cells; therefore, all rapidly dividing cells are affected, which is what leads to chemotherapy adverse effects. The most common adverse effects seen with chemotherapy include hair loss (resulting from the cell division rate associated with the cells of the skin, gastrointestinal [GI] tract, and bone marrow), GI upset, neutropenia, and thrombocytopenia.¹¹

Hair loss (alopecia) is a cosmetic adverse effect of chemotherapy that may concern clients. It is more commonly noted in breeds with continuously growing coats but can be seen in any breed. Hair generally will grow back after treatment is discontinued, but the color or texture may change.

GI upset generally affects patients 2 to 5 days after chemotherapy administration and more commonly affects dogs than cats.¹² GI adverse effects are generally exhibited as decreased appetite, nausea, and/or diarrhea. A proactive approach to GI adverse effects, such as prophylactic administration of antiemetics (e.g., maropitant, ondansetron) and appetite stimulants (e.g., capromorelin, mirtazapine) and medical management of diarrhea the moment it occurs (e.g., probiotics, fiber supplementation, crofelemer), is highly recommended. In the author’s experience, GI adverse effects can cause major distress for the client, leading to discontinuation of therapy. A proactive approach to managing adverse effects along with client education on what to expect can be effective.

Bone marrow suppression is primarily limited to neutrophils and platelets due to their shorter life cycle and rapid cell division. Thrombocytopenia is generally transient and not life-threatening; however, if thrombocytopenia is moderate to severe, chemotherapy delays may be needed. Neutropenia is the primary dose-limiting toxicity and (although rare) can be life-threatening due to the role that neutrophils play in fighting infection. Because bone marrow suppression itself, in the absence of a secondary infection, does not result in clinical signs, frequent laboratory work (e.g., CBC) is recommended during chemotherapy protocols, especially before administering chemotherapy, as well as the point at which the neutrophils reach their lowest (the nadir) after chemotherapy administration. Most commonly the neutrophil nadir is 7 days after treatment, although it can vary according to the drug used.¹² If the neutropenia is moderate to severe, antibiotics may be needed to protect the patient from a secondary infection. If a patient with neutropenia is febrile, hospitalization is recommended.¹¹

The goals of chemotherapy vary and consist of adjuvant chemotherapy (given after surgery and/or radiation), neoadjuvant chemotherapy (given before surgery and/or radiation), induction chemotherapy (given to induce remission with chemotherapy alone), rescue chemotherapy (given after a relapse or lack of response), palliative chemotherapy (given to decrease clinical signs or slow progression), and radiosensitization chemotherapy (given to enhance the cytotoxicity of radiation therapy).

Veterinary nurses are often the team members administering chemotherapy to veterinary patients. Many chemotherapy drugs are either irritants or vesicants; therefore, the utmost caution and skill are required during intravenous catheter placement to avoid extravasation. Because administration considerations for each chemotherapy drug vary (TABLE 3), dedicated training associated with chemotherapy administration is necessary for the safety of the patient. Handling cytotoxic drugs also poses a risk for personnel. Research has shown that human healthcare personnel working with hazardous drugs experience more reproductive difficulties, fetal loss, DNA changes, and cancer.^14-17 Before chemotherapy drugs are handled, safety mechanisms should be in place to minimize exposure (e.g., personal protective equipment, closed-system devices, needleless devices, a class II biological safety cabinet). For more information regarding chemotherapy safety for veterinary nurses, visit go.navc.com/48afSG6.

Targeted Therapies

Targeted therapies are drugs that focus on 1 or more of the hallmarks of cancer. In veterinary medicine, the only U.S. FDA-approved targeted therapy is toceranib phosphate (Palladia; Zoetis, zoetisus.com), which works by targeting the proliferative signaling found in dysregulated cancer cells. However, similar to the other therapies, the inability to distinguish between healthy cells and cancer cells can lead to adverse effects because rapidly dividing healthy cells also rely on the pathways that are being blocked.

Although not a true targeted therapy, NSAIDs are commonly used in oncologic treatment to target tumor-promoting inflammation as well as angiogenesis, both of which are hallmarks of cancer.

Immunotherapies

The ability to harness the immune system’s ability to fight cancer is a newly advancing area of veterinary oncology that is often used in human oncology. Immunotherapies work through a variety of mechanisms and include cancer vaccines, checkpoint inhibitors, adoptive T-cell therapies, and others.¹⁸ Currently, there are only 2 immunotherapeutic agents on the market for dogs:

• Oncept vaccine (Boehringer Ingelheim, bi-animalhealth.com), used for stage II or III canine oral melanomas
• Gilvetmab (Merck, merck-animal-health-usa.com), used for stage II or III canine melanomas and stage I to III canine mast cell tumors

Many clinical trials and research efforts are ongoing, which may lead to future treatment options.

Summary

Although cancer has been around as long as humans have existed, minimal progress has been made in finding a cure. However, both human and veterinary oncologists continue to advance our understanding of the disease and surge forward in the efforts to find new treatments and better manage cancer patients. Ethically, managing veterinary cancer patients should prioritize quality over quantity of life, which can be challenging for clients. Veterinary nurses play a key role in not only the management of oncology patients but also the support of clients through education and quality-of-life discussions. Understanding the etiology of cancer and the various treatments available will support veterinary nurses in the oncology setting.