Therapeutic Modalities: Chemotherapy

Chemotherapy is commonly used in veterinary cancer medicine and offers a variety of approaches tailored to small animal patients. Conventional chemotherapy, metronomic chemotherapy, and targeted therapies, including tyrosine kinase inhibitors (TKIs), are all available to small animal practitioners and differ in their indications and goals (Table 5.1). To use these modalities effectively, clinicians must understand the basic principles of each approach. This includes knowing the regulatory agency approval or licensing status of the drugs (Section 2) and appropriate extralabel administration techniques, adhering to proper safety protocols for handling chemotherapy agents (see Safety Considerations in this section), and understanding the potential side effects of the drugs (see Chemotherapy Side Effects in this section). Table 5.1 provides an overview of chemotherapeutics and immunotherapeutics with antineoplastic activity that are commonly used in veterinary medicine.

Educating clients about chemotherapy is equally important. It involves setting realistic expectations, discussing potential side effects, and giving guidance on monitoring and home care. Effective communication with clients not only helps manage their concerns but also contributes greatly to the overall success of the treatment plan (see Section 4, Client Communication).

TABLE 5.1 Overview of Antineoplastic Chemotherapy and Immunotherapy Agents Commonly Used in Veterinary Medicine

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DLT, dose-limiting toxicity; GI, gastrointestinal; IM, intramuscular; IP, intraperitoneal; IT, intratumoral; MCT, mast cell tumor; MDR1, multidrug resistance 1; MOA, method of administration; NSAID, nonsteroidal anti-inflammatory drug; SC, subcutaneous; SCC, squamous cell carcinoma; SHC; sterile hemorrhagic cystitis; TKI, tyrosine kinase inhibitor.

General Principles of Conventional Chemotherapy

Conventional chemotherapy, also known as maximally tolerated dose (MTD) chemotherapy, involves administering chemotherapeutic agents at the highest tolerated dose, with the primary goal of targeting and killing rapidly dividing cancer cells. However, because some normal cells also have a high turnover rate, they can be temporarily damaged by MTD chemotherapy (see Chemotherapy Side Effects).

This necessitates a recovery period between treatments to allow these normal cell populations, such as those in the bone marrow and GI tract, to recover. MTD chemotherapy is typically administered weekly to every 3 weeks (e.g., CHOP protocols to treat lymphoma or giving carboplatin every 3 weeks to treat osteosarcoma).

Although this approach maximizes tumor cell death and is generally associated with a low chance of serious side effects, the intervals between treatments may also allow for tumor regrowth. Depending on the tumor type being treated and the stage of the disease, MTD chemotherapy may be administered alone or as an adjuvant to surgery or radiation therapy. It is indicated for the treatment of tumors known to be sensitive to drug therapy, such as hematologic malignancies (e.g., lymphoma, leukemia, multiple myeloma), and highly metastatic malignancies, such as osteosarcoma, hemangiosarcoma, and high-grade MCTs.

When conventional chemotherapy is used against solid tumors such as osteosarcoma, it is often applied in an adjuvant setting after primary tumor treatment to slow the progression of occult micrometastatic disease. Occasionally, drugs are also administered in the neoadjuvant setting to downstage a chemosensitive primary tumor (e.g., MCT) before definitive surgery or radiation therapy. Table 5.1 provides an overview of chemotherapeutics and immunotherapeutics with antineoplastic activity that are commonly used in veterinary medicine.

The main objectives of conventional chemotherapy are tumor control, maintaining or improving the patient’s quality of life, and improved disease-free interval.

Appropriate Extralabel Drug Use in Veterinary Cancer Patients

Extralabel use of medications is common in veterinary oncology owing to the limited number of drugs specifically approved for animals. For example, toceranib phosphate is FDA approved for MCTs in dogs, but it is often used extralabel for other cancers like anal sac adenocarcinoma and thyroid carcinoma. Veterinarians frequently rely on clinical experience and/or published evidence to apply these treatments to different cancers. Additionally, most chemotherapy drugs used in veterinary medicine, such as doxorubicin and carboplatin, are approved for human use and are administered extralabel in animals. Understanding and appropriately prescribing extralabel treatments is essential to providing optimal care for veterinary cancer patients, and this includes knowing the legal limitations of using FDA CA drugs (see Section 2, What’s New in Veterinary Oncology).

Metronomic Chemotherapy

Metronomic chemotherapy involves the continuous administration of low-dose cytotoxic drugs, typically given orally by the pet caregiver on a daily or every-other-day schedule, usually in combination with nonsteroidal anti-inflammatory drugs (NSAIDs). This approach reduces the tumor’s ability to repair damage or adapt to its microenvironment by targeting angiogenesis. Unlike conventional chemotherapy, which aims to reduce tumor burden, metronomic chemotherapy focuses on disease stabilization. Early studies show it may be effective against several tumor types, with benefits such as reduced toxicity, ease of administration, and lower costs. ¹ It is often considered when conventional protocols fail or are declined by the client. Side effects are generally mild and transient.

Despite the promise of metronomic chemotherapy, this approach is currently limited by significant gaps in knowledge regarding best indications as well as optimal dosing schedules and drug combinations. The types of cancer best suited to metronomic therapy and the best methods to gauge tumor treatment response are also not fully understood. However, several published studies in veterinary medicine, mostly prospective phase 1 and phase 2 trials, have investigated the use of metronomic chemotherapy and reported generally positive responses. The most commonly evaluated neoplasms in these studies were hemangiosarcoma, soft tissue sarcoma, and transitional cell carcinoma. An assortment of other neoplasms, such as osteosarcoma, melanoma, and various carcinomas, were also evaluated, although in a smaller number of patients. ^2,3,4,5,6

In the majority of these studies, the oral chemotherapy drug cyclophosphamide was used. ^7,8,9 Other chemotherapeutic agents that have been assessed include lomustine (also known as CCNU) and chlorambucil.  ^10,11 These oral chemotherapeutics were often combined with an NSAID because of the antiangiogenic properties of the NSAID drug class.¹² Toceranib is also used with metronomic cyclophosphamide. ¹³ Because sterile hemorrhagic cystitis is a risk associated with cyclophosphamide chemotherapy, whether administered as metronomic or MTD, this sequela should be monitored with periodic urinalysis of a voided sample. ¹⁴ Furthermore, because other unanticipated toxicities may occur when multiple agents are combined in a protocol, close monitoring of patients is imperative. ¹⁵

Targeted Chemotherapy Using TKIs

Tyrosine kinases are enzymes that activate proteins involved in the signaling pathways to regulate normal cell proliferation and survival. Because many of these pathways are dysregulated in cancer cells, TKIs are anticancer drugs that block signal transduction, thereby preventing tumor growth. TKIs target specific signal transduction pathways, and they can induce toxicities to rapidly dividing normal cells that also rely on these pathways (see Chemotherapy Side Effects).

Currently, only one oral TKI, toceranib phosphate, is FDA approved for use in dogs with cancer in the United States. Toceranib is approved to treat grade 2 or 3 recurrent cutaneous MCTs with or without regional lymph node involvement.

Toceranib may prove useful for treating a variety of tumors in dogs extralabel, including heart-base tumors, ¹⁶ sarcomas, carcinomas, and melanomas. Toceranib has been investigated in combination with radiation therapy ¹⁷ and in combination with other therapies such as prednisone, low-dose continuous (metronomic) cyclophosphamide alone ¹⁸ or with piroxicam, ¹⁹ piroxicam  and MTD chemotherapy including doxorubicin, ²⁰ lomustine, ^21,22,23 carboplatin, ²⁴  and vinblastine. ²⁵ More widespread use of TKIs awaits further investigation of several important questions, such as the tumor types in which TKIs are most likely to be effective and their optimal combination with conventional chemotherapy agents.

Safety Considerations

Personnel Safety

Research has shown that human health care personnel working with hazardous drugs have higher instances of reproductive difficulties, fetal loss, DNA alterations, and cancer. ^{26,27,28,29,30,31} Similar studies have been performed rarely in veterinary medicine, but exposure of veterinary personnel handling hazardous drugs could be comparable to human medical personnel owing to lack of regulations, challenges with patient compliance, frequent exposure to contaminated patient excrement, inconsistent personnel training, and variable access to safety equipment. ³² Veterinarians have legal and ethical responsibilities to educate their staff on the safe handling of chemotherapeutic agents.

In these guidelines, the terms hazardous drugs (HDs) and chemotherapeutic agents will be used interchangeably. The Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health have compiled a comprehensive list of HDs. ³³  Additionally, the United States Pharmacopeia (USP) provided updated guidelines in 2017 titled “USP General Chapter 800,” which outline standards regarding personnel protection for preparation and handling of HDs. Because an in-depth discussion of HD controls is beyond the scope of these guidelines, readers can refer to the USP for detailed information on this topic at usp.org.

Exposure to HDs can occur at any point from the receipt of the drug to when it is excreted from the animal and into the environment. The routes of exposure for health care workers include skin or eye contact, inhalation, ingestion, or sharps injury. ³⁴ Table 5.2 outlines various safety equipment that should be used when working with HDs. Clearly label all HDs with chemotherapy warning labels. Individuals who are pregnant, trying to conceive, breastfeeding, or immunocompromised should not handle HDs.

If chemotherapy is uncommon in your practice, consider ordering premeasured single-dose chemotherapeutics to reduce hazardous drug manipulation in the clinic. This option negates the need for a biological safety cabinet and may decrease costs for clients.

After administering chemotherapeutic agents, discard the administration materials and personal protective equipment (PPE) into chemotherapy waste receptacles. Use PPE while thoroughly cleaning all areas and equipment that came into contact with HDs (Table 5.3). To prevent aerosolization, avoid spraying cleaning products directly on spills or contaminated surfaces.

Properly trained technicians play a key role in ensuring that crucial HD cleaning procedures are followed.

TABLE 5.2 Safety Equipment Necessary for Handling Hazardous Drugs

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*ASTM D6319, American Society for Testing and Materials standard D6978

TABLE 5.3 Summary and Sequence of Spill Management Cleaning Steps*

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Adapted from International Society of Oncology Pharmacy Practitioners Standards of Practice.

*Reprinted with permission from Biller B, Berg J, Garrett L, et al. 2016 AAHA Oncology Guidelines for Dogs and Cats. J Am Anim Hosp Assoc.
2016;52(4):181-204.

EPA, Environmental Protection Agency.

Client Safety

HD exposure risk does not end at the hospital. Clients with pets undergoing chemotherapy may be exposed to HDs through their pet’s urine and feces and by administering oral cytotoxic drugs. Clients or other individuals caring for the pet should:

• Avoid exposure to the pet’s waste for 72 hours after chemotherapy administration. If exposure must occur (cleaning litter boxes, waste cleanup), wear gloves and a mask.
• Do not split or crush oral HDs. Compounded liquid of HDs is available but not recommended because of exposure risk.
• Wear gloves when handling oral HDs, and do not handle oral HDs in food storage or preparation areas.

Patient Safety

In veterinary medicine, chemotherapeutic agents are often dosed in milligrams per meter squared (mg/m2), which offers ample opportunity  for drug calculation errors. Given the narrow therapeutic index of these drugs and the potential for serious side effects, adhering to precise drug dosing is essential. It is recommended that two individuals calculate chemotherapeutic doses to double-check accuracy before administration.

Technicians proficient in medical math can assist in double-checking chemotherapy drugs and dosing.

Some of the most common chemotherapeutics are irritants and vesicants. Drug extravasation can result in discomfort, swelling, redness, blistering, and necrosis. Make every effort to avoid extravasation by performing clean-stick IV catheter placement, using proper patient restraint, flushing the catheter adequately, and delivering the drug manually (syringe pumps are discouraged). If an extravasation occurs, withdraw as much drug as possible (do not flush) and implement a mitigation protocol (see Chemotherapy Extravasation Management at http://aaha.org/chemo-extravasation). ³⁵

Chemotherapy Side Effects

The primary goal of chemotherapy in veterinary oncology is to maintain the best possible quality of life for pets while effectively managing their cancer. Most veterinary chemotherapy protocols are well tolerated, with side effects that are typically mild and manageable. Studies show that approximately 15–30% of dogs undergoing chemotherapy experience side effects, most of which are mild (e.g., vomiting, diarrhea, or lethargy) and manageable with medical intervention. Severe, life-threatening side effects, such as febrile neutropenia, which may require hospitalization, occur in ~5–7% of cases. ³⁶ In most cases, patients will complete treatment without the need for dose adjustments or early discontinuation because of toxicity.

Febrile neutropenia, although uncommon, is a recognized potential complication. In a retrospective study of 673 chemotherapy treatments in dogs with lymphoma, febrile neutropenia was documented in 12 cases (1.8%), most often after the first CHOP cycle. ³⁷ A broader multiprotocol retrospective study reported neutropenia in 23 of 155 dogs (14.8%), with 17 of those dogs (11.0%) also developing fever consistent with febrile neutropenia. ³⁸ Although many neutropenic dogs remain clinically stable, a prospective study found bacteremia in 4 of 34 neutropenic patients (12.3%), emphasizing the importance of individualized monitoring and supportive care. ³⁹

Cats tend to tolerate chemotherapy even better than dogs, with a lower overall toxicity rate. Only ~10–15% of cats experience side effects, and severe reactions are even less common, likely affecting fewer than 5% of cases. ⁴⁰ A proactive approach to treatment, including preventive medications, can help minimize the occurrence and duration of side effects.

MTD chemotherapy primarily damages rapidly dividing cells, which include cancer cells and certain normal cells. The tissues most sensitive to MTD chemotherapy are the bone marrow, hair follicles, and gastrointestinal lining, often referred to collectively as the “BAG” (bone marrow, alopecia, gastrointestinal) effects.

The most common side effects from toceranib are GI, including diarrhea, decrease or loss of appetite, weight loss, and hematochezia. Other less common side effects are hepatotoxicity, neutropenia, lameness or muscle pain, coagulopathies, proteinuria, hypertension, and, rarely, pancreatitis.

Bone Marrow Suppression and Neutropenia

Bone marrow suppression most commonly results in neutropenia, which is the dose-limiting toxicity in veterinary oncology. Neutrophils and platelets are particularly at risk owing to their shorter circulating lifespan. Cats tend to be more tolerant of these adverse effects compared with dogs.

The degree of myelosuppression varies depending on the chemotherapy drug:

• Mild to none: corticosteroids, L-asparaginase
• Moderate: vincristine, vinblastine, cyclophosphamide, melphalan, rabacfosadine
• High: doxorubicin, lomustine, mitoxantrone, carboplatin, combination protocols

Neutropenia in cancer patients can also result from bone marrow infiltration by neoplastic cells (e.g., leukemia, advanced lymphoma, multiple myeloma) or from increased neutrophil consumption because of infection.

Neutropenia is the primary dose-limiting toxicity in veterinary oncology.

Prophylactic antibiotics are sometimes prescribed to be given at the expected neutropenic nadir (lowest neutrophil count), although this practice is controversial. Commonly used antibiotics include trimethoprim sulfamethoxazole and amoxicillin-clavulanic acid. Some oncologists may consider prophylactic antibiotic use when administering highly myelosuppressive agents like doxorubicin, carboplatin, or lomustine, particularly in high-risk patients, but not all task force members agreed with this practice. In a double-blind, placebocontrolled study, prophylactic trimethoprim sulfadiazine was associated with fewer hospitalizations and reduced nonhematologic toxicities during chemotherapy for lymphoma and osteosarcoma. ⁴¹ However, a more recent multi-institutional retrospective study in dogs treated with lomustine found no significant reduction in febrile neutropenia with antimicrobial prophylaxis, reinforcing the importance of individualized decision making and antibiotic stewardship. ⁴²

For chemotherapy drugs with high potential for bone marrow suppression (e.g., doxorubicin, carboplatin, lomustine), a CBC is typically checked after treatment to monitor the nadir, which is the lowest neutrophil count. This check helps determine if antibiotics or a dose reduction is necessary. The nadir usually occurs 7 days after treatment, although it can vary, especially for drugs like carboplatin and lomustine. Chlorambucil and melphalan can cause irreversible, delayed thrombocytopenia after long-term use, necessitating discontinuation of the drug.

At the nadir appointment, it is important to run a CBC, gather a thorough history, take vital signs (especially temperature, as identifying fever is crucial in neutropenic patients), and conduct a complete physical examination. The neutrophil count, not the total white blood cell count, is the primary indicator of concern (Table 5.4). Antibiotics are recommended if the neutrophil count drops below 1000/mL, although a recent publication suggested that a cutoff of 750/mL is safe and may reduce unnecessary antimicrobial use. ⁴³ If the patient is afebrile and feeling well, they can often be managed as an outpatient. However, if the neutrophil count is 1500/mL and the patient is febrile or showing signs of illness, hospitalization with supportive care is required.

Febrile neutropenia is an oncologic emergency and requires hospitalization.

TABLE 5.4 Nadir Appointment Action Plan

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IV, intravenous

Alopecia

Alopecia occurs as a result of damage to the rapidly dividing hair follicles. Dog breeds with continuously growing coats, such as poodles, Scottish terriers, and West Highland white terriers, are more likely to experience this effect. Alopecia is rare in cats, but shaved areas (e.g., from limb catheters or AUS) may take longer to regrow, and cats may lose their whiskers. Hair and whiskers typically regrow once treatments are completed, but hair may sometimes grow back with a different texture or color. Although pets are unaffected by this cosmetic side effect, it is important to inform clients about potential changes in whiskers and hair coat to avoid surprises.

GI Toxicity

Drugs used in veterinary oncology have varying risks of chemotherapy-induced nausea and vomiting (CINV):

• Low risk: L-asparaginase, chlorambucil
• Moderate risk: vincristine, vinblastine, lomustine, cyclophosphamide, mitoxantrone, carboplatin, toceranib
• High risk: doxorubicin, rabacfosadine, cisplatin

CINV is classified as either acute (within 24 hours) or delayed (1–5 days after chemotherapy). Acute CINV is primarily mediated by serotonin (5-HT3) pathways, whereas delayed CINV is associated with substance P neurokinin-1 (NK1) receptor pathways.

GI toxicity, including vomiting, diarrhea, decreased appetite, and nausea, is usually self-limiting and lasts an average of 3 days. These side effects are less common in cats than in dogs. Taking a proactive approach to prevent these side effects is helpful, and appropriate medications can be used as needed to minimize and manage them.

Importance of Managing and Preventing GI Side Effects

One of the most common reasons clients stop chemotherapy prematurely is because their pet has hyporexia or anorexia. This side effect can be distressing for pet caregivers and can lead to unnecessary discontinuation of treatment. It is crucial to emphasize to clients that appetite loss is often manageable with proper intervention and addressing it early can help keep pets on their treatment plan.

Educate clients about the likelihood of appetite changes and reassure them that this is a manageable side effect.

Encourage clients to report even mild changes in their pet’s eating habits so that supportive measures can be implemented quickly. By addressing appetite loss early, pets can remain on their cancer treatment plan and their overall well-being during therapy can be substantially improved.

Prevention Strategies

Nausea is often a primary cause of appetite loss. Proactively using maropitant or other antiemetic drugs after chemotherapy can help reduce nausea and improve appetite. For acute CINV, pretreatment with maropitant IV or subcutaneously or ondansetron may be useful for high-risk drugs (e.g., doxorubicin, rabacfosadine). To prevent delayed CINV, especially in dogs, administer oral maropitant for 4–5 days after chemotherapy. Cats typically require less preventive treatment unless they have experienced prior GI issues. If breakthrough CINV occurs, additional antiemetic therapy may be needed.

In addition, proactive use of appetite stimulants can be very helpful. Appetite stimulants such as capromorelin or mirtazapine, particularly
transdermal mirtazapine in cats, can be useful for stimulating appetite and preventing anorexia. Administering these at the first sign of decreased appetite can prevent prolonged periods of inappetence. Both antinausea and appetite stimulant medications may be needed concurrently in some patients. For pets with pre-existing inappetence, additional medications may be prescribed at treatment to prevent worsening of appetite loss during chemotherapy.

It is highly beneficial for chemotherapy patients to go home with “just in case” medications if side effects occur after hours, clients can start treatment promptly, preventing unnecessary discomfort or emergency visits. Provide a client information sheet that explains how to manage side effects at home and details the proper usage of these medications.

Management for diarrhea may include dietary modifications and probiotics. Crofelemer-CA1 may be of benefit, and antibiotics such as tylosin or metronidazole have anecdotally been useful. For more information on antimicrobial stewardship and treatment of diarrhea, see the
2022 AAFP/AAHA Antimicrobial Stewardship Guidelines at aaha.org.

Encourage clients to provide small, frequent meals of palatable foods to entice pets to eat. Offering a variety of textures (e.g., wet food, homemade diets) can help stimulate interest in food. In addition, close monitoring of a pet’s appetite and body weight and adjusting the treatment plan as needed can make a substantial difference. If appetite continues to be an issue, adjusting chemotherapy doses, adding supportive care, or delaying chemotherapy can often resolve the problem without completely stopping treatment.

In-Hospital Versus Outpatient Treatment of GI Side Effects

With a proactive approach and early recognition, most cases of inappetence, CINV, and diarrhea can be managed at home. However, in more severe cases where there is a concern for dehydration or oral medications are ineffective, IV treatment may be necessary.

When a patient is brought to the hospital, the goal is to determine whether outpatient or inpatient care is required, based on the physical examination findings, clinical signs, and diagnostic workup. Consider running a CBC, chemistry panel, and urinalysis or urine specific gravity and possibly fecal floatation and/or bacterial cultures (blood and/or urine). If abdominal pain is present, radiography or ultrasonography may be necessary to rule out foreign bodies, obstruction, or intussusception. For pets with GI neoplasia, distinguishing between chemotherapy side effects and the disease can be challenging, and obtaining a thorough history, including the timing of symptoms, is essential.

Outpatient treatment typically includes a period of nothing by mouth, followed by a bland diet, IV or subcutaneous fluids, injectable
antiemetics, appetite stimulants, and antidiarrheals as needed. It is also important to temporarily discontinue any oral chemotherapy or medications contributing to inappetence, with appropriate adjustments made for future treatments.

Some patients may require hospitalization because of side effects. In such cases, patients are typically hospitalized for 24–48 hours for supportive care, including IV fluids, injectable antiemetics, and possibly antibiotics. It is important to reassure clients not to consider euthanasia at this stage, as many patients show rapid improvement with supportive care. Most can resume treatment with dose reductions and additional prophylactic measures.

Other Toxicities

In addition to general side effects, certain chemotherapy drugs are known to cause specific and unique toxicities. For example:

• Doxorubicin is contraindicated in dogs with impaired cardiac function or those that have reached a total cumulative dose of 180–240 mg/m2. It can also exacerbate renal disease in cats.
• Cyclophosphamide has the potential to cause sterile hemorrhagic cystitis in dogs, and rarely in cats, leading to bladder irritation and discomfort.
• Rabacfosadine can cause cumulative dermatopathy and, in rare cases, life-threatening pulmonary fibrosis.

For more detailed information on chemotherapy drug–specific toxicities, refer to Table 5.1, consult resources such as veterinary drug formularies, or seek advice from a veterinary oncologist (see Section 6).

The 2026 AAHA Oncology Guidelines for Dogs and Cats are generously supported by CareCredit, Hill’s Pet Nutrition, Merck Animal Health, and Zoetis.