Box 28-2 lists the equipment necessary for intravenous administration of cytotoxic drugs. PPE, as previously described, should be worn by the individual administering the drug and any personnel involved in restraint of the cat. An absorbent pad with a plastic backing should be placed underneath the limb into which the drug is to be delivered. A butterfly catheter can be used for cooperative cats receiving small chemotherapy volumes (<3 mL). For larger volumes an indwelling catheter should be placed and the cat closely monitored throughout the infusion. The catheter should be flushed thoroughly with nonheparinized saline before administration to ensure its patency. Chemotherapy agents should not be infused with an intravenous fluid pump. Chemotherapy drugs should be administered by slow gravity drip or manual syringe infusion over the recommended time of administration. The fluid bag should be lowered beneath the cat every few minutes to ensure that blood is able to flow back in the catheter. If the drug is administered through a syringe, the plunger should be aspirated back several times during administration of the drug to ensure that blood still appears in the hub of the catheter. The catheter site should be monitored throughout administration and administration discontinued if any swelling at the catheter site is observed. Once the chemotherapy infusion is complete, the catheter should be flushed again with nonheparinized saline before removal. A light bandage should be placed over the catheter site after removal.

Intramuscular, Subcutaneous, and Intralesional Administration

Intramuscular or subcutaneous injections are administered in the same manner as any other intramuscular or subcutaneous injection, but disposable gloves should always be worn. Because L-asparaginase is more likely to cause an anaphylactic reaction when administered intravenously, aspiration of the syringe should be performed before intramuscular or subcutaneous administration to ensure that a blood vessel has not been inadvertently entered. Chemotherapy drugs that are administered intralesionally are always suspended in oil or another vehicle to help prevent the drug from leaking out of the tumor tissues into the bloodstream. Disposable gloves and a protective gown and eyewear should be worn during administration, and a disposable, absorbent pad should be placed underneath the part of the body to receive the intralesional chemotherapy. All materials used in intramuscular, subcutaneous, or intralesional chemotherapy administration should be disposed of in the same manner as for intravenous administration. Urinary and fecal waste should be handled as previously described in the hospital and at home after intralesional injection.

Intracavitary Administration

Chemotherapy agents such as carboplatin and mitoxantrone may be administered in the pleural or peritoneal space to mitigate malignant effusions. The intracavitary dose of chemotherapy is generally the same as that administered intravenously and can be administered into a single body cavity or divided between the thorax and the abdomen. The chemotherapy drug should be diluted with the appropriate diluent to a maximal volume of 60 mL for intrathoracic administration and 250 mL for intraabdominal administration.³⁴ As appropriate, effusions should be drained from the cavity before instillation of the chemotherapy agent.

For intrathoracic chemotherapy administration, the cat can be positioned in sternal or lateral recumbency and the thoracic wall overlying the seventh to ninth ribs aseptically prepared. Proper PPE should be worn in a similar fashion as for intravenous administration. An 18-gauge catheter is then inserted between the ribs, the stylet removed, and the catheter flushed with 2 to 5 mL of warmed saline to ensure patency. If the cat is uncomfortable or begins to cough, or the catheter does not flush easily, the catheter should be removed and a new one inserted. If the cat tolerates the flush well, the drug can then be administered while the catheter site is monitored continuously to ensure that the drug is not inadvertently administered subcutaneously. The catheter insertion site can be blocked with a small amount of buffered lidocaine before the procedure to minimize discomfort.

For intraperitoneal administration the cat should be placed in dorsal recumbency, and a site on the abdomen just caudal to the umbilicus should be aseptically prepared. The urinary bladder should be identified with palpation to prevent accidental puncture. The 18-gauge catheter can then be placed and the chemotherapy administered as previously described. After administration of intracavitary chemotherapy, some authorities recommend allowing the cat to move around for several minutes to ensure distribution of the drug throughout the body cavity.

General Adverse Effects of Chemotherapy

Gastrointestinal

Chemotherapy agents can be directly cytotoxic to the intestinal epithelial crypt cells resulting in gastrointestinal side effects about 2 to 5 days after administration. Less commonly, some chemotherapy agents may cause release of 5-HT from enterochromaffin cells in the gastrointestinal tract, which binds to 5-HT₃ receptors on peripherally vagal nerves or centrally in the chemoreceptor trigger zone. 5-HT₃–mediated nausea and vomiting tend to occur within 24 hours of chemotherapy administration. These side effects may include mild to severe inappetence, nausea, vomiting, and diarrhea. For the majority of cats, gastrointestinal side effects secondary to chemotherapy are mild and self-limiting and often can be easily managed by owners at home with the administration of oral antinausea and antidiarrheal drugs on an as-needed basis. Oral antiemetics such as metoclopramide, ondansetron, and maropitant (see Table 28-5) can be dispensed at the time of the first chemotherapy appointment, whereupon owners should be instructed when to give the medications. Medications such as tylosin and metronidazole can be dispensed in a similar manner for owners to administer in the case of soft stools or diarrhea. Probiotics can also be administered throughout the duration of chemotherapy and have been anecdotally reported to decrease the frequency and severity of chemotherapy-induced diarrhea.

Cats that are unwilling to eat for several days or that have intractable vomiting should be hospitalized for supportive care with intravenous fluids to correct any hydration deficits and electrolyte abnormalities. Injectable antiemetics should be administered until the cat is eating readily on its own. Dosage of the particular chemotherapy agent should be reduced by 20% for cats that require hospitalization for significant gastrointestinal toxicosis.

Hematologic

Myelosuppression, particularly neutropenia, is a common sequela of chemotherapy administration. Most affected cats remain asymptomatic, but a small number may develop serious, life-threatening complications as a result of neutropenia and subsequent development of sepsis. The neutrophil nadir occurs approximately 7 to 10 days after chemotherapy administration, with exceptions to this noted in subsequent sections. To monitor for myelosuppression, a CBC should be checked before each chemotherapy administration to ensure that neutrophil and platelet counts are adequate. Treatment with chemotherapy should be delayed if the neutrophil count is less than 2000 to 3000 cells/uL or if the platelet count is less than 75,000 to 100,000 cells/uL. These ranges are merely guidelines, and CBC values should be assessed in conjunction with the overall health of the cat in mind. If neutropenia or thrombocytopenia occurs, a treatment delay of 5 to 7 days is generally recommended, at which time a CBC should be rechecked to ensure that cell counts have normalized. For chemotherapy agents that are administered every 2 to 3 weeks, a CBC should be checked 7 to 10 days after the first treatment with that drug. If neutrophil counts are greater than 1000 to 1500 cells/uL and the cat is afebrile and clinically well, reduction in subsequent doses is not needed.

Cats with neutrophil counts greater than 1000 cells/uL have a low risk of systemic infection. Most cats with significant neutropenia (≤1000 neutrophils/uL) can be managed on an outpatient basis, provided they are feeling well and afebrile. A broad-spectrum oral antimicrobial that is sparing to the normal gastrointestinal flora, such as trimethoprim–sulfa or enrofloxacin, can be administered for 5 to 7 days prophylactically. Cats that are febrile or systemically unwell with a concurrent neutropenia should be hospitalized for supportive therapy with intravenous fluids and antimicrobials to correct any hydration deficits or electrolyte abnormalities. In addition to a CBC, a biochemical profile and urinalysis should be obtained at admission. Treatment with intravenous broad-spectrum antimicrobials should be instituted until the cat is eating well and able to receive oral medications. Cats generally recover from febrile neutropenic episodes in 1 or 2 days. Cats that are slow to recover or are declining in the face of appropriate therapy should have thoracic radiographs, urine culture, and blood cultures performed to determine whether a resistant source of infection exists. Neutrophil counts need not be normal before the cat is released from the hospital as long as it is afebrile, eating, and tolerating oral medications.

Alopecia

Alopecia is a common concern for pet owners whose cat may require chemotherapy as part of its cancer treatment. Cats rarely develop diffuse alopecia, but this can happen with chronic administration of high-dose chemotherapy. Owners should be cautioned that most cats undergoing treatment with chemotherapy may lose their whiskers and other guard hairs, and previously shaved areas may be slow to regrow. Generally, hair will grow back once chemotherapy is discontinued.

Extravasation

Many intravenously administered chemotherapy agents are vesicants and can cause local tissue irritation or necrosis if administered outside of the vein. Of the more common chemotherapy drugs used in cats, doxorubicin, vincristine, and vinblastine are all vesicants. If there is any doubt as to whether a drug is a vesicant, it should be administered as though it is.

Signs of extravasation may include pain, erythema, moist dermatitis, and necrosis and may appear 1 to 10 days after extravasation of the drug.²⁸ If extravasation is suspected at the time of administration, the infusion should be stopped immediately. An attempt should be made to aspirate the drug with up to 5 mL of blood back into the syringe. The catheter is removed once this has been accomplished. Recommendations regarding additional treatment are generally extrapolated from experiences in human oncology and are based on the type of drug that was extravasated. In the case of vinca alkaloid extravasation, warm, dry compresses can be applied for several hours and hyaluronidase injected into the local site.¹⁰ The volume of hyaluronidase injected should equal the volume of drug extravasated. Administration of dexrazoxane (Zinecard), a free-radical scavenger marketed to prevent doxorubicin-associated cardiotoxicity in humans, is indicated in the case of doxorubicin extravasation. The recommended dose is 1 : 10 of vesicant to dexrazoxane, and this should be administered intravenously through a separate catheter within 6 hours of extravasation.^10,³⁰ Dexrazoxane is expensive and may be too costly for practitioners to stock. Availability at a local human hospital should be investigated because timely administration (within 3 to 6 hours) after extravasation may help mitigate tissue necrosis. Alternatively, topically applied dimethyl sulfoxide (DMSO) to the site of extravasation may help minimize tissue damage as well.⁵¹ Aggressive surgical débridement may be required to manage severe cases of perivascular necrosis.

Hypersensitivity Reactions

L-asparaginase and doxorubicin are drugs that may cause hypersensitivity reactions in cats. Cats receiving doxorubicin should be monitored for pruritus, head shaking, erythema of the skin and mucous membranes, facial edema, wheezing, and dyspnea during the doxorubicin infusion. If any of these signs are noted, the infusion should be stopped and the cat administered diphenhydramine (2 to 4 mg/kg intramuscularly) and dexamethasone SP (0.2 to 0.4 mg/kg intravenously). Once the reaction has subsided, then infusion can be restarted at a slower rate of administration. Treatment with L-asparaginase may result in anaphylaxis. This generally occurs within 60 minutes of administration and is more likely to occur with subsequent doses than the first dose. Cats that have been treated with L-asparaginase should be closely monitored for 60 minutes after treatment for respiratory difficulty, vomiting, diarrhea, and collapse. Aggressive supportive care may be required if anaphylaxis occurs. Cats that have previously experienced hypersensitivity reactions should be premedicated with diphenhydramine and dexamethasone SP before every subsequent dose of the drug to which they had the reaction. Reactions that are severe warrant discontinuation of the drug. Subsequent hypersensitivity reactions can be more severe or even life-threatening.

Commonly Used Chemotherapy Drugs

This section deals with chemotherapy agents commonly used for treating cats with cancer, as well as some newer agents about which limited information is known. Table 28-1 summarizes these chemotherapy drugs, common indications, dosages, and associated toxicities.

TABLE 28-1 Commonly Used Chemotherapy Drugs

Alkylating Agents

Chlorambucil (Leukeran)

Chlorambucil is an orally administered DNA alkylating agent that is used to treat low-grade lymphoma, chronic lymphocytic leukemia, and, less commonly, multiple myeloma. Reported dosages include 2 mg orally every 2 or 3 days, 2 to 4 mg/m² orally every other day, 15 mg/m² orally every day for 4 consecutive days once every 3 weeks, and 20 mg/m² orally once every 2 weeks.^13,^23,⁴⁹

Chlorambucil is generally well tolerated, and gastrointestinal signs are uncommon. Myelosuppression may occur after prolonged used. Rare toxicities may include neurotoxicity, which has been reported in a single cat, and there may be an increased risk of developing a second malignancy with prolonged therapy.^4,⁴⁹

Cyclophosphamide (Cytoxan)

Cyclophosphamide is a prodrug that requires hepatic activation and is excreted primarily by the kidneys. It is most commonly combined with other chemotherapy drugs to treat lymphoma or various sarcomas. It can be administered either orally or intravenously, and dosages range from 200 to 300 mg/m² or 10 mg/kg, as dictated by the protocol used. Cyclophosphamide may be administered as a single bolus, or the oral dose may be divided over 3 to 4 days. For example, if the cat’s total dose is 75 mg, then the cat may be administered a 25-mg tablet orally once daily for 3 days. Tablets should never be divided, and it may be necessary to compound cyclophosphamide for smaller cats. Alternatively, the injectable form is relatively inexpensive, and dosing is very flexible.

Common side effects include myelosuppression and gastrointestinal toxicity. Less commonly, sterile hemorrhagic cystitis may develop secondary to cyclophosphamide administration.⁸ If signs of hematuria, pollakiuria, or stranguria are observed in a cat that has been recently treated with cyclophosphamide, a urinalysis and urine culture should be performed. If the urine culture is negative, a presumptive diagnosis of sterile hemorrhagic cystitis can be made, and cyclophosphamide therapy should be discontinued permanently.

Lomustine (CCNU, CeeNU)

Lomustine is an oral DNA alkylating agent that is most frequently used against mast cell tumors and lymphoma.^11,^41,⁴² Because of its ability to cross the blood–brain barrier, it is also used to treat brain tumors, but efficacy against these tumor types is not documented in cats. It may be efficacious against fibrosarcoma and multiple myeloma.¹¹ Lomustine is administered at 50 to 60 mg/m² or 10 mg/cat orally once every 3 to 6 weeks.^11,^41,⁴² It may be necessary to compound capsules to smaller sizes for more accurate dosing because the 10 mg/cat dose may underdose or overdose some cats.

Myelosuppression, particularly neutropenia, is the dose-limiting toxicity for lomustine. Severe and persistent thrombocytopenia can occur that warrants discontinuation of the drug if platelet numbers do not return to normal levels in 6 weeks. Gastrointestinal signs can occur with this drug as well. Hepatotoxicity has not been reported in cats to date, but routine monitoring of liver enzymes is still recommended. Pulmonary fibrosis can occur in people treated with CCNU, and a report of pulmonary fibrosis developing after chronic CCNU therapy exists for a single cat.⁴⁶ Renal toxicity is an uncommon side effect in humans and has not been reported in cats, but routine monitoring of kidney values should be performed for cats with documented renal insufficiency that are receiving CCNU.

Melphalan

Melphalan is an oral DNA alkylating agent that is most commonly used in treatment of multiple myeloma and occasionally lymphoma. Melphalan can be administered at 0.1 mg/kg orally once daily or 0.1 mg/kg orally daily for 14 days followed by 0.1 mg/kg orally every other day.^5,⁷ Tablets may need to be compounded for more accurate dosing because they should not be split.

Myelosuppression, in particular thrombocytopenia, is the most common toxicity and generally occurs with chronic administration. A CBC should be monitored once weekly for the first month and then every 4 to 8 weeks during melphalan therapy.

Anthracyclines

Doxorubicin (Adriamycin)

Doxorubicin is an anthracycline that exerts its antineoplastic effects by way of a number of mechanisms, including topoisomerase II inhibition, intercalation of DNA, and generation of free radicals. Doxorubicin is commonly used in multidrug protocols for lymphoma, injection-site and other soft tissue sarcomas, and feline mammary carcinomas. Doxorubicin is diluted in 30 to 50 mL 0.9% NaCl and administered at 1 mg/kg or 25 mg/m² intravenously over 20 to 60 minutes every 2 to 3 weeks.

More common side effects of doxorubicin administration include gastrointestinal signs and myelosuppression. Doxorubicin is a potent vesicant, and utmost caution should be used to ensure that extravasation does not occur during administration. Cumulative nephrotoxicity may occur with doxorubicin administration, and this drug should not be used in cats with renal insufficiency.³⁶ Renal values and urine specific gravity should be monitored routinely in cats receiving doxorubicin and the drug discontinued if isosthenuria or azotemia occur. Cats can also have an acute hypersensitivity reaction with doxorubicin, and some practitioners routinely premedicate cats receiving doxorubicin with diphenhydramine or dexamethasone SP (or both). Regardless of whether premedication with antihistamines or corticosteroids is performed, the cat should be closely monitored during the infusion for any indications of a hypersensitivity reaction, such as head shaking, erythema of the pinna or mucous membranes, facial swelling, dyspnea, and agitation. Cumulative cardiotoxicity with doxorubicin administration is well documented in humans and dogs but is infrequent in cats.³⁶ Administration of doxorubicin to cats with underlying cardiac disease is discouraged, and some practitioners recommend not exceeding cumulative doses of 180 to 240 mg/m² in cats with normal cardiac function.

Liposmal-Encapsulated Doxorubicin (Doxil)

Liposomal-encapsulated doxorubicin was formulated to avoid the significant cardiotoxicity in humans that limits doxorubicin administration. This drug may have efficacy against similar tumor types as doxorubicin, including injection-site sarcomas, and is dosed at 1 mg/kg intravenously every 3 weeks.⁴⁰

Liposomal-encapsulated doxorubicin has a similar toxicity profile in cats as native doxorubicin. Gastrointestinal side effects are generally mild and self-limiting. Liposomal-encapsulated doxorubicin is associated with nephrotoxicity, and renal function should be closely monitored after administration of the drug.⁴⁰ It is a vesicant and should be administered only through a cleanly placed intravenous catheter. Cats may also develop a nonpainful alopecia and erythema with hyperpigmentation around their mouths and distal limbs.⁴⁰ Cats may experience a hypersensitivity reaction characterized by salivation and bradycardia during their first treatment with liposomal-encapsulated doxorubicin; this can be managed with administration of diphenhydramine and dexamethasone SP.⁴⁰ Intracavitary administration of liposomal-encapsulated doxorubicin has been reported in dogs but has not been evaluated in cats.

Mitoxantrone

Mitoxantrone is an anthracycline derivative that exerts its cytotoxic effects by inhibiting topoisomerase II. This drug likely has a similar antitumor profile to doxorubicin and may be efficacious against lymphoma and various carcinomas and sarcomas.³⁵ The mitoxantrone dosage is 6 to 6.5 mg/m² intravenously every 3 weeks. The drug is diluted in 20 to 50 mL 0.9% NaCl before intravenous administration over 10 to 15 minutes. Mitoxantrone can be administered in the pleural or peritoneal space to help alleviate malignant effusions.

The most common adverse effects observed with mitoxantrone are mild, self-limiting gastrointestinal signs and myelosuppression. Unlike doxorubicin, mitoxantrone does not induce hypersensitivity reactions and is not as potent a vesicant if extravasated. Owners should be cautioned that urine and sclera may be blue-tinged after administration.⁷

Antimetabolites

Cytosine Arabinoside (Cytarabine, Cytosar-U, ara-C)

Cytosine arabinoside is a deoxycytidine analog that interferes with DNA synthesis through DNA polymerase inhibition. Because this drug is cell cycle specific with an extremely short plasma half-life, it is most efficacious when administered by constant-rate infusion or with the dose divided into twice-daily subcutaneous injections over several days. Cytosine arabinoside is used in cats primarily to treat lymphoma or leukemia, particularly when there is central nervous system (CNS) involvement, because of the ability of the drug to cross the blood–brain barrier. Cytosine arabinoside is often substituted for cyclophosphamide for treatment of renal lymphoma because CNS involvement occurs in approximately 40% of these cases.³³ The dosage of cytosine arabinoside is 600 mg/m² divided into four doses administered subcutaneously twice daily for 2 days or administered as a constant-rate infusion at 300 mg/m² per day for 2 days.⁷

Cytosine arabinoside is generally well tolerated, with myelosuppression being most common and gastrointestinal signs occurring rarely.

Gemcitabine

Gemcitabine is an analog of deoxycytidine that is activated intracellularly, resulting in DNA synthesis inhibition. There is limited information on the use of gemcitabine as a single agent in cats. It has been used as a radiation sensitizer in the treatment of oral squamous cell carcinoma (SCC) and also in combination with carboplatin as therapy for various carcinomas.^22,^29,³¹ This drug is expensive compared with other chemotherapy drugs, and optimal dosing in cats is not known at this time.

Adverse effects when administered intravenously at 2 mg/kg weekly in conjunction with carboplatin included moderate gastrointestinal toxicity and myelosuppression.³¹ When administered intravenously at 25 mg/m² twice weekly as a radiation sensitizer, significant hematologic and local tissue toxicity occurred.²⁹ Additional research investigating efficacy, dosage, and toxicity of gemcitabine as a single agent drug is necessary before it can be used routinely in cats with cancer.

Methotrexate

Methotrexate is an antifolate that inhibits dihydrofolate reductase, thereby blocking DNA synthesis. It has been used primarily in combination chemotherapy protocols for lymphoma at a dosage of 0.8 mg/kg weekly, either intravenously or orally.^32,^33,⁴⁵

Adverse effects of methotrexate administration are most commonly gastrointestinal signs, with myelosuppression occurring less commonly.

5-Fluorouracil (5-FU)

5-Fluorouracil (5-FU) is available in injectable and topical formulations. Because this drug has been documented to cause fatal neurotoxicity in cats, it should not be administered, even topically, to this species.^17,^18,⁵²

Antitubulin Agents

Vinblastine and vincristine are naturally occurring vinca alkaloids derived from the periwinkle plant, and vinorelbine is a second-generation synthetic vinca alkaloid. These drugs disrupt cell division by binding to the microtubular proteins in the mitotic spindle. Metabolism of this class of drugs occurs in the liver, and dosage adjustments should be made for liver dysfunction. The antitubulin agents share a similar toxicity profile, with exceptions for each drug noted in subsequent sections. They are generally well tolerated, but mild gastrointestinal toxicosis and myelosuppression may occur. The antitubulin agents are all vesicants and should be administered using a cleanly placed catheter.

Vinblastine

Vinblastine is used as a treatment for mast cell tumor or substituted for vincristine in lymphoma protocols when vincristine is not tolerated by the cat or the disease has become refractory to vincristine in a rescue setting. Anecdotally, cats can tolerate intravenous dosages of 2 mg/m² weekly to every other week, but published data are lacking.

Vincristine

Vincristine is used commonly to treat lymphoma and leukemia; reported dosages range from 0.5 to 0.75 mg/m² given as an intravenous bolus once weekly. Peripheral neuropathy, which may present as constipation in cats, is uncommon but may occur with prolonged administration.⁷

Vinorelbine (Navelbine)

There is no published information regarding vinorelbine and its possible antitumor spectrum, dosage, or toxicity profile in tumor-bearing cats.

Platinum Drugs

Carboplatin

Carboplatin is a platinum-derived alkylating agent that may have efficacy against various carcinomas and sarcomas.^7,²⁴ The most common route of administration is intravenous, but carboplatin can also be administered intracavitarily, in the thorax or abdomen, and intralesionally. Carboplatin is administered intravenously at 240 mg/m² every 3 to 4 weeks. Dosing of carboplatin on the basis of glomerular filtration rate has been investigated and may allow for more appropriate dosing in cats, but this is clinically impractical for most practitioners.^2,³ Carboplatin can also be used intralesionally for facial SCC. General anesthesia is required for treatment, and carboplatin is administered at 1.5 mg/cm³ in purified sesame oil emulsion injected every 0.5 cm in the tumor and adjacent tissues weekly for up to four treatments.⁵³ Carboplatin has been reported to be administered intracavitarily at 180 to 200 mg/m² to help alleviate malignant effusions; however, information regarding efficacy is limited.^47,⁴⁸

Myelosuppression is the dose-limiting toxicity of carboplatin. Neutrophil and platelet nadirs generally occur 2 to 3 weeks after administration.²⁴ Gastrointestinal signs occur less commonly with carboplatin. Because carboplatin is excreted by the kidneys, it is important to assess renal function (blood urea nitrogen, creatinine, and urine specific gravity) before each treatment. Carboplatin is not commonly directly nephrotoxic, but decreased excretion occurs with decreased renal function, thereby increasing the likelihood of toxicity.

Cisplatin

Administration of cisplatin to cats induces a fatal pulmonary edema. It should not be administered to cats at any dosage.²⁵

Tyrosine Kinase Inhibitors

Tyrosine kinases are proteins expressed on cell surfaces that are integral to regulation of cell growth and differentiation. These kinases, such as KIT, epithelial growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), bind their specific growth factor, leading to downstream intracellular signaling and regulation of cell growth, differentiation, and survival. Tyrosine kinases can become constitutively activated with some types of cancer, thereby leading to unregulated cell growth. Tyrosine kinase inhibitors are a newer class of antineoplastic agents that inhibit these kinases by binding to the ATP-binding pocket, resulting in downregulation of cellular growth. Tyrosine kinase inhibitors used in veterinary oncology include imatibinib (Gleevec; Novartis), toceranib (Palladia; Pfizer), and masitinib (Kinavet CA-1; AB Science). Both toceranib and masitinib have recently been approved by the Food and Drug Administration for the treatment of canine mast cell tumors. Gastrointestinal side effects are common in dogs, and it is recommended that patients have a “drug holiday” until gastrointestinal signs resolve. Use of these drugs for cats remains off-label, and there is limited information regarding dosage, tumor specificity, efficacy, and toxicity of tyrosine kinase inhibitors in this species.

Imatinib (Gleevec)

Imatinib has been used to treat feline cutaneous, splenic, and disseminated mast cell tumors at doses at 10 to 15 mg/kg orally once daily. The most common side effects noted are mild gastrointestinal upset.^20,^21,²⁷

Toceranib (Palladia)

Information regarding use of toceranib in cats is limited. Preliminary results suggest that dosage of 2.8 mg/kg orally every other day or on a Monday/Wednesday/Friday schedule may have some efficacy against oral SCC and injection-site sarcomas.¹⁹ Most common side effects are gastrointestinal, particularly anorexia with weight loss and vomiting.¹⁹

Masitinib (Kinavet CA-1)

Masitinib has been administered to healthy cats at a dosage of 50 mg/cat orally every 24 to 48 hours and was well tolerated over a 4-week period.⁹ Gastrointestinal toxicosis was most common, with neutropenia and proteinuria occurring less frequently.⁹ There is no information at this time regarding dosage, safety, and efficacy for masitinib in cats with cancer.

Miscellaneous

L-asparaginase

L-asparaginase is an enzyme derived from Escherichia coli that depletes cells of asparagine, an essential amino acid for protein synthesis. Lymphoreticular cells are particularly sensitive to the effects of L-asparaginase because they lack asparagine synthetase and cannot produce asparagine. For this reason L-asparaginase is primarily used in treatment of lymphoma and leukemia. It is administered at 400 mg/kg or 10,000 IU/m² intramuscularly or subcutaneously as part of a multidrug protocol.

The most common toxicity associated with L-asparaginase administration is anaphylaxis, which may be characterized by dyspnea, pruritus, edema, vomiting, diarrhea, hypotension, and collapse. Additional rare side effects may include myelosuppression, particularly when administered simultaneously with vincristine, or pancreatitis.

Hydroxyurea

Hydroxyurea is an oral chemotherapy agent that suppresses proliferation of myeloid, erythroid, and platelet precursors by inhibiting DNA synthesis.³⁷ The main indications for hydroxyurea are treatment of polycythemia vera and chronic myelogenous leukemia. The recommended dosage is 10 mg/kg orally once daily.⁷

Side effects associated with hydroxyurea therapy in cats may include myelosuppression and gastrointestinal toxicity.⁷

Imiquimod (Aldara)

Imiquimod 5% cream (Aldara) is a topical immune response modifier that has been shown to have antitumor effects by enhancement of both innate and cell-mediated immunity. Data are limited at this time, but imiquimod 5% cream may be effective in treating multifocal, cutaneous SCC in situ or actinic (solar-induced) SCC in cats.^14,³⁸ Reported topical application schedules range from once daily to three times a week on affected areas.

Adverse events that have been reported include mild erythema at the site of application.^14,³⁸ Potential systemic toxicities have been reported as well, and these are likely secondary to ingestion of imiquimod 5% cream by the cat because the drug should not have systemic effects when applied topically. These side effects include mild gastrointestinal upset, neutropenia, and elevated liver enzymes.¹⁴ It is recommended that routine monitoring of CBC and biochemistry panel be performed every 4 to 8 weeks in cats treated with imiquimod 5% until more information is known about this drug in cats.

Prednisone and Prednisolone

Prednisolone and its prodrug prednisone are glucocorticoids frequently used in veterinary oncology. In most species prednisone is converted to prednisolone in the liver, but there is some concern that this step does not occur efficiently in some cats. Therefore use of prednisolone rather than prednisone is recommended in this species.³⁹ Prednisolone is commonly used in multidrug chemotherapy protocols, and there is evidence that prednisolone has activity against lymphoma, plasma cell tumors, and mast cell tumors.* The antitumor dose of prednisolone is 2 mg/kg orally once daily. This dose is tapered over approximately 1 month and then generally discontinued when used in combination chemotherapy protocols. Other common uses for prednisolone include decreasing edema associated with tumors of the CNS and as an antiinflammatory for pain control in cats that cannot tolerate administration of nonsteroidal antiinflammatory drugs. For these indications, prednisolone is generally administered at antiinflammatory dosages (0.5 to 1 mg/kg orally once daily).

Prednisolone is generally well tolerated in cats. Adverse effects may include polyphagia, polydipsia, polyuria, and gastrointestinal irritation. Rarely, chronic high-dose prednisolone therapy may lead to development of diabetes mellitus in cats.¹²

References

1 ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2006;63:1172.

2 Bailey DB, Rassnick KM, Dykes NL, et al. Phase I evaluation of carboplatin by use of a dosing strategy based on a targeted area under the platinum concentration-versus-time curve and individual glomerular filtration rate in cats with tumors. Am J Vet Res. 2009;70:770.

3 Bailey DB, Rassnick KM, Erb HN, et al. Effect of glomerular filtration rate on clearance and myelotoxicity of carboplatin in cats with tumors. Am J Vet Res. 2004;65:1502.

4 Benitah N, de Lorimier L-P, Gaspar M, et al. Chlorambucil-induced myoclonus in a cat with lymphoma. J Am Anim Hosp Assoc. 2003;39:283.

5 Betts GJ, Clarke SL, Richards HE, et al. Regulating the immune response to tumours. Adv Drug Del Rev. 2006;58:948.

6 Burroughs GE, Connor TH, McDiarmid MA, et al. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings in Cincinnati, OH. National Institute for Occupational Safety and Health. 2004.

7 Chun R, Garrett LD, Vail DM. Cancer chemotherapy. In: Withrow SJ, Vail DM, editors. Withrow & MacEwen’s small animal clinical oncology. ed 4. St Louis: Saunders Elsevier; 2007:163-192.

8 Crow SE, Theilen GH, Madewell BR, et al. Cyclophosphamide-induced cystitis in the dog and cat. J Am Vet Med Assoc. 1977;171:259.

9 Daly M, Sheppard S, Cohen N, et al. Safety of masitinib mesylate in healthy cats. J Vet Intern Med. 2011;25:297.

10 Dhaliwal RS. Managing oncologic emergencies. In: Henry CJ, Higginbotham ML, editors. Cancer managment in small animal practice. St Louis, Mo: Saunders Elsevier; 2010:122-135.