I. GENERAL PRINCIPLES OF CANCER CHEMOTHERAPY

A. The goal of treatment with chemotherapy in veterinary medicine is to increase the length and quality of life of patients based on an accurate histologic diagnosis of the tumor and the clinical stage or extent of the neoplastic process.

B. Chemotherapy is best used as treatment for systemic disease, palliation for metastatic, or nonresectable disease, large tumor size reduction, making them more amenable to surgery and/or radiation therapy called neoadjuvant chemotherapy, adjuvant therapy after surgery and/or radiation therapy to slow metastasis or kill residual tumor cells, and to increase tumor cell sensitivity to the lethal effects of radiation therapy.

C. The kinetics of chemotherapy drug-induced cell kill is first-order—a constant percentage (not a constant number) of cells is killed with each dose. Antineoplastic drugs are most effective when the tumor is small (microscopic) and is rapidly growing (high growth fraction).

D. Because tumor cells undergo a high spontaneous mutation rate, up to 1 in every 10,000 tumor cells may have acquired mutations that can confer resistance at the time of diagnosis, even in the absence of previous exposure to chemotherapeutic agents. Thus, multimodality and multiagent therapy administered as early in the course of disease as is possible, is likely to be the most helpful.

E. Drug resistance develops in neoplastic cells with mechanisms similar to those observed in antibiotic resistant bacteria. These include the following:

1. Decreased cell permeability or uptake, or increased efflux of drugs

2. Increased production of enzymes which degrade the drug

3. Increased capacity to repair or bypass the effects of the drug

4. Decreased binding of drug to receptors or target enzymes

F. In general, multidrug protocols are more efficacious than single drug protocols. They are designed using drugs with different mechanisms of action to augment cell kill and slow the development of resistance. Additionally, the nonoverlapping adverse effects of each drug decrease overall toxicity to the patient. The drugs are given at the maximum dose and schedule with acceptable or no adverse effects for optimal tumor cell kill.

G. Most drugs are dosed on the basis of body surface area (BSA) in square meters (an estimate of metabolic rate), because of the narrow therapeutic index of antineoplastic drugs. The BSA method of dosage calculation overestimates the metabolic rate of smaller dogs and cats therefore increased toxicity (and perhaps, efficacy) is seen in smaller animals with some drugs. Doxorubicin is an example of a drug that is more toxic to smaller patients (<10–15 kg body weight) when dosed using BSA than when calculated on using milligrams per kilogram body weight. Some overweight pets may need dosage calculation based on their lean body weight.

FIGURE 17-1. The cell cycle. Mitosis (M) is followed by the first growth phase (G₁), or by a resting phase (G₀). During the S phase, DNA synthesis takes place. The S phase is followed by a second growth phase (G₂). (From Figure 12-1, NVMS Pharmacology.)

H. Rapidly multiplying and growing cells are most susceptible to drug effects. These include the normal cells of the hair follicles, gastrointestinal tract, and bone marrow. Thus, hair loss, vomiting and diarrhea, and leucopenia and thrombocytopenia are common side effects of therapy.

I. Minimum baseline assessment consists of a physical examination, complete blood count, serum biochemical panel, and urinalysis. A complete blood count should be performed before each subsequent dose. Treatment should be temporarily suspended if the neutrophil count falls below 3,000/mm³ or platelet count below 100,000/mm³ for dogs depending on the normal range for each laboratory.

J. Collie-type breeds and others (long-haired whippet) have a higher risk of toxicity reactions from antineoplastic drugs that are actively transported by the p-glycoprotein membrane pump. Natural products (doxorubicin, vinca alkaloids, actinomycin-D, and the taxanes) cause increased toxicity when given to dogs with a mutation of the multidrug resistance 1 (MDR 1) allele coding for p-glycoprotein, because the mutation diminishes the excretion of drugs dependent on p-glycoprotein.

K. Chemotherapeutic drugs have the potential to be mutagenic, embryotoxic, teratogenic, carcinogenic, and cytotoxic. They are skin irritants and can enter the body by absorption through mucous membranes (oral especially), the eyes (including soft contact lenses), and the skin, or by inhalation. To prevent accidental exposure, appropriate handling techniques for hazardous drugs are necessary based on the Occupational and Safety Health Administration guidelines (found on the United States Department of Labor website).

II. THE CELL CYCLE

Knowledge of the cell cycle is essential to the understanding of the action of antineoplastic drugs. Many drugs are cell cycle specific in that they kill tumor cells in specific phase of the cell cycle (Figure 17-1).

A. G₁ phase. In the G₁ phase there is synthesis of proteins (enzymes) and RNA required for DNA replication in the S phase. The duration of the G₁ phase varies from hours to days depending on the cell type.

B. S phase. DNA synthesis occurs in the S phase. Its duration usually is 2–4 hours. Many drugs act at this phase of the cycle.

C. G₂ phase. The G₂ phase is characterized by the synthesis of proteins and RNA required for mitosis and cell division. Its duration usually is 3–8 hours.

D. M phase. Mitosis: its duration is 1 hour.

E. G₀ phase. The G0 phase is the resting phase. The nonproliferating cells in G0 are resistant to the cytotoxic action of drugs. The duration is variable, hours to weeks depending on the cell type. Most normal cells are found in this phase.

III. ALKYLATING AGENTS

A. Chemistry. Alkylating agents contain one or more alkyl groups (R-CH₂-CH₂-X) which are converted to reactive intermediates to form covalent bonds with compounds containing hydroxyl, amino, phosphate, sulfhydryl, or other nucleophilic groups. The alkyl radical

replaces a hydrogen atom on these groups.

B. Mechanism of action

1. Alkylating agents cross-link DNA and inhibit replication.

2. Alkylation labelizes DNA and increases breakdown of the molecule.

3. Alkylation of proteins and RNA may also occur. These drugs are considered non-cell cycle specific.

C. Nitrogen mustards

1. Cyclophosphamide (Cytox^®)

a. Therapeutic uses. Cyclophosphamide is the most commonly used alkylating agent in veterinary medicine. It is used for immunosuppression and alone or in combination protocols for lymphoreticular neoplasms, mammary gland and other carcinomas, soft tissue sarcomas, multiple myelomas, and mast cell tumors.

b. Pharmacokinetics

(1) Cyclophosphamide is inactive until being hydroxylated in the liver by microsomes as the first step in conversion to phosphoramide mustard and acrolein, the active metabolites. Thus, it should not be injected directly into tumors.

(2) Cyclophosphamide is well absorbed orally, widely distributed except to the CNS, and the parent compound and metabolites are slowly excreted by the kidneys over 48–72 hours.

(3) After IV injection, the t_½ of cyclophosphamide is ~4–12 hours.

c. Administration. Cyclophosphamide may be administered orally or IV at intervals which vary with the type of cancer and the protocol employed. A common regimen is once a day (in the AM, see below) for 4 consecutive days/weeks or once a week IV. The oral form is coated with a protective layer and should not be broken or crushed. A CBC is required before administration and periodic urinalyses.

d. Adverse effects. Myelosuppression (white blood cell nadir of 7 days) is most common. Mild alopecia in susceptible breeds, and sterile hemorrhagic cystitis are less common side effects. GI signs (nausea, vomiting, diarrhea) are infrequent. A rare complication is transitional cell carcinoma of the bladder. Cystitis is most common in dogs and is due to the irritant effects of acrolein and other metabolites. Concurrent administration of furosemide (IV most effective) with cyclophosphamide decreases the risk (to <1%) and/or delays the onset of cyclophosphamide-induced hemorrhagic cystitis. Administration of cyclophos phamide in the morning, stimulation of water intake and frequent voiding will reduce the frequency of cystitis. Initial treatment includes discontinuation of diuresis (no furosemide or corticosteroids) and cyclophosphamide.

2. Chlorambucil (Leuker^®)

a. Therapeutic uses and administration. Chlorambucil is most commonly used as an immunosuppressive agent and for treatment of lymphocytic leukemia, gastrointestinal lymphoma (cats), multicentric lymphoma (dogs and cats), multiple myeloma, and polycythemia vera. Chlorambucil is administered orally every 2 days. Initially, a CBC is required every 1–2 weeks.

b. Pharmacokinetics.

(1) Chlorambucil is a slow-acting nitrogen mustard, which is well tolerated following oral administration. The peak plasma concentration reaches maximum within 1 hour of oral administration.

(2) A total of 99% of circulating chlorambucil is bound by albumin. It is metabolized by the liver to form active metabolite, phenylacetic acid mustard.

(3) The t_½ is 1.5 hours (chlorambucil) and 2.4 hours (phenylacetic acid mustard). A total of 15–60% is excreted in urine after 24 hours.

c. Adverse effects. Chlorambucil is very well tolerated. Cumulative myelosuppression with chronic administration is the most common adverse effect in cats and dogs. Chlorambucil may be used as a substitute for cyclophosphamide when hemorrhagic cystitis has developed.

3. Melphalan (Alker^®)

a. Therapeutic uses and administration. Melphalan has been used predominantly in the treatment of multiple myeloma and other lymphoreticular neoplasms, as well as, anal sac adenocarcinoma. Melphalan is administered orally. Initially, a CBC is required every 7–14 days.

b. Pharmacokinetics. Melphalan does not require hepatic metabolism for activation like cyclophosphamide. Its oral absorption is variable. It is eliminated mainly by hydrolysis in the plasma. In humans, terminal t_½ is ~90 minutes. In humans, 10% is excreted in the urine.

c. Adverse effects. Myelosuppression is the most common adverse effect. It may be cumulative when used with other myelosuppressive drugs.

4. Mechlorethamine HCl (Mustarg^®)

a. Therapeutic uses and administration. This drug is most commonly used for treatment of relapsed lymphoreticular neoplasms or given intracavitary for pleural and peritoneal effusions. Although available in an ointment, it is highly immunosuppressive and topical administration is not recommended. It is most commonly given IV. Immediate administration is required as mechlorethamine is highly unstable. Deactivation of the remaining drug is required after dosing as it is highly toxic.

b. Pharmacokinetics. It is widely distributed in tissues despite rapid (minutes) deactivation in tissues.

c. Adverse effects. Bone marrow depression and GI toxicity (nausea and vomiting) are most common in dogs and cats. Hair loss and hepatotoxicity are possible. Tissue necrosis occurs with extravasation. A CBC is required before each treatment and periodic serum biochemical panel assessment.

5. Nitrosoureas. Nitrosureas are lipid soluble and cross the blood–brain barrier.

a. Lomustine (CCNU, Cee^®)

(1) Therapeutic uses and administration. Lomustine is useful in the management of CNS neoplasms, relapsed lymphoma, histiocytic sarcoma, mycosis fun-goides, and mast cell tumors in cats and dogs. Lomustine is well tolerated when administered orally. A CBC is needed prior to and 7–10 days after administration. Assessment of serum liver enzymes should be done before each treatment or before alternate treatments (see toxicity).

(2) Pharmacokinetics. Lomustine is readily absorbed following oral administration and metabolized by the liver into active metabolites. In humans, the elimination t_½ of lomustine is ~20 minutes, whereas the plasma t_½ of the metabolites is ~16 hours to 2 days. A total of 60–70% of the total dose is excreted in the urine in 96 hours. It has high lipid solubility.

(3) Adverse effects. In dogs, lomustine may cause delayed, cumulative doserelated, chronic, irreversible hepatotoxicity and should not be used in patients with preexisting hepatic disease. Reversible hepatic enzyme increase is far more frequent (4 times elevation in ALT is indication for drug discontinuation). Hepatotoxicity may be delayed, prevented, or treated with S-adenosyl methionine (anecdotal) or other antioxidants. Hepatic toxicity is infrequent in cats.

Potentially, severe neutropenia may be found in dogs and cats treated with lomustine. Neutrophil nadirs are variable for dogs (1–4 weeks after administration, typically 1 week) and cats (1–5 weeks after administration). Thrombocytopenia lasting 4–6 weeks is possible with cumulative dosing. Dose escalation based on a nadir neutrophil count of >2,000 cells/μL (dogs) helps avoid severe neutropenia. Starting dose for dogs (50 mg/m² increasing to 90 mg/m² every 3 weeks) and cats (40 mg/m² increasing to 60 mg/m² every 4 weeks). GI complications are rare. Alopecia is seen in susceptible breeds.

b. Carmustine (BiC^®)

(1) Therapeutic uses and administration. Like lomustine, carmustine is also useful for treatment of lymphoma and CNS malignancies (anecdotal in cats). Carmustine is given IV every 6 weeks for brain tumors or orally for lymphoma. Carmustine crosses the blood–brain barrier.

(2) Pharmacokinetics. Carmustine is rapidly degraded in plasma into active metabolites. In humans 60–80% of the total dose is excreted in urine. It is lipophilic and crosses the blood–brain barrier.

(3) Adverse effects. Potentially severe neutropenia (7-day nadir) is the predominant potential toxicity in dogs.

6. Streptozocin (Zanos^®)

a. Mechanism of action. Streptozocin activity is not well understood, but it is thought to alkylate and thus, inhibit DNA formation.

b. Therapeutic uses. As streptozocin selectively, typically, and irreversibly destroys the pancreatic (β-cells in dogs resulting in diabetes mellitus (species-specific characteristic). It is used investigationally for treatment of insulinomas when complete surgical excision is not possible.

c. Pharmacokinetics. After IV administration, it is distributed to most tissues; concentrations in the pancreas are higher than those found in the plasma. Streptozocin is metabolized, probably in the liver. Both unchanged and metabolized drug are excreted in the urine. After rapid IV injection, unchanged drug is rapidly cleared from the plasma with t_½ of 35 minutes in humans.

d. Administration. IV administration with extensive saline diuresis both before and after streptozocin administration to decrease the potential for severe renal toxicity. Antiemetic therapy is necessary both before and for 72 hours after streptozocin infusion as severe, prolonged vomiting is possible.

e. Adverse effects—See d. Nausea and vomiting and renal toxicity may be frequent and severe. Like doxorubicin, extravasation causes intense tissue necrosis. Less common and less serious are myelosuppression and increases in liver enzymes. Hypoglycemia-induced weakness may occur after infusion. Before each treatment, a complete blood count, biochemical panel, and urinalysis is needed. Risk for renal insufficiency is greater if the patient is dehydrated or concurrently receiving other potentially nephrotoxic drugs.

7. Procarbazine (Matula^®)

a. Therapeutic uses and administration. Procarbazine is used in combination with other drugs for treatment of relapsed and CNS lymphoma as well as granulomatous meningoencephalitis. It is well absorbed orally and is given daily often in combination with other antineoplastic drugs. Adverse effects in cats and dogs may necessitate every other day dosing (see toxicity below).