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* This is the Veterinary Version. *

Overview of Antineoplastic Agents

By Lisa G. Barber, DVM, Assistant Professor, Cummings School of Veterinary Medicine, Tufts University ; Kristine E. Burgess, DVM, DACVIM (Oncology), Assistant Professor, Cummings School of Veterinary Medicine, Tufts University

Antineoplastic chemotherapy is an important component of small animal practice and is routinely used for selected tumors of horses and cattle. Effective use of antineoplastic chemotherapy depends on an understanding of basic principles of cancer biology, drug actions, toxicities, and drug handling safety.

Tumor Growth and Response to Chemotherapy:

The fundamental biochemical and genetic differences between cancer cells and healthy cells are areas of intense investigation, because these divergences are not fully understood. None of the empirically developed conventional antineoplastic drugs appears to act on a process entirely unique to cancer cells. Newer therapies that specifically target markers or pathways unique to particular cancers are evolving. However, the mainstay of cancer therapy continues to be traditional chemotherapy. Clinically useful drugs achieve a degree of selectivity on the basis of certain characteristics of cancer cells that can be used as pharmacologic targets. These characteristics include rapid rate of division and growth, variations in the rate of drug uptake or in the sensitivity of different types of cells to particular drugs, and retention in the malignant cells of hormonal responses characteristic of the cells from which the cancer is derived, eg, estrogen responsiveness of certain breast carcinomas.

Aspects of normal cell growth and the cell cycle provide the rationale for and are of major importance in successful application of antineoplastic chemotherapy. In the S phase, DNA synthesis occurs; the M phase begins with mitosis and ends with cytokinesis; and the Go phase is a dormant or nonproliferative phase of the cell cycle. Tumor doubling time is related to the length of the cell cycle and the growth fraction (the proportion of a population of cells undergoing cell division). Antineoplastic agents can be classified according to a number of schemes relative to effects at different stages of the cell cycle. In the simplest sense, cycle-nonspecific agents are considered to be lethal to cells in all phases of the cell cycle. Cells are killed exponentially with increasing drug levels, and the dose-response curves follow first-order kinetics. Phase-specific agents exert their lethal effects exclusively or primarily during one phase of the cell cycle, usually S or M; the greater the rate of cell division, the more effective the drug. The Go phase of the cell cycle is important, not as a target for chemotherapeutic agents, but as a time during which dormant tumor cells can escape or repair the effects of drug therapy.

Principles of Antineoplastic Chemotherapy:

The decision to use antineoplastic chemotherapy depends on the type of tumor to be treated, the stage of malignancy, the condition of the animal, and financial considerations. Chemotherapy can be used as an adjuvant to surgery and irradiation and can be administered immediately after or before the primary treatment. Neoadjuvant therapy is administered before surgery or irradiation and is intended to improve the effectiveness of the primary therapy by possibly decreasing tumor size, stage of malignancy, or presence of micrometastatic lesions. Responses to cancer chemotherapy can range from palliation (remission of secondary signs, generally without increase in survival time) to complete remission (in which clinically detectable tumor cells and all signs of malignancy are absent). The percentage and duration of complete remissions are criteria for the success of a particular chemotherapeutic protocol.

Effective clinical use of antineoplastic drugs depends on the ability to balance the killing of tumor cells against the inherent toxicity of many of these drugs to host cells. Because of the narrow therapeutic indices of antineoplastic agents, dosages are frequently calculated based on body surface area (BSA) rather than body mass. However, evidence suggests that small dogs and cats may best be treated based on body weight to avoid overdosage. This is especially true if the primary toxicity is bone marrow suppression. Evidently, BSA does not correlate well with either stem cell number in the bone marrow or resulting hematopoietic toxicity. Correlation is better between body weight and these toxicities. Antineoplastic agents can be administered by PO, IV, SC, IM, topical, intracavitary, intralesional, intravesicular, intrathecal, or intra-arterial routes. The route chosen depends on the individual agent and is determined by drug toxicity; location, size, and type of tumor; and physical constraints.

Antineoplastic agents are commonly administered in various combinations of dosages and timing; the specific regimen is referred to as a protocol. A protocol may use one or as many as five or six different antineoplastic agents. Selection of an appropriate protocol should be based on type of tumor, grade or degree of malignancy, stage of the disease, condition of the animal, and financial considerations. Preferences of individual clinicians for treatment of specific neoplastic conditions may also vary. Regardless of the protocol chosen, a thorough knowledge of the mechanism of action and toxicities of each therapeutic agent is essential.

Combination antineoplastic chemotherapy offers many advantages. Drugs with different target sites or mechanisms of action are used together to enhance destruction of tumor cells. If the adverse effects of the component agents are different, the combination may be no more toxic than the individual agents given separately. Combinations that include a cycle-nonspecific drug administered first, followed by a phase-specific drug, may offer the advantage that cells surviving treatment with the first drug are provoked into mitosis and, therefore, are more susceptible to the second drug. Another advantage of combination therapy is the decreased possibility of development of drug resistance.

Special considerations associated with administration of antineoplastic drugs include evaluation of the animal’s quality of life, medical and nutritional support, control of pain, and psychologic comfort for the owner. Many owners who choose to treat neoplasia in their pets have experienced cancer themselves or have been involved with individuals or family members who have had cancer. Discussion of neoplasia in pets should be handled tactfully and should provide the owners with appropriate information for decision-making.

Resistance to Antineoplastic Agents:

Failure to respond, or resistance, to antineoplastic agents can be seen for several reasons. Pharmacokinetic resistance is seen when the concentration of a drug in the target cell is below that required to kill the cell. This may be due to altered rates of drug absorption, distribution, biotransformation, or excretion. In addition, marginal blood flow to a tumor may not provide sufficient drug, resulting in inadequate therapeutic drug concentrations and the potential for creation of a population of quiescent, less susceptible cells. Cytokinetic resistance is seen when the tumor cell population is not completely eradicated; this may be a result of dormant tumor cells, dose-limiting host toxicity associated with drug therapy, or the inability to achieve a 100% kill rate even at therapeutic drug dosages. Resistance can also develop via biochemical mechanisms within the tumor cell itself that block transport mechanisms for drug uptake, alter target receptors or enzymes critical to drug action, increase concentrations of healthy metabolites antagonized by the antineoplastic drug, or cause genetic changes that result in protective gene amplification or altered patterns of DNA repair. Acquired multidrug resistance can result from amplification and overexpression of a multidrug resistance gene. This gene encodes a cell transmembrane protein that effectively pumps a variety of structurally unrelated antineoplastic agents out of the cell. As intracellular drug concentrations decline, tumor cell survival and resistance to therapy increase.

Patterns of Toxicity:

Conventional antineoplastic agents that act primarily on rapidly dividing and growing cells produce multiple adverse effects or toxicities, including bone marrow or myelosuppression, GI complications, and immunosuppression. Patterns of toxicity may be either acute or delayed. Acute vomiting may develop during administration of an emetogenic drug or within 24 hr after administration of chemotherapy, probably from direct stimulation of the chemoreceptor trigger zone. Several drugs are available aimed at preventing these toxicities, including dolasetron, ondansetron, and maropitant citrate. Dolasetron and ondansetron act as serotonin receptor (5HT3) antagonists that work centrally on the brain to prevent emesis. Maropitant citrate is an oral or subcutaneous FDA-approved medication for acute nausea/ vomiting in veterinary medicine. It works by inhibiting both central and peripheral vomiting pathways by blocking neurokinin-1 receptors to prevent activation of the emetic center.

Administration of oral antiemetics may be indicated for delayed GI toxicities, which can occur 3–5 days after chemotherapy administration. Neurokinin-1 receptor antagonists are used in human oncology to treat delayed emesis, and there is evidence they may work synergistically or at least in an additive fashion with 5HT3 inhibitors. In addition to the NK-1 inhibitor maropitant, common antiemetic therapy in veterinary oncology includes metoclopramide, which functions through direct antagonism of central and peripheral dopamine receptors. This drug has the added benefit of stimulating motility of the upper GI tract without stimulating gastric, biliary, or pancreatic secretions. This effect can be useful in dogs that develop ileus secondary to vincristine administration.

Allergic reactions and anaphylaxis may also be of immediate concern with selected drugs and can be treated with antihistamines or corticosteroids as needed. In more severe cases, epinephrine and IV fluids may be indicated.

Other delayed toxicities may develop days to weeks after antineoplastic therapy. Myelosuppression, a common delayed toxicity, can be life-threatening because of the increased risk of infection associated with neutropenia. Less commonly, increased risk of hemorrhage associated with thrombocytopenia and anemia may be seen.

Other important delayed toxicities include tissue damage associated with extravasation of selected drugs, and alopecia caused by hair follicle damage, particularly in nonshedding breeds with continuous hair growth. Adverse effects on spermatogenesis and teratogenesis may be of concern in breeding animals. Unlike in people, chemotherapy-induced stomatitis or ulcerative enteritis are rare events in dogs and cats.

Prevention and management of toxicities are crucial to successful antineoplastic therapy. Collection of an adequate database before treatment can identify potential problems so that contraindicated drugs can be avoided. Several antineoplastic agents should not be used in the presence of specific organ impairment. For example, doxorubicin should not be used in dogs with certain cardiac abnormalities that impair left ventricular function, and cisplatin is contraindicated in animals with impaired renal function.

When a drug is chosen, supportive or preventive therapy aimed at ameliorating toxic adverse effects may be required. Potential cardiotoxicity of doxorubicin may be abrogated with coadministration of dexrazoxane, an iron chelator that inhibits formation of free radicals implicated in myocardial injury. Active diuresis should accompany administration of nephrotoxic agents (eg, cisplatin). Administration or availability of appropriate antihistamines may be indicated with l-asparaginase and doxorubicin therapy.

The availability of recombinant products is an additional resource to manage myelosuppression and immunosuppression induced by antineoplastic chemotherapy. Recombinant human (rhG-CSF) and canine (rcG-CSF) granulocyte colony-stimulating factors have been used effectively to manage cytopenias induced by chemotherapy and radiation therapy. Administration of rcG-CSF results in a rapid, significant increase in neutrophil numbers that is sustainable as long as the factor is administered. Neutrophil counts drop quickly when therapy is discontinued. Neutrophil phagocytosis, superoxide generation, and antibody-dependent cellular cytotoxicity all increase with G-CSF treatment. Until rcG-CSF is commercially available, longterm (>2–3 wk) or repeated use of recombinant human products should be avoided in dogs and cats, because it can result in anti-factor antibody formation and a subsequent decline in targeted cell numbers.

Prophylactic antibiotics have been shown to reduce hospitalization rates and death in human cancer patients receiving chemotherapy. These are occasionally used in veterinary medicine to reduce the occurrence or severity of hematologic and nonhematologic complications that can result from administration of particular chemotherapy agents.

Safe Handling of Antineoplastic Chemotherapeutic Agents:

Most antineoplastic chemotherapeutic agents are potentially toxic as mutagens, teratogens, or carcinogens. Handling of these agents can result in hazardous personal or environmental exposure in several ways.

A common route of exposure is inhalation due to aerosolization during mixing or administration of cytotoxic drugs. This may occur when a needle is withdrawn from a pressurized drug container or on expulsion of air from a drug-filled syringe. Transferring drugs between containers, opening drug-filled glass ampules, or crushing or splitting oral medications may also aerosolize drug residues.

The best way to prepare cytotoxic drugs to avoid aerosolization is in a biologic safety cabinet or hood; a Class II, type A vertical laminar air flow hood exhausted outside the building is recommended. Aerosol exposures can be further decreased through use of closed system transfer devices that limit escape of air from drug vials into the environment. Administration of chemotherapy should occur in dedicated areas, and meticulous attention to technique should be maintained. Intravenous lines used to administer chemotherapy should be primed with nontoxic solution whenever possible. Disposal of contaminated vials, syringes, needles, and gloves in this area should be anticipated, and the proper puncture-proof chemotherapy waste containers provided.

Personal protection equipment should be used for chemotherapy preparation, administration, cleanup, and disposal. This should include powder-free chemotherapy gloves, nonpermeable gowns, respiratory protection, plastic-backed underpads for the working surface, eye and/or splash protection, shoe covers, and a spill kit.

Another potential route of exposure to antineoplastic agents is by absorption of drug through the skin. This could occur during preparation or administration of drug, cleaning of the drug preparation area, or handling of excreta from animals that have received selected cytotoxic drugs. Conscientious wearing of disposable, powder-free gloves and careful handling of drug-contaminated needles or catheters may avoid most exposures of this type. Re-capping of needles containing drug residues is discouraged to avoid accidental self-inoculation. In addition, use of sprayers and pressure washers to clean cages, kennels, or stalls of treated animals should be avoided to minimize aerosolization of hazardous wastes.

Antineoplastic agents can be inadvertently ingested if food, drink, or tobacco products are allowed in the vicinity of drug preparation areas, treatment areas, or kennels housing treated animals. Any ingestible materials should be restricted to a separate area that is far enough away to avoid any possible contamination with these agents.

All personnel should handle antineoplastic agents with care. Women of child-bearing age should be particularly cautious, and women who are pregnant or breastfeeding should not handle antineoplastic drugs.

A source of exposure to cytotoxic drugs that is commonly overlooked is the handling of body fluids and excreta of treated patients. Uniform guidelines to handle these potentially dangerous substances have not been published. Nevertheless, simple measures can be taken to help minimize exposure of veterinary personnel and pet owners. Collection of biologic samples, such as blood, urine, or tissue, should be performed before chemotherapy administration. The duration and type of precautionary measures that should be taken after treatment depend on the half-life and routes of elimination of the drug administered. Pet owners and veterinary hospital personnel should be advised to allow dogs to urinate and defecate in a confined area outdoors, away from spaces where people may congregate or children play. A mask should be worn when cleaning litterboxes, and the contents placed in a sealed plastic bag. The use of low-dust kitty litter should be encouraged. Powder-free, disposable gloves should be used when cleaning up urine, feces, or vomitus. Veterinarians are encouraged to contact their local board of health and other federal, state, and local regulatory agencies for regulations regarding disposal of hazardous waste.

Classification of Antineoplastic Chemotherapeutic Agents:

Conventional cytotoxic antineoplastic agents can be grouped by biochemical mechanism of action into the following general categories: alkylating agents, antimetabolites, mitotic inhibitors, antineoplastic antibiotics, hormonal agents, and miscellaneous. The clinically relevant drugs used in veterinary medicine are discussed below, and the indications, mechanism of action, and toxicities of selected agents are summarized in Mechanisms of Action, Indications, and Toxicities of Selected Antineoplastic Agents.

Mechanisms of Action, Indications, and Toxicities of Selected Antineoplastic Agents

Drug

Mechanism of Action

Major Indications

Toxicities

Alkylating Agents

Cyclophosphamide

Undergoes hepatic biotransformation to active metabolites that alkylate DNA; alkylation leads to miscoding of DNA and cross-linking of DNA strands

Lymphoma, mammary adenocarcinoma, sarcomas, lymphocytic leukemia

Nausea, vomiting (infrequent), moderate to severe myelosuppression, sterile hemorrhagic cystitis

Melphalan

Alkylates DNA causing miscoding and cross-linking of DNA strands

Multiple myeloma

Nausea, vomiting, anorexia, moderate myelosuppression (may be more myelosuppressive in cats)

Chlorambucil

Alkylates DNA causing miscoding and cross-linking of DNA strands; slowest-acting alkylating agent

Chronic lymphocytic leukemia, small-cell lymphoma

Nausea, vomiting, mild to moderate myelosuppression

Lomustine (CCNU)

Alkylates DNA causing miscoding and cross-linking of DNA strands; inhibits both DNA and RNA synthesis; not cross-resistant with other alkylating agents

Lymphoma, mast cell tumor, histiocytic sarcoma, CNS neoplasias, multiple myeloma

Nausea, vomiting, moderate to severe myelosuppression (may be delayed for 4–6 wk), hepatotoxicity, nephrotoxicity, pulmonary toxicity

Streptozotocin

Inhibits DNA synthesis; high affinity for pancreatic β cells

Insulinoma

Severe, potentially fatal nephrotoxicity (if given without diuresis) and hepatotoxicity, nausea (immediate and delayed), vomiting, mild myelosuppression

Dacarbazine (DTIC)

Undergoes hepatic biotransformation to active metabolites that alkylate DNA; inhibits RNA synthesis

Lymphoma, sarcomas

Severe acute nausea, vomiting, phlebitis, moderate myelosuppression, hepatotoxicity, anecdotal reports of pleural effusion in cats

Ifosfamide

Analogue of cyclophosphamide; undergoes hepatic biotransformation to active metabolites that alkylate DNA; alkylation leads to miscoding of DNA and cross-linking of DNA strands

Various sarcomas

Nausea, vomiting, myelosuppression, sterile hemorrhagic cystitis, possible nephrotoxicity

Antimetabolites

Methotrexate

Inhibition of dihydrofolate reductase that is required for formation of tetrahydrofolate, a necessary cofactor in thymidylate synthesis; thymidylate essential for DNA synthesis and repair

Lymphoma

Nausea, vomiting, moderate myelosuppression, GI ulceration, hepatotoxicity, pulmonary toxicity

5-Fluorouracil

Pyrimidine analogue; interferes with DNA synthesis and may be incorporated into RNA to cause toxic effects

Carcinomas (systemic); cutaneous carcinomas (topical)

Systemic: nausea, vomiting, moderate myelosuppression, neurotoxicity, GI ulceration, neurotoxicity, hepatotoxicity Topical: local irritation, pain, hyperpigmentation Cannot be given to cats (fatal neurotoxicity)

Cytarabine

Pyrimidine analogue; incorporates into DNA causing steric hindrance and inhibition of DNA synthesis

Lymphoma (including CNS), leukemias; no activity in solid tumors

Nausea, vomiting, moderate myelosuppression, nephrotoxicity, hepatotoxicity

Gemcitabine

Pyrimidine analogue; incorporates into DNA, causing steric hindrance and inhibition of DNA synthesis

Limited efficacy seen in lymphoma and various carcinomas

Mild nausea, vomiting, mild to moderate myelosuppression, pulmonary toxicity, nephrotoxicity

Antibiotic Antineoplastics

Doxorubicin

Intercalates and binds to DNA, disrupting helical structure and DNA template; inhibits RNA and DNA polymerases; causes DNA topoisomerase II–mediated chain scission; generates free radicals that cause DNA scission and cell membrane damage

Lymphoma, leukemias, multiple myeloma, osteosarcoma, hemangiosarcoma, and various other sarcomas and carcinomas

Nausea, vomiting, moderate myelosuppression, hemorrhagic colitis, severe cutaneous reactions if extravasated; red urine (not hematuria), transient ECG changes and arrhythmias, nephrotoxicity, anaphylactoid reactions; Cumulative dose-related congestive heart failure in dogs; cumulative nephrotoxicity in cats

Mitoxantrone

Topoisomerase II–mediated chain scission; DNA aggregation, oxidation, and strand breakage

Lymphoma, various carcinomas

Nausea, vomiting, moderate to severe myelosuppression, diarrhea, bluish discoloration to sclera; less severe adverse effects than others in this group

Bleomycin

Mixture of glycopeptides; generates oxygen radicals that cause chain scission and fragmentation of DNA

Carcinomas

Nausea, vomiting, myelosuppression, fever, allergic reactions including anaphylaxis, hyperpigmentation, skin ulceration, pneumonitis, pulmonary fibrosis

Dactinomycin (Actinomycin D)

Intercalates and binds to DNA, disrupting helical structure and DNA template; inhibits RNA and DNA polymerases; causes DNA topoisomerase II–mediated chain scission; generates free radicals that cause DNA scission and cell membrane damage

Lymphoma, various sarcomas

Nausea, vomiting, moderate to severe myelosuppression, phlebitis; severe tissue reaction if extravasated

Mitotic Inhibitors

Vinblastine

Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

Lymphoma and leukemias, mast cell tumors

Mild nausea, vomiting, severe myelosuppression, neurotoxicity with high doses, inappropriate secretion of antidiuretic hormone

Vincristine

Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

Lymphoma and leukemias, transmissible venereal cell tumors, various sarcomas

Mild to moderate nausea, vomiting, mild to moderate myelosuppression, severe tissue reaction if extravasated, cumulative peripheral neuropathy, constipation, paralytic ileus, inappropriate secretion of antidiuretic hormone

Vinorelbine

Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

Primary lung tumors, limited efficacy in mast cell tumors

Mild nausea, vomiting, myelosuppression

Paclitaxel

Binds to tubulin, stabilizing microtubule polymer and arresting mitosis

Mammary carcinoma, squamous cell carcinoma

Myelosuppression, nausea, vomiting, hypersensitivity (when Cremor EL is used as vehicle)

Miscellaneous

Cisplatin

Reacts with proteins and nucleic acids; forms cross-links between DNA strands and between DNA and protein; disrupts DNA synthesis

Osteosarcoma, carcinomas, and mesothelioma

Intense nausea, vomiting, mild to moderate myelosuppression, potentially fatal nephrotoxicity if not given with diuresis, anaphylaxis, ototoxicity, peripheral neuropathy, hyperuricemia, hypermagnesemia; Cannot be given to cats (fulminant pulmonary edema)

Carboplatin

Reacts with proteins and nucleic acids; forms cross-links between DNA strands and between DNA and protein; disrupts DNA synthesis

Osteosarcoma, carcinomas

Mild nausea, vomiting, diarrhea, moderate to severe myelosuppression

l-Asparaginase

Inhibits protein synthesis by hydrolyzing tumor cell supply of asparagine

Acute lymphoid leukemias and lymphoma

Hypersensitivity reactions, anaphylaxis especially after repeated doses, alteration in coagulation parameters, hepatotoxicity, pancreatitis (people), potential inhibition of immune responsiveness (B and T cells)

Mitotane (o,p′DDD)

Destroys adrenal zona fasciculata and zona reticularis

Pituitary hyperadrenocorticism, palliation of adrenal cortical tumors

Nausea, vomiting, anorexia, diarrhea, adrenal insufficiency, CNS depression, dermatitis

Hydroxyurea

Inhibits conversion of ribonucleotides to deoxyribonucleotides by destroying ribonucleoside diphosphate reductase

Polycythemia vera, granulocytic and basophilic leukemia, thrombocythemia, investigational for meningiomas

Nausea, vomiting, mild myelosuppression, alopecia, sloughing of claws, dysuria

Procarbazine

Mechanism is unclear; inhibits DNA, RNA, and protein synthesis, perhaps through alkylation

Lymphoma, as part of MOPP chemotherapy protocol; brain tumors

Nausea, vomiting, myelosuppression, diarrhea

Hormones

Prednisone

Lympholytic; inhibits mitosis in lymphocytes

Lymphoma, mast cell tumors, multiple myeloma, palliative treatment of brain tumors

Sodium retention, GI ulceration, protein catabolism, muscle wasting, delayed wound healing, suppression of hypothalamic-pituitary-adrenal axis,immunosuppression

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* This is the Veterinary Version. *