Overview of Antineoplastic Agents
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.
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.
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.
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.
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.
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.
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.