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Overview of Antineoplastic Agents

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

The fundamental biochemical and genetic differences between cancer cells and normal cells are areas of active investigation as these divergences are not fully understood. None of the empirically developed conventional antineoplastic drugs appears to act on a process or component that is entirely unique to cancer cells. Newer therapies are evolving that specifically target markers or pathways that are unique to particular cancers. 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 the 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 constraints. Chemotherapy can be used as an adjuvant to surgery and irradiation and can be administered immediately after or before the primary treatment. Neo-adjuvant 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 micro-metastatic 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 their narrow therapeutic indices, dosages for antineoplastics 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. Apparently, 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 almost any route including PO, IV, SC, IM, topical, intra-cavitary, intralesional, intravesicular, intra-thecal, or intra-arterial. 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 administered in various combinations of dosages and timing; the specific regimen is referred to as a protocol. A protocol may use 1 or as many as 5 or 6 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 constraints. 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 individual therapeutic agent are 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 psychological 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, bio-transformation, 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 normal 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.

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

Administration of oral antiemetics may be indicated for delayed GI toxicities that can occur 3–5 days after chemotherapy administration. Common antiemetic therapy includes metoclopramide, which functions through direct antagonism of central and peripheral dopamine receptors. Metoclopramide has the added benefit of stimulating motility of the upper GI tract without stimulating gastric, biliary, or pancreatic secretions. This can be useful in dogs that develop ileus secondary to vincristine administration. Neurokinin-1 receptor antagonists are routinely used in human oncology to treat delayed emesis, and they are under investigation for this purpose in veterinary oncology.

Allergic reactions and anaphylaxis may also be of 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 due to the increased risk of infection associated with neutropenia. Less commonly, anemia and increased risk of bleeding associated with thrombocytopenia 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. 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 reducing toxic side effects may be required. Potential myocardial damage from doxorubicin may be avoided with the administration of dexrazoxane, a free radical inhibitor. 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 for managing myelosuppression and immunosuppression induced by antineoplastic chemotherapy. Recombinant human (rhG-CSF) and canine (rcG-CSF) granulocyte colony-stimulating factor have been used effectively in management of 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 cytoxicity all increase with G-CSF treatment. Longterm (>2–3 wk) or repeated use of recombinant human products should be avoided in dogs and cats as 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 the administration of particular chemotherapy agents.

In recent years, a number of alternative modes of cancer therapy have been investigated. Foremost among these has been the development of biologic response modifiers aimed at enhancing innate anti-tumor defense mechanisms of the host. Nonspecific immunomodulators, including intact bacteria or bacterial cell components, acemannan, IL-2 or IL-12, interferon alpha, levamisole, and cimetidine, have variable efficacy to enhance immune responsiveness and improve outcomes after surgery or antineoplastic chemotherapy. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine is perhaps the best studied nonspecific immunomodulator in veterinary medicine. This synthetic bacterial wall component has been used effectively with chemotherapy to increase survival in dogs with splenic hemangiosarcoma and osteosarcoma.

Another class of biological response modifiers includes NSAID that may be either nonselective or selective cyclooxygenase-2 (COX-2) inhibitors, such as aspirin and piroxicam or deracoxib, firocoxib, and meloxicam, respectively. These drugs directly inhibit COX-2 enzyme activity, which is frequently over-expressed by many tumors. Piroxicam has been the drug most researched in dogs, but any of the newer NSAID with more COX-2 selective inhibition could yield equal or improved effects. These drugs may work by reducing cell proliferation, increasing apoptosis, inhibiting angiogenesis, and modulating immune function. The clinical usefulness has been demonstrated in canine transitional cell carcinoma and other tumor types in dogs and cats.

A novel or nontraditional means of administering chemotherapy, known as metronomic or antiangiogenic dosing, consists of oral drugs that are administered at a continuous, often daily, low dose. This chemotherapy protocol affects the tumor vasculature and antitumor immunosuppression rather than the tumor itself. Preliminary studies suggest this may be a promising alternative to maximally tolerated doses of conventional chemotherapy administered on an episodic basis. The intended outcome of low-dose chemotherapy is disease stabilization. Limited side effects are an added benefit.

The development of a therapeutic vaccine to stimulate active immunity against cancer has long been a goal in both human and veterinary oncology. This recently became a reality with the introduction of a canine melanoma vaccine. The vaccine exploits the immune response induced by human tyrosinase, an enzyme in the pathway of melanin formation. The antibodies and T-cell responses produced by xenogeneic tyrosinase cross-react with the tyrosinase overexpressed on canine melanoma cells. Initial studies reported prolonged survival in dogs with advanced stage oral malignant melanoma treated with radiation therapy or surgery of the primary tumor, followed by vaccine administration. The vaccine is licensed by the USDA.

Another investigational melanoma vaccine incorporates the administration of either nonviable canine melanoma cells or cells expressing a common melanoma antigen (hgp-100) with a gene that acts as a pleuripotent immune cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). The goal of this therapy is to generate an immune response against the cancer cells.

Development of lymphokines and cytokines (eg, interleukins, interferon, and tumor necrosis factor) for clinical use in cancer patients has long been an attractive goal. The potential of these potent immunomodulators has not been fully realized, largely due to their toxicity. These agents are not commonly used in veterinary medicine.

Passive immunotherapy using mono-clonal antibodies has grown substantially in human oncology in recent years. Monoclonal antibodies may attach to specific antigens on cancer cells, thereby either marking the cancer cells for destruction by the immune system or impairing functional pathways within the neoplastic cells. Furthermore, monoclonal antibodies may be conjugated to other antineoplastic agents (such as chemotherapy agents, radionuclides, or other toxins) to allow for more targeted delivery of cytotoxic therapy to cancer cells while sparing normal tissues. However, such therapies are not currently marketed for veterinary use and may not have activity across different species.

Beyond enhancement of immune recognition and control of neoplastic disease, new therapies attempt to exploit specific pathways that are aberrantly or overexpressed in neoplastic cells. Paramount among these is angiogenesis, because tumors must develop their own vascular supply if they are to grow beyond a few millimeters in diameter. Various drugs, such as angiostatin, thrombospondin-1, and matrix metalloproteinase inhibitors, have been investigated with varying results. Specific angiogenesis inhibitors for veterinary patients are not yet commercially available, although metronomic chemotherapy cocktails are the most practical approach to antiangiogenic therapy at this time.

Targeting of specific pathways that are aberrant or dysregulated in cancers has yielded novel therapies in a variety of human cancers. An example of such a target is the receptor for tyrosine kinases, which mediate processes involved in tumor growth, progression, and metastasis. Toceranib recently received FDA approval for treatment of recurrent cutaneous mast cell tumors in dogs. Its primary action is inh⅓ ∼⅓ of these high-grade tumors. Because toceranib impacts multiple tyrosine kinase pathways, it may have activity against other tumor types.

Most antineoplastic chemotherapeutic agents are potentially toxic as mutagens, teratogens, or carcinogens. Handling of these agents can result in unhealthy personal or environmental exposure in a number of different 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 upon 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 avoid aerosolization is to prepare cytotoxic drugs in a biologic safety cabinet or hood; a Class II, type A vertical laminar air flow hood exhausted outside the building is recommended. If a hood is not available, drugs should be prepared in a specified low-traffic area with proper ventilation where no food, drink, or tobacco products are allowed. This area should be equipped with supplies needed for drug reconstitution, including a disposable, plastic-backed liner for the working surface; powder-free latex gloves; gown; goggles; and mask with a filter. Disposal of contaminated vials, syringes, needles, and gloves in this area should be anticipated, and the proper puncture-proof containers provided. Aerosol exposures can be further decreased through the use of chemotherapy-dispensing pins (“chemopins”) or closed, dry-membrane dispensing systems.

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. Most exposure of this type may be avoided by conscientious wearing of latex gloves and careful handling of drug-contaminated needles or catheters. Re-capping of needles containing drug residues is discouraged to avoid accidental self-inoculation.

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 pregnant women should not handle anti-neoplastic 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 for handling of these potentially dangerous substances have not been published. Nevertheless, simple measures can be taken to minimize exposure to veterinary personnel and pet owners. Collection of biologic samples, such as blood, urine, or tissue, should be performed prior to 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 a litterbox and the contents placed in a sealed plastic bag. Powder-free, disposable gloves should be worn when cleaning up urine, feces, or vomitus. Veterinarians are encouraged to contact their local Board of Health and other regulatory agencies for local 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 see Table 1: Mechanisms of Action, Indications, and Toxicities of Selected Antineoplastic AgentsTables.

Table 1

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Last full review/revision March 2012 by Deborah T. Kochevar, DVM, PhD, DACVCP; Lisa G. Barber, DVM, DACVIM (Oncology); Kristine E. Burgess, MS, DVM, DACVIM (Oncology)

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