Overview of Antineoplastic Agents

The fundamental biochemical and genetic differences between cancer cells and healthy cells continue to be areas of intense investigation because these divergences are not fully understood. None of the empirically developed conventional antineoplastic chemotherapy drugs appear to act on a process entirely unique to cancer cells.

Newer treatments that specifically target molecular markers or cellular pathways dysregulated in particular cancers are evolving. Although the mainstay of cancer treatment continues to be conventional chemotherapeutics, novel targeted agents are being used increasingly as first-line agents for a variety of cancers. When these targeted agents are used in combination with conventional chemotherapy, clinical responses can sometimes be enhanced in patients with cancers refractory to initial treatment.

Clinically useful drugs achieve some selectivity when characteristics of cancer cells can be used as pharmacologic targets. These features 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, hormonal responses characteristic of the cells from which the cancer is derived, and upregulation of cellular pathways that drive tumor progression.

Aspects of normal cell growth and the cell cycle provide the rationale for conventional antineoplastic chemotherapy. In S phase of the cell cycle, DNA synthesis occurs; the M phase begins with mitosis and ends with cytokinesis; and the G₀ phase is a dormant or nonproliferative phase of the 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 based on their effects at different phases 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 concentrations, 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 G₀ phase of the cell cycle is also important: during this phase, dormant tumor cells can escape or repair the effects of drug treatment.

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 local treatment. Neoadjuvant therapy refers to any initial chemotherapy administered before surgery or irradiation, which is intended to improve the effectiveness of the primary treatment by decreasing tumor size, stage of malignancy, or presence of micrometastatic lesions.

Responses to cancer chemotherapy can range from palliation (remission of clinical signs, often without substantial increase in survival time) to complete remission (absence of clinically detectable tumor cells and of all signs of malignancy). Historically, the percentage and duration of complete remissions have been the criteriafor determining the success of a particular antineoplastic 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. For conventional anticancer chemotherapy, the more chemotherapy administered, the greater the number of neoplastic cells killed. Therefore, conventional treatment generally aims for the maximum tolerated dose.

Because of the narrow therapeutic indices of antineoplastic agents, dosages for conventional drugs are frequently based on body surface area rather than body mass. However, evidence suggests that it is better for small dogs and cats to be dosed by body weight to avoid overdosage. This is especially true if the primary toxicosis is bone marrow suppression. Correlation is better between body weight and such toxicoses in animals weighing < 10 kg.

Antineoplastic agents can be administered by oral, intravenous, subcutaneous, intramuscular, 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 six different antineoplastic agents. Selection of an appropriate protocol should be based on the type of tumor, grade or extent of malignancy, stage of disease, condition of the animal, financial considerations, and goals of treatment. Preferences of individual veterinarians for treatment of specific neoplastic conditions may also vary. Regardless of the protocol chosen, knowledge of the mechanism of action and of the 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 the 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 administered 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 recruited into the cell cycle and therefore are more susceptible to the second drug. Another advantage of combination treatment is the decreased possibility that drug resistance will develop.

When considering treatment with antineoplastic drugs, the animal’s quality of life, medical and nutritional support, pain control, and owners' expectations should all be considered. Many owners who choose to treat neoplasia in their pets have firsthand experience with cancer themselves or with family members or other individuals who have had cancer.

Discussion of neoplasia in pets should be handled tactfully and should provide the owners with appropriate information for decision-making. The conversation routinely includes exploring treatment priorities and explaining differences in adverse-effect profiles between veterinary species and humans.

Failure to respond to antineoplastic agents can occur for several reasons. Pharmacokinetic resistance develops when the concentration of a drug in the target cell is lower than that required to kill the cell. An insufficient concentration of the drug may be due to altered rates of drug absorption, distribution, biotransformation, or excretion. In addition, irregular perfusion to a tumor may deliver subtherapeutic drug concentrations, and could allow less susceptible cells to proliferate.

Cytokinetic resistance occurs when the tumor cell population is not completely eradicated. Reasons for incomplete eradication include dormant tumor cells, dose-limiting host toxicosis associated with drug treatment, and 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 metabolites that antagonize antineoplastic drug actions, or cause genetic or epigenetic alterations 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 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 treatment increase.

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

Alkylating agents form covalent bonds in nucleic acids, creating both intrastrand and interstrand breaks that inhibit DNA and RNA synthesis. Monofunctional alkylators transfer a single alkyl group and usually result in miscoding of DNA and strand breakage. Bifunctional alkylating agents transfer two alkyl groups and often cause strand cross-linking and inhibition of DNA replication. Individual alkylating agents are generally cell cycle–nonspecific; however, they are most potent in late G₁ and S phases. Agents can be classified according to chemical structure into the subgroups nitrogen mustards, ethyleneamines, alkyl sulfonates, nitrosoureas, and triazene derivatives.

Antimetabolites are structurally similar to biological molecules that are the components of DNA or important enzymes and other cofactors needed for DNA synthesis. These counterfeit molecules subvert normal metabolic pathways in a toxic manner. Actions of these drugs are specific to S phase of the cell cycle. Three subgroups of antimetabolites are used in cancer treatments: analogues of folic acid, of pyrimidine, and of purine.

Mitotic inhibitors bind to tubulins, the main components of microtubules, thereby disrupting the dynamic processing of microtubules. Vinca alkaloids prevent the polymerization of tubulin dimers. Taxanes promote tubulin polymerization and inhibit the disassembly of microtubules. Both classes of drugs exert their effects in M phase and cause cell cycle arrest in metaphase.

Conventional antineoplastic agents that act primarily on rapidly dividing cells, regardless of whether those cells are normal or neoplastic, produce multiple adverse effects or toxicoses remote from the primary treatment target. Myelosuppression is the most common dose-limiting toxicosis across conventional chemotherapy agents in veterinary species.

Neutropenia often occurs 5–7 days after treatment for many agents; however, it can occur as late as 3 weeks after treatment with some drugs, such as carboplatin or lomustine. Severe neutropenia can be life-threatening through increased risk for systemic infection, often because of the translocation of resident GI flora.

Routine monitoring with CBCs performed at the time of the anticipated lowest neutrophil concentration, along with the use of prophylactic antimicrobials, has been shown to decrease hospitalization rates and death in human and veterinary cancer patients. The threshold for using antimicrobials in an afebrile patient is generally 1,000 neutrophils/mcL. Recommended antimicrobials have a good gram-negative spectrum while sparing anaerobes.

Recombinant products are an additional resource available to manage myelosuppression and immunosuppression induced by antineoplastic chemotherapy. Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used effectively to manage neutropenia in humans, thereby enabling routine dose escalation of chemotherapy. Until recombinant canine and feline forms of G-CSF are commercially available, the recombinant human product should be limited to emergency use related to chemotherapy drug overdose or use in bone marrow priming for hematopoietic stem cell transplantation in dogs and cats, because longterm (> 2–3 weeks) or repeated use of recombinant human products can result in antifactor antibody formation and a subsequent decline in targeted cell numbers, and ultimately bone marrow failure.

Anemia and thrombocytopenia typically are not clinically important dose-limiting toxicoses; however, they can occur as cumulative toxicoses when progenitor cells are depleted with longterm chemotherapy.

GI toxicosis includes decreased appetite, nausea, vomiting, and diarrhea. Chemotherapy-induced nausea and diarrhea can be either acute, occurring within 24 hours after drug administration, or delayed. Delayed nausea and vomiting often occur 2–5 days after treatment. The mechanisms of acute and delayed emesis differ: acute emesis is triggered by serotonin released from injured enterochromaffin cells; delayed emesis is mediated by substance P. However, the pathophysiology is complex, with overlapping actions in both the peripheral and central nervous systems.

Serotonin receptor (5HT3) blockers, such as ondansetron, have been recommended in humans for acute emesis; and neurokinin-1 inhibitors, for delayed emesis. However, maropitant citrate inhibits both central and peripheral vomiting pathways by blocking neurokinin-1 receptors to prevent activation of the emetic center. Maropitant has been demonstrated to prevent acute cisplatin-related emesis in dogs, and there is evidence that neurokinin-1 inhibitors and 5HT3 blockers may be synergistic, or at least additive, in treating drug-induced nausea and vomiting.

Acute vomiting may develop during administration of an emetogenic drug or of chemotherapy, probably from direct stimulation of the chemoreceptor trigger zone. Several drugs aimed at preventing these toxicoses are available, including dolasetron, ondansetron, and maropitant citrate. Dolasetron and ondansetron act as 5HT3 antagonists that work centrally on the brain to prevent emesis. Maropitant citrate is an oral or subcutaneous FDA-approved medication for acute nausea or vomiting in veterinary medicine. Maropitant inhibits both central and peripheral vomiting pathways by blocking neurokinin-1 receptors to prevent activation of the emetic center.

Another common antiemetic used in veterinary oncology is metoclopramide, which directly antagonizes 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 effect can be useful in dogs that develop ileus secondary to vincristine administration.

Overall, GI toxicosis is milder in veterinary cancer patients compared with humans. In addition, stomatitis and ulcerative enteritis, common problems in human cancer patients, rarely occur in dogs and cats.

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.

An adverse effect unique to cyclophosphamide and its analogue ifosfamide is bladder irritation. Sterile hemorrhagic cystitis may result from aseptic chemical inflammation of the bladder urothelium due to acrolein, a metabolite of cyclophosphamide. Prevention of this toxicosis is key to its management: a diuretic may be administered concurrently with cyclophosphamide to increase urine volume, diluting the toxic metabolite once it arrives in the bladder. In addition, cyclophosphamide may be administered in the morning so that patients have several opportunities to urinate throughout the day to minimize the amount of time acrolein is in contact with the bladder lining.

In patients with evidence of sterile hemorrhagic cystitis, cyclophosphamide use should be discontinued permanently. Chlorambucil is often substituted for cyclophosphamide in this situation. Although the clinical signs of sterile hemorrhagic cystitis are often self-limiting, treatment with fluids, NSAIDs, methylsulfonylmethane, and intravesicular DMSO may be considered. Mesna is a drug that binds and inactivates the urotoxic metabolites of cyclophosphamide within the bladder as a preventive. Mesna coadministered with fluid diuresis is recommended when ifosfamide (an analogue of cyclophosphamide) or high-dose cyclophosphamide is used.

Cardiotoxicosis in veterinary oncology is clinically limited largely to the use of doxorubicin. Acute cardiac effects are primarily transient cardiac arrhythmias that are not clinically important. Delayed cumulative, dose-related cardiac toxicosis can be fatal, and it limits the recommended lifetime dose of doxorubicin in dogs to 180 mg/m². Hydroxyl radical damage and accumulation of reactive oxygen species are associated with the binding of doxorubicin to cardiac DNA and free radical damage to myocardial membranes. A nonspecific decrease in the mitochondrial activity of cardiac myocytes is considered to be the main mechanism of injury; however, the inhibition of topoisomerase II beta by doxorubicin may also play a role.

Cardiac myocyte degeneration and subsequent left ventricular systolic function can lead to congestive heart failure unresponsive to treatment. Because the cardiotoxic effects of doxorubicin are related to the peak plasma concentrations (rather than area under the curve), slow IV administration over 15–30 minutes is recommended to help lessen cardiac injury. Myocardial damage from doxorubicin also can be prevented by coadministration of dexrazoxane, at 10 times the dose of doxorubicin. In cats, doxorubicin can result in cumulative nephrotoxicosis and should be avoided or used judiciously in cats with preexisting renal insufficiency.

Because doxorubicin has a low margin of safety, newer-generation drugs aimed specifically at decreasing cardiotoxicosis have been developed and are available in human medicine. Two of these, idarubicin and epirubicin, have been studied in dogs and cats; however, neither is commonly used in veterinary medicine in the US.

A pegylated liposomal encapsulated form of doxorubicin, called doxorubicin HCl liposome, has been used effectively in both human and veterinary medicine. The liposomal formulation results in a longer drug circulation time and decreased myelosuppression and cardiotoxicosis. In dogs, the dose-limiting toxicosis of liposomal doxorubicin is a cutaneous reaction called palmar-plantar erythrodysesthesia. In cats, a delayed nephrotoxicosis is the dose-limiting toxicosis of both conventional and liposomal doxorubicin.

Other important delayed toxicoses include tissue damage associated with extravasation of selected drugs, and alopecia due to hair follicle damage, particularly in nonshedding breeds with continuous hair growth. Adverse effects on spermatogenesis and teratogenesis may be of concern in breeding animals.

The prevention and management of toxicoses are crucial to successful treatment with antineoplastics. Establishing baseline clinicopathologic values 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 impaired left ventricular function, and cisplatin is contraindicated in animals with impaired renal function.