Chapter 33 Chemotherapy

Before appropriate treatment for a particular cancer can be instituted, the tumor must first be diagnosed by cytology or histopathology. Testing is then conducted to allow staging of the tumor—to determine if there is clinically visible evidence of metastatic spread. Lymph node cytology or biopsy, radiographs, ultrasound examinations, and computed tomography or magnetic resonance imaging scans may be used as staging procedures. The biological behavior typical for the cancer must be considered. If, as a rule, the tumor tends to remain localized, surgery or radiation therapy—or a combination of the two—may be the best way to obtain cure or control. If the tumor is likely to metastasize by lymphatics or hematogenously, however, some form of systemic therapy must be added to make a cure more likely. Systemic therapy involves the administration of biological agents, hormones, or cytotoxic chemotherapy. Theoretically, cancer chemotherapy is given to kill or suppress the growth of malignant cells without killing normal cells; in fact, however, most of the commonly used drugs are capable of killing both normal and malignant cells, depending on the dose administered. To be useful in clinical practice, an antineoplastic drug must possess selective toxicity—that is, it should be more toxic to cancer cells than to normal host cells at conventional doses. Finally, the clinician must determine whether the patient has concurrent diseases, with a complete blood count (CBC), biochemical panel, urinalysis, and possibly testing for feline leukemia virus and feline immunodeficiency virus. This section of the chapter addresses the principles of chemotherapy and the side effects seen in dogs and cats.

Drugs used in chemotherapy cause their anticancer effects by interacting with important substrates or enzymes that are related to DNA synthesis or function. Therefore most anticancer drugs are ineffective against cells that are not actively proliferating. Tumors with a high mitotic index (e.g., lymphoma) are much more likely to be sensitive to chemotherapy than those in which mitotic activity is low. Because chemotherapeutic drugs are effective principally on cells that are actively replicating, it is important to have an understanding of the phases of the cell cycle before discussion of individual drugs (Figure 33-1). The part of the cell cycle in which active mitosis occurs has been termed the M phase; it is quite short in all cells, generally lasting less than 1 hour. The period during which DNA synthesis occurs for chromosome doubling in preparation for mitosis is called the S phase and ranges from 8 to 30 hours. When scientists began to learn about cell division, they realized that there were other phases in the cell cycle; because they initially did not understand what was occurring in the cell at these times, the phases were called G (G₁ and G₂) for gap. G₁ follows mitosis, and protein synthesis and RNA transcription occur during this phase. G₁ is extremely variable in length depending on the cell type, ranging from 7 to 170 hours. G₂ precedes the next mitotic event and is usually brief, ranging from 1 to 4 hours. G₀ has been used to describe those cells that are not actively cycling. Certain cell types, such as myocytes and neurons, enter G₀ and never cycle again. Other cell types, such as hepatocytes, proliferate in young animals and then cease cycling at maturity but are capable of beginning to cycle again if cell replacement is necessary. Fibroblasts become terminally differentiated in connective tissue, but stem cells remain in the tissue. These can become reproductively active again to repopulate the tissue if a wound occurs.

Figure 33-1 Cell generation cycle: M—mitosis; S—DNA content is being doubled in preparation for mitosis; G₁ and G₂—gaps. Protein synthesis and RNA transcription are occurring in these phases; G₀—cells that are not actively cycling.

Chemotherapeutic drugs can be classified into three groups on the basis of their activity in the phases of the cell cycle (Box 33-1). Agents that are considered to be lethal to cells in all phases of the cell cycle, with resting cells as sensitive as proliferating cells, are called cycle nonspecific. Examples include nitrogen mustard (the first chemotherapy agent; its activity was discovered in 1919 with the effects of mustard gas on the troops in World War I) and high-dose cyclophosphamide. Agents that are capable of damaging both resting and cycling cells (although cells in cycle are much more sensitive) include conventional-dose cyclophosphamide and doxorubicin. These drugs spare resting cells and are called cycle specific. Agents that are phase specific exert their lethal effects exclusively or primarily during one phase of the cell cycle, usually S or M; resting cells and cells in the other phases of the cell cycle are not killed. Examples include methotrexate, cytosine arabinoside, vincristine, and vinblastine.

There are three phases in the development of a new chemotherapeutic drug (Box 33-2). Many artificial chemicals and naturally occurring compounds are screened (generally by the National Cancer Institute or by industry) for cytotoxicity, first in cultures of cancer cells and then in mice or rats. If a particular compound looks promising, a phase I trial is conducted, providing an initial pharmacologic evaluation. The appropriate mode of administration is established for the drug, and common side effects are discovered. Patient tolerance of increasing dosage is also determined. Phase I trials are conducted on very small numbers of patients, generally with advanced and ultimately terminal cancers for which no conventional treatment is available, and doses tolerated by these patients may be below the ultimate therapeutic range. If the compound shows no prohibitive toxicity and shows even slight efficacy (a partial response in a few patients), the phase II trial begins. In this phase screening for efficacy of the drug against a variety of tumors is conducted. After the spectrum of activity is determined, dose–response relationships are determined. The phase III trial is then used to determine drugs that work effectively together, and the new combination protocol is ultimately compared with the existing best treatment. Phase IV trials are known as postmarketing surveillance trials. They involve safety surveillance after the necessary authorities permit the drug to be sold. This surveillance may be required by regulatory authorities. The chemotherapy agent may not have been tested for interactions with other drugs, for example. The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the phase I through phase III clinical trials. Harmful effects discovered during phase IV trials may result in a drug being removed from the market.

Most cancers in animals and humans are diagnosed only after they are well advanced. In the 1960s, Skipper and coworkers¹ used the rodent L1210 leukemia to illustrate this point and determine cell kill kinetics in tumors. The L1210 leukemia is a rapidly growing tumor with a growth fraction of 100% and a doubling time of only 12 hours. At this rate of growth, a billion cells would accumulate in the rodent only 19 days after injection of a single cell. After treatment of the leukemia with chemotherapy, the investigators determined that cytotoxic drugs kill by log kill kinetics—that is, a given dose of an effective drug kills a constant fraction of cells and not a constant number, regardless of the number of cells present. This principle is known as the fractional kill hypothesis. For example, if a certain drug is known to kill 90% of the tumor cells present, it will kill 90% of the cells whether the beginning number is 10 cells or 10 billion cells (Table 33-1). Thus it should be theoretically possible to cure with chemotherapy, with rapid successive administration of chemotherapy drugs. In fact, antineoplastic drugs kill an extremely variable fraction of cells, ranging from a very small fraction to a maximum of 99.99%; for many tumors the fractional kill is disappointingly small. What prevents theoretical “cures” with chemotherapy is (1) the inability to give drugs in rapid succession, because of host toxicity, and (2) the development of a drug-resistant population of tumor cells during the course of treatment.

Table 33-1 Tumor Depopulation Related to Successive Drug Cycles Assuming a 90% Fractional Cell Kill in a Model System

Tumors as small as 1 g (10⁹ tumor cells—a billion) may be detected in the body, especially if they are located in areas such as the skin or mouth. However, it is far more common for tumors to escape detection until they are 10 g (10¹⁰ tumor cells) or more. The maximum malignant tumor mass compatible with human life is about 1 kg (10¹² tumor cells). If it is assumed that a given tumor originates from a single cell, then a 1-g tumor (10⁹ cells) has gone through 30 doublings from the original cell. To get to 1 kg, only about 10 more doublings will take place.² It should be clear from these sobering numbers that a large, unresectable tumor burden with only modest sensitivity to chemotherapy cannot be cured or, in many cases, even palliated with conventional chemotherapy administration protocols. The average volume doubling time for various human solid (e.g., nonleukemic) tumors is about 2 months. However, for certain rapidly growing tumors such as embryonal nephroma, seminoma, lymphoma, and leukemia, the volume-doubling time is less than 1 month. For other tumors the volume-doubling time is as long as 1 year. Because chemotherapy affects rapidly dividing cells, tumors with short volume-doubling times are generally chemotherapy sensitive, whereas tumors with long volume-doubling times are generally chemotherapy resistant.

With regard to the efficacy of chemotherapeutic drugs, criteria have been described for measuring response; these are called RECIST (Response Evaluation Criteria in Solid Tumors). To evaluate a tumor’s response to treatment, the clinician must have a marker lesion, a repeatably measurable tumor mass or parameter that can be periodically rechecked and remeasured (preferably with the same person doing the repeat measurements). This may be a lymph node or nodes that can be measured with calipers, a liver lesion measured by ultrasound, nodules visible on a radiograph, a biochemical value such as the calcium level, and so forth. The evaluation as to efficacy of treatment is conventionally made after two cycles of chemotherapy or an appropriate trial of another agent has been administered:

Complete response (CR)—Resolution of all measurable neoplastic disease (or return of marker to normal, if there is no measurable disease), with appearance of no new lesions. A chemotherapeutic drug that can cause a CR in a significant number of animals with a specific cancer is quite likely to increase disease-free survival, especially when used as an adjuvant agent.

Partial response (PR)— Reduction in measurable tumor dimensions of 30% or greater, with no appearance of new lesions. Although a temporary PR may provide the patient with some decrease in discomfort from the cancer, it is unlikely to have a significant effect on survival. However, this drug might be useful in other patients at an earlier stage of disease or in patients in which the tumor can be surgically removed before chemotherapy. A PR proves that the drug does have some activity against the tumor that is being treated.

Stable disease (SD)—No significant change is noted in measurable tumor dimensions, or a response is seen that is less than a PR. Actual values are less than a 30% decrease in marker lesion size and less than a 20% increase in marker lesion size.

Progressive disease (PD)—The tumor is clearly growing (20% or greater increase in lesion size), or new lesions appear.

Certain criteria may be useful for declaring a treatment protocol ineffective or unsafe in a specific patient. Progressive growth (usually greater than 20%) in a measurable tumor lesion or the appearance of new lesions after two cycles of chemotherapy would suggest that the drug or protocol is not at all useful for the tumor being treated. Severe toxicity with irreversible, cumulative, or unpredictable manifestations also generally suggests that the drug should no longer be used in this particular patient. If symptoms from the cancer cause the patient’s condition to deteriorate, with the only response to drug treatment being SD or PR, the drug should be discontinued and another treatment selected if possible.

The common cancers in dogs and cats can be broadly divided into three categories:

In principle, all cells that are actively cycling in the body should be sensitive to chemotherapy; however, the fact that chemotherapy is generally only modestly effective speaks to the fact that this is not entirely true. In many cancers the tumor cells are actually less sensitive to cytotoxic drugs than are the hematopoietic cells within the marrow cavity. This forces the clinician to give a chemotherapeutic drug and wait to evaluate the toxic effects produced before another course of treatment can be administered. During the interval of time in which the patient’s neutrophil or platelet count is too low to give another drug, endogenous hematopoietic growth factors are being produced, mediating proliferation of stem cells, the bone marrow recovers, and peripheral cell counts return to normal. Return of blood cell counts to normal after chemotherapy is the usual point at which another course of treatment may be given. It is important not to give another cycle of chemotherapy when peripheral blood counts are extremely low because stem cells are actively proliferating at this time; treatment with cytotoxic drugs administered when stem cells are actively dividing increases the chance that the stem cell population may be killed and recovery may never occur. In humans this is the point at which bone marrow or stem cell transplantation is performed.

Unfortunately, tumor cells may recover from chemotherapeutic injury and begin to proliferate again before the animal’s marrow recovers. Even when a tumor is exquisitely sensitive to drug treatment and an apparent complete response is obtained, a line of drug-resistant cells often develops. It is a common clinical experience to find that a tumor may respond quite well to the first treatment with a drug, with progressively less impressive responses as the drug is given repeatedly. Classically, multidrug resistance occurs when large numbers of the cells in a tumor overexpress a gene (the MDR1 gene) that encodes P-glycoprotein, a transmembrane protein important in cell transport. This protein pumps chemotherapeutic drugs from the inside of the cell to the extracellular environment so that they cannot act within the cell; P-glycoprotein is a transmembrane drug efflux pump. Other mechanisms leading to acquired drug resistance include (1) the development in the tumor cell of alternative metabolic pathways to avoid the chemotherapeutic drug’s mechanism of action; (2) the fraction of tumor cells actively dividing decreases after several cycles of treatment, thus protecting the remaining noncycling cells against damage; and (3) tumor cells may enter a biological “sanctuary site” in which they are protected from injury because of a lack of drug diffusion into that area (e.g., brain, eye, testicle, spinal cord).

Delaying administration of chemotherapy because of hematopoietic or gastrointestinal toxicity often results in a patient appearing to be in remission, with no visible neoplastic disease but with large amounts of microscopic tumor. Thus drug resistance sometimes develops as a result of chemotherapy being administered in a regimen that is “too little, too late.” The highest possible doses of chemotherapy given as frequently as can be tolerated by the patient, early in the course of the neoplastic disease (when smaller numbers of cells are present), should have a much higher chance of producing a cure or long-term remission than chemotherapy given after a large number of tumor cells have infiltrated various organs. In human patients the wait for marrow recovery has been overcome with the use of bone marrow or stem cell transplants, performed after chemotherapy treatment is given in doses high enough to kill tumor cells as well as ablate normal marrow cells. The extreme expense, technical difficulty, and high morbidity rates associated with this procedure do not allow for its use in dogs and cats as a routine clinical procedure, at least at this time. In veterinary oncology in the early twenty-first century, clinicians are usually limited to palliation of tumors; only rarely can they expect to cure their patients.

A regimen of chemotherapy treatment can be divided into several phases. The period of induction is the initial intensive chemotherapy intended to produce remission. Remission is defined as the point at which no measurable tumor mass can be found; for lymphoma remission is declared when the enlarged lymph nodes, liver, and spleen have returned to normal size and malignant cells have disappeared from the peripheral blood and bone marrow. This does not mean that all (or even most) tumor cells have been killed, however, and consolidation therapy with different drugs may be given after apparent clinical remission to produce a larger tumor cell kill. For some tumors such as lymphoma, the animal may be given “pulse” doses of drugs after induction and consolidation to maintain the gains obtained with the induction protocol; this is called the maintenance phase of chemotherapy. Recently, intensification protocols have been described for tumors in which drug resistance is common. These protocols are administered during the maintenance period, when the patient is in apparent remission, and are an attempt to kill developing drug-resistant clones of cells by using one or two new drugs at high doses.

Combination chemotherapy is, in general, more effective than single-agent therapy. Using multiple drugs sequentially provides additive antitumor effects without greatly increasing host toxicity, especially if drugs are selected carefully for different toxicities. Combination chemotherapy may delay tumor resistance to drugs compared with single agents. Selecting different drugs that have effects on more than one cell cycle phase may also result in a greater fractional cell kill per cycle of chemotherapy.

Traditionally, in estimating the appropriate dose of a drug to administer to a patient, clinicians have used body weight of the patient as the main criterion; the dose has been figured as the number of mg/kg to be given. In a series of studies begun in the 1880s, however, it was demonstrated that many physiologic parameters could better be estimated on the basis of body surface area (BSA). Basal metabolic rate, blood volume, cardiac output, and renal function parameters were found to correlate much more closely to the individual’s BSA than to weight. It was then found that drug doses calculated per unit of body weight were greater in smaller animals and children than in larger animals and adults, whereas doses calculated per unit of surface area were similar for all species and ages. On the basis of the findings in these studies, researchers concluded that BSA might be useful as a standard for calculating drug doses in cancer chemotherapy. The calculation for determining BSA for a given species is made by using the following formula:

In the preceding formula, K_m is a factor based on the different metabolic rate of each species; for the cat it is 10, and for the dog it is 10.1. W is the body weight in grams. Because the K values for dogs and cat are quite close, a table has been formulated that permits quick estimation of the BSA on the basis of the animal’s weight in kilograms. The appropriate dose of the chemotherapeutic agent to be administered is calculated by multiplying the dose/m² by the patient’s BSA (m²) taken from the table. A serious and potentially fatal mistake made by some clinicians when using a nomogram or table to estimate the BSA has been to use the animal’s weight in pounds rather than in kilograms. To avoid this error, a good rule is to calculate the dose of a chemotherapeutic drug and then ask another person to calculate it again separately before the drug is administered.

More recently, the use of BSA as a means of calculating doses for all chemotherapeutic agents has been questioned. For many chemotherapy drugs, myelosuppression is the most common toxicity and is dose limiting; it has been found that BSA does not correlate well with either stem cell number in the bone marrow or with resulting hematopoietic toxicity. In fact, correlation is highly significant between bone marrow effects of the cytotoxic drugs and body weight. A phase I study in dogs was performed to evaluate toxicity of doses of intravenous melphalan calculated by BSA. A significantly greater number of small dogs experienced significant toxicity than did large dogs. Another study compared marrow toxicity induced by doxorubicin given at 30 mg/m² to that induced by the drug given at doses calculated at 1 mg/kg. It was found that a disproportionately greater number of dogs weighing less than 10 kg developed severe myelosuppression at the 30 mg/m² dose than at the 1 mg/kg dose.³ Limited toxicosis was seen in dogs weighing more than 10 kg with either of the dosing schemes, however. Plasma doxorubicin concentrations were less after treatment at the 1 mg/kg dose in both large and small dogs than in those given 30 mg/m², and it is possible that 1 mg/kg may be an inappropriately low dose for treatment of animals with cancer. For drugs that may produce severe myelosuppression, measurement of hematopoietic stem cell numbers for each individual patient would clearly provide the most information to prospectively calculate doses for chemotherapeutic agents. Until such a test is available, however, clinicians must use the doses available in the literature, always carefully taking into account the individual animal’s response to the previous drug dose before administering the next treatment. If a doxorubicin dose of 1 mg/kg is well tolerated by a dog or cat weighing less than 10 kg, the next dose may be increased slightly, gradually approaching the dose calculated by BSA; this is called dose escalation. In daily clinical practice veterinarians judge the adequacy of therapy by measuring the response of visible, measurable masses; only much later are they able to evaluate the results of their treatment by survival results. In a rodent model for osteosarcoma, reduction in the dose intensity of melphalan and cyclophosphamide caused a marked decrease in the cure rate long before there was a reduction in the rate of complete clinical remission. On average, it is estimated that a dose reduction of approximately 20% leads to a loss of 50% in the cure rate. A positive relationship between dose intensity and response rate has been demonstrated in many human tumors, including lymphoma and ovarian, colon, and breast cancers. Clinicians should administer the highest dose of a chemotherapeutic drug that can be tolerated by the patient if they are attempting to cure; if palliation is the only goal, a dose that will produce clinical remission without dose escalation may be appropriate, however. Careful patient monitoring for therapeutic response and toxicity is still the best way to titrate the drug dose for each individual patient (Box 33-3).

Because chemotherapeutic drugs are quite toxic, the following guidelines for making the decision to begin chemotherapy are critically important:

Common Side Effects of Chemotherapy

Most clients are extremely satisfied with their experience with chemotherapeutic treatment of their pet’s cancer. Fewer than one in four animals are reported to have significant side effects of chemotherapy, and only 5% will have a serious event that requires hospitalization. However, if a pet does experience a serious reaction, there are certainly adverse consequences. The animal’s quality of life is decreased, at least for a time; there may be unexpected expenses for the owner associated with hospitalization and costly treatments; and it may be necessary to delay the next scheduled chemotherapy session, which sometimes allows the cancer to visibly return in the delayed interval between treatments. All this is likely to result in clients who are less enthusiastic about the idea of chemotherapy for their pet than they were before the occurrence of the unexpected side effect.

Many adverse effects of chemotherapy can be minimized or prevented by careful management, but some animals experience unanticipated side effects that no amount of care or forethought could have prevented. Certain breeds, especially Collies and rarely Australian Shepherds and Shetland Sheepdogs, are carriers of a mutation of the P-glycoprotein multidrug resistance 1 (MDR1) gene. If dogs that are homozygous for this gene are given anthracyclines or vinca alkaloids, the cellular excretion of the drugs is diminished, and they have increased drug exposure and thus increased toxicity. It is estimated that 70% of Collies in the United States are heterozygous for this mutated gene, and 31.2% of Collies are homozygous, with much lower percentages for Australian Shepherds, Shetland Sheepdogs, and other herding dogs. A test for the mutation status of this gene is available through the Veterinary Clinical Pharmacology Laboratory at the College of Veterinary Medicine, University of Washington (http://www.vetmed.wsu.edu/depts-vcpl/). If this test is not performed, dogs of these breeds with cancer should be given conservatively low doses of anthracyclines and vinca alkaloids, or the drugs should not be given at all.

Cells of normal tissue are damaged by chemotherapy; most, given time, will recover. Tissues that are especially affected include those in which the cells have a short life span and require constant renewal (e.g., bone marrow, gastrointestinal mucosa, gonads, hair follicles). Box 33-4 provides a brief overview of the classes of body tissue and, if applicable, typical renewal properties.

Box 33-4 Three Growth Classes of Body Tissue

Static: Highly differentiated and have lost capacity to divide (e.g., nerve, muscle)

Expanding: Differentiated cells that survive for the lifetime of the organism and do not require replacement. With injury, however, the organ can replace lost cells (e.g., liver).

Renewing: Differentiated with a short life span requiring constant renewal (e.g., bone marrow, gastrointestinal mucosa, hair follicle)

Myelosuppression

Myelosuppression and subsequent infection are the most common dose-limiting toxic effects of chemotherapy. Drugs that can be particularly myelosuppressive in dogs and cats include lomustine (CCNU), cyclophosphamide, carboplatin, doxorubicin (particularly when used in combination with another chemotherapeutic agent), and vinblastine. In some cats vincristine has been noted to produce a marked and prolonged neutropenia.

Many mechanisms contribute to infection after chemotherapy. Certain chemotherapeutic agents prevent phagocyte mobilization or impair function of these cells. Some cancers infiltrate the bone marrow, producing myelophthisis and contributing to cytopenias. Suppression of leukopoiesis by chemotherapy drugs may lead to associated barrier disruptions of the skin, oral cavity, and alimentary tract mucus, and the normal pulmonary “mucociliary elevator” may not function effectively to clear bacterial organisms. Endogenous bacterial infections may develop, caused by the host’s native microbial flora; these are commonly due to aerobic and anaerobic gram-negative bacteria from the gastrointestinal tract or Staphylococcus organisms from the skin. In addition, hospitalized patients frequently develop catheter-related bacteremias, often caused by microbes transmitted to the susceptible patient from the hospital environment or from another animal; these organisms may be antibiotic resistant. Patients with absolute neutrophil numbers greater than 1500/μL are generally protected against endogenous infections. If the number is between 1000 and 1500/μL, the owner is advised to monitor the animal’s condition and report any fever or anorexia. If the number is between 500 to 1000/μL, prophylactic antibiotics are generally dispensed unless the period of neutropenia is anticipated to be very short. When the absolute neutrophil number is less than 500/μL, treatment with granulocyte colony-stimulating factor (G-CSF, filgrastim, Neupogen, Amgen) or granulocyte/macrophage colony-stimulating factor (GM-CSF, sargramostim, Leukine, Berlex) may be considered (discussed later), although many patients recover without the administration of one of these cytokines—of course, antibiotics should also be administered. If the patient is not febrile, it should probably not be hospitalized because its likelihood of acquiring a hospital-acquired resistant bacterial infection is high. If the patient is febrile, however, it should usually be hospitalized for blood cultures and intravenous antibiotic administration. In general, antibiotics should not be given prophylactically for neutropenia unless they are necessary, because they increase the risks for development of bacterial resistance and fungal infection in these immunocompromised patients. When necessary, choice of an empirical antibiotic regimen should take into account the type of infection the patient is likely to have: home acquired (probably endogenous) or hospital acquired (likely to be exogenous and possibly antibiotic resistant). Appropriate antibiotic combinations for use in the febrile neutropenic patient would be an aminoglycoside (e.g., amikacin) plus an antipseudomonal penicillin (ticarcillin, carbenicillin, piperacillin) or cephalosporin (cephalothin, cefazolin, cefoxitin). The third-generation cephalosporin ceftazidime is an antibiotic with an excellent spectrum of efficacy against gram-negative bacteria and Pseudomonas, and it is moderately effective for treatment of Staphylococcus infections. Because it has poor efficacy against anaerobic organisms, it must be combined with a drug such as clindamycin, metronidazole, or an antipseudomonal penicillin; these combinations are very useful in treating infections in neutropenic cancer patients. Imipenem is useful as a single agent in these patients, with excellent efficacy against enteric gram-negative bacteria, Pseudomonas, anaerobes, and Staphylococcus, but the high cost of this antibiotic limits its use in veterinary medicine at this time. It is also an antibiotic that should probably be reserved for use in humans with antibiotic-resistant infections.

If myelosuppression is severe and life-threatening, recombinant G-CSF or GM-CSF is often administered. These products are human glycoproteins that regulate production of neutrophils within the bone marrow; they are produced in Escherichia coli bacteria. Both stimulate neutrophil progenitor proliferation, differentiation, and functional activity with minimal toxicity. Long-term (i.e., longer than 30 days) use of human G-CSF in the dog or cat results in antibody formation, however, with significant and prolonged decreases in neutrophil counts. At a daily dose of 5 μg/kg subcutaneously, the effects of canine G-CSF on the normal canine bone marrow are rapid and predictable: Mean neutrophil counts in normal dogs increased to 26,330/μL after one injection, with a maximum count of 72,125/μL by day 19 of administration. The neutrophil counts returned to normal in these dogs within 5 days after daily therapy was discontinued.⁴ Canine G-CSF is not commercially available, but recombinant human G-CSF has resulted in similar elevations of neutrophil counts in the dog. In cats 10 to 14 days of human G-CSF resulted in maximum neutrophil counts ranging from 20,370 to 61,400/μL.⁵ Thus a short course of G-CSF may be used in dogs or cats either before aggressive chemotherapy, in an attempt to ameliorate or prevent myelosuppression, or as a rescue after chemotherapy has induced significant neutropenia.

Gastrointestinal Side Effects

Another frequent side effect of chemotherapy relates to the gastrointestinal toxicity of these drugs; anorexia, vomiting, and diarrhea may be noted in some individuals treated with cytotoxic agents. These side effects are not noted in dogs and cats as predictably as in humans, but they can occur in sensitive individuals with most of the commonly used drugs. Agents with a high potential for acute nausea after administration include cisplatin, dacarbazine, and high-dose cyclophosphamide; those with a moderate potential include carboplatin, conventional-dose cyclophosphamide, doxorubicin, mitoxantrone, and occasionally vincristine. In animals with only mild to moderate nausea, metoclopramide (0.2 to 0.5 mg/kg orally or subcutaneously thrice daily), or prochlorperazine (0.3 mg/kg orally or subcutaneously thrice daily) may be effective. Premedicating with subcutaneous administration of butorphanol at 0.4 mg/kg will sometimes block the postadministration vomiting caused by cisplatin. In animals with severe nausea and vomiting caused by chemotherapy (which is rare, fortunately), one of the serotonin 5-hydroxytryptamine (5-HT) receptor antagonists may be given either orally, subcutaneously, intramuscularly, or rectally. The most commonly available member of this class of drugs is ondansetron, but several newer antiemetics of the class are now also available (e.g., dolasetron), and the price of the drugs has dropped to make them reasonable to use now that ondansetron is available as a generic. The dose of ondansetron in the dog is 0.1 to 0.3 mg/lb intravenously or subcutaneously twice daily (oral dose is 0.5 to 1 mg/kg every 12 to 24 hours), and the dose of dolasetron is 0.5 to 0.6 mg/kg subcutaneously or intravenously every 24 hours. The serotonin receptor antagonists act more specifically than other antiemetics to prevent the vomiting induced by chemotherapy or radiation. Serotonin receptors of the 5-HT type are located on vagus nerve terminals and in the chemoreceptor trigger zone. Serotonin is released from enterochromaffin cells in the small intestine when they are severely damaged. The released serotonin stimulates vagal afferents through the 5-HT receptors, and nausea and vomiting ensue. Ondansetron and dolasetron block the 5-HT receptor site, which prevents the serotonin effect.

A new antiemetic that is proving to be very effective in the control of chemotherapy-induced nausea and vomiting is maropitant (Cerenia). It is a neurokinin-1 (NK-1) receptor antagonist and is available both in injectable form and as tablets; the dose is 1 mg/kg subcutaneously once daily or 2 mg/kg orally once daily. The NK-1 receptor antagonists drugs work at NK-1 receptors in the emetic center to block both peripheral and central stimuli that cause emesis, by inhibiting the binding of substance P. Substance P is found in significant concentrations in the nuclei that make up the emetic center and plays a central role as a neurotransmitter in the afferent pathways of the emetic reflex.

Other gastrointestinal side effects may also occur as sequelae to chemotherapy drug administration. Diarrhea occurs much less often than vomiting and nausea and is generally readily treated with loperamide (0.08 mg/kg orally thrice daily). Doxorubicin sometimes produces a severe hemorrhagic colitis in dogs, for which hospitalization and symptomatic treatment with antibiotics and intravenous fluids may be necessary; rarely, this side effect caused by doxorubicin can be life-threatening. Anorexia may be noted with several drugs, especially in cats with doxorubicin or vincristine administration. Appetite stimulation with drugs such as cyproheptadine may help in these cats, but enteral feeding is sometimes necessary.

Phlebitis and Necrosis

Several commonly used chemotherapeutic drugs will produce phlebitis or local necrosis (or both) at the site of administration if extravasated. Drugs that can be expected to produce severe reactions include the vinca alkaloids, doxorubicin, and dactinomycin; moderate reactions may be seen with bleomycin, cisplatin, dacarbazine, and mitoxantrone. These cytotoxic drugs may irritate the lining of access veins during administration, producing phlebitis, or may escape the cutaneous vasculature and spread throughout the surrounding tissues, causing a local inflammatory reaction (chemical cellulitis). Alternatively, some of the drugs will produce local tissue necrosis if extravasated. Doxorubicin produces the most dramatic and severe reactions. Extravasation will produce marked epidermal hyperplasia, with mitosis of many epidermal cells at the margins of the lesion; the reaction will contain individual necrotic keratinocytes, lobular panniculitis, and reactive fibroblasts and endothelial cells. No inflammatory reaction will be seen. In the area of direct extravasation, pan-epidermal, dermal, and subcutaneous tissue necrosis will be present. This necrosis begins 1 to 2 weeks after the drug is extravasated and may continue for up to 4 months. With all these drugs, extreme precautions should be taken to prevent extravasation, particularly with venipuncture and catheter placement. A “first-stick” catheter should always be used; infusion through a preexisting catheter is not advised. The animal should be observed closely (and possibly restrained) during the entire time of the infusion, in case movement should dislodge the catheter.

Infusion of the chemotherapy drug should be terminated immediately if the patient shows signs of pain during drug administration or if there is blebbing at the catheter or needle entrance site. If the catheter or needle is still present, the clinician should aspirate any fluid from the extravasated area. A continuing dilemma in the management of extravasation injuries is the absence of evidence-based management strategies. Almost all the recommendations in the literature are (of course) based on anecdotes; even knowing for sure that an extravasation occurred is sometimes difficult, so assessing whether there has been a positive response to a particular treatment is also questionable. However, the current recommendations for vinca alkaloid extravasation are to inject 150 units of hyaluronidase (if available; hyaluronidase has become difficult to obtain) through the patent catheter or needle and then apply local heat for 15 to 30 minutes four times daily for 48 hours. For anthracycline extravasation, the clinician should apply an ice pack for 15 to 30 minutes four times daily and 90% dimethyl sulfoxide (DMSO) topically several times daily for 7 to 14 days; surgical removal should be considered if the area of extravasation is confined. DMSO is a free radical scavenger that causes potent vasodilation and has pain reduction and antiinflammatory mechanisms. Dexrazoxane is a drug that has been used to prevent anthracycline-induced cardiotoxicity. It may also decrease free radical formation, and when given intravenously immediately after extravasation (1000 mg/m² intravenously, repeated at the same dose the next day), it appears to prevent the tissue necrosis associated with anthracycline extravasation. Growth factors regulate and coordinate wound healing, and they may also be helpful in altering damage from chemotherapy drug extravasation. In animal models both G-CSF and GM-CSF have been shown to be significantly better than saline or no treatment in decreasing the severity and extent of necrosis with doxorubicin extravasations. In one human patient who did not respond to injected dexrazoxane, GM-CSF injected into an ulcerated area of extravasation led to tissue granulation and complete healing within 8 weeks. With any luck, clinicians will never have to use the following protocol: A 1-mL vial of GM-CSF was diluted with saline. Several small injections were then given within the borders of the ulcer. As new granulation tissue formed, GM-CSF injections were given three times weekly for 2 weeks, then twice a week for 2 weeks. Because treatment of extravasation injuries is not yet uniformly effective in preventing the local irritation and necrosis caused by extravasation of these drugs, prevention is the best answer.

Alopecia

Alopecia is common in certain breeds of dogs after chemotherapy, particularly after administration of doxorubicin or cyclophosphamide. Hair loss is predictable in Poodles and in mixed-breed dogs of Poodle lineage; it is also commonly seen in Terriers and Old English Sheepdogs. Occasionally, it may be noted in other breeds as well. It is common for cats to lose their whiskers during chemotherapy. For some owners the alopecia induced by chemotherapy is very distressing, and owners of breeds in which this is likely to occur should be prepared for this possibility. Hair regrowth begins 1 to 2 months after chemotherapy is discontinued. However, an alteration in the color or texture of the new hair may be noted; the regrown hair may be a lighter or darker shade and may be softer or curlier than the animal’s previous hair.

Reproductive Side Effects

Although generally less important in dogs and cats with cancer than in humans, the effects of chemotherapy on gonadal function should be explained to owners considering treatment, particularly if the animal is shown or has been used for breeding. Most chemotherapy drugs will cause hypofertility or infertility by impairing production of sperm and oocytes. In the male animal, loss of libido may result from Leydig cell dysfunction and decreased testosterone levels, especially with corticosteroid treatment for lymphoma. Owners should consider cryostorage of sperm from the dog before beginning chemotherapy. However, it is common to find on semen evaluation that general debility from the cancer itself has resulted in poor semen quality even before chemotherapy drugs have been given. Reversibility of gonadal dysfunction produced by chemotherapy is variable depending on the agent administered, the dose intensity of the protocol used for treatment, and the age of the patient itself. During chemotherapy and for a variable period after the treatment is completed, a male dog or cat should not be used for breeding and a female should not become pregnant because congenital malformations may result in the offspring.

Palmar–Plantar Erythrodysesthesia

Palmar–plantar erythrodysesthesia (PPES), also known as hand–foot syndrome in humans, has been seen with constant-rate infusions of doxorubicin, cyclophosphamide, ifosfamide, 5-fluorouracil, and other agents in humans. In dogs PPES has been most commonly associated with the administration of liposome-encapsulated doxorubicin (Doxil).⁶ PPES is a primarily a dermal toxicity characterized by reddening of the skin. It is followed by edema and eventual ulceration of the skin. PPES tends to occur in areas of friction, such as the weight-bearing portions of the feet and the axillary regions. Histologically, these lesions are described as focal areas of parakeratosis, acantholysis, and chronic active inflammation of the skin and underlying dermis. PPES often resolves quickly after discontinuation of the drug but may recur if the drug is reinstituted. Oral pyroxidine may help ameliorate some of the side effects, although it will not completely prevent PPES.⁷

Human Health Hazards

Exposure of hospital personnel and owners to carcinogenic, mutagenic, and teratogenic drugs and drug-containing animal waste must be considered. In the days before clinicians took appropriate precautions when mixing and administering chemotherapy, there were many reports in the human literature of fetal loss and birth of infants with congenital defects among nurses and pharmacy staff members who were frequently exposed to chemotherapy drugs.^8,9 Proper storage, preparation, and administration of chemotherapeutic agents, as well as proper disposal of cytotoxic drug waste and urine and stool of the animal being treated, should be a concern of every clinician who treats an animal for cancer.^8,9 Reviews on proper handling of chemotherapy in the workplace are available; the Occupational Safety and Health Administration (OSHA) publication “Controlling Occupational Exposure to Hazardous Drugs” may be downloaded from OSHA’s website (www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html).

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