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Chemotherapy Tidbits

CHEMOTHERAPY TIDBITS

by Kevin A. Hahn, D.V.M., Ph.D., D.A.C.V.I.M. (Oncology) & Overall Nice Guy

The information below is a summary of information obtained from the current veterinary literature and from personal experiences.  It does NOT replace your regular veterinarian.  Please consult with your primary veterinarian first, but if needed, don't hesitate to consult with me by email at drhahn@gulfcoastvetspec.com.   To find an oncologist in your area, please visit www.acvim.org.  

 

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PRINCIPLES OF CHEMOTHERAPY.. 91

WHEN SHOULD CHEMOTHERAPY BE CONSIDERED?. 91

TUMOR GROWTH AND RESPONSE TO CHEMOTHERAPY.. 91

PHARMACOLOGIC PRINCIPLES OF CHEMOTHERAPY.. 93

CHEMOTHERAPY SAFETY GUIDELINES. 100

MANAGEMENT OF CHEMOTHERAPY SIDE EFFECTS. 106

CHEMOTHERAPY DOSAGES, INDICATIONS, & ADVERSE REACTIONS. 113

CHEMOTHERAPY DOSAGE CONVERSION CHART. 119

PRINCIPLES OF CHEMOTHERAPY

WHEN SHOULD CHEMOTHERAPY BE CONSIDERED?

When considering the use of chemotherapy in the tumor-bearing patient, the approach to therapy will vary greatly depending on the therapeutic intent.  Will the therapeutic goal be cure or palliation?  It is important to determine the goal clearly at the outset.  Cure is the ideal outcome, but is not necessarily realistic in most cases or likely to be achieved unless it is the initial intent.  If cure is the intended outcome, aggressive therapy may provide substantial long-term benefit and a relatively high level of short-term toxicity may be justified.  More commonly, the accepted goal of cancer therapy in veterinary medicine is palliation.  Toxicity to chemotherapy is minimized in an attempt to prolong an acceptable quality of life. 

Although localized primary tumors which have a minimal risk for metastasis are most commonly treated with surgery and/or radiation, chemotherapy may occasionally be used instead of or in addition to standard local therapy.  Systemic chemotherapy is also indicated following local treatment for adjunctive therapy in tumors that are commonly widespread or demonstrate a high rate of metastatic behavior (e.g., osteosarcoma, oral melanoma).   

TUMOR GROWTH AND RESPONSE TO CHEMOTHERAPY

An understanding of cell growth, the biologic behavior of tumors, and the metastatic pattern of specific tumor types are essential prior to formulating a treatment plan.  The phases of the cell cycle are S, in which new DNA is synthesized, gap G1, a period of RNA and protein synthesis, M, when the cell undergoes mitosis, and a second gap, G2.  The duration of each phase varies for different cell types.  Resting cells, G0, may retain the capacity to divide upon proper stimulation.  Normal and neoplastic cell populations are composed of both proliferating and resting cells; the proportion and the rate of cell death vary with the tissue type.  Growth fraction refers to the proportion of a population of cells, which is actively proliferating, in contrast to those that are viable but quiescent.  This concept must be distinguished from growth rate, which refers to the increase in size of the tumor over time. 

It is helpful to consider the rate of growth of a tumor more in terms of doubling time than in terms of size per time.  Doubling time refers to the time required for doubling of cell number, which is clinically evident as volume.  Some tumors are anatomically difficult to characterize, however most can be assumed to be roughly spherical for purposes of calculation. 

The smallest clinically detectable tumor generally has a mass of 1g, about 1 cm diameter and contains approximately 109 cells.  If a tumor is assumed to have originated from a single cell, then it has already undergone 30 doublings by the time it is clinically detected.  To increase in size to 1 kg theoretically takes only another ten doublings, assuming that all cells survive.  Thus the majority of the lifespan of a tumor is probably spent in the subclinical phase. 

Depending on the growth fraction and the rate of cell death, normal cell growth is classically thought of as an exponential phenomenon in which the rate of doubling of the population remains fixed over time.  Tumor cell populations, however, tend to adhere more closely to Gompertzian kinetics, meaning that the doubling time tends to increase exponentially over time then reach a plateau phase.  The plateau phase is most likely due to a decrease in the growth fraction due to hypoxia, depletion of nutritional factors, and an increase in the rate of cell death rather than an increase in the length of the cell cycle. 

In general, the higher the growth fraction of a population of cells, the more chemosensitive they are expected to be.  This explains why the most common side effects of chemotherapy are gastrointestinal disturbances and bone marrow suppression, since these populations are constantly proliferating.  Likewise, a tumor that is reaching the plateau phase of the growth curve due to hypoxia and poor cell nutrition will be more chemoresistant than one in the exponential or linear phase. 

Whether palliation or cure is the therapeutic goal, remission of tumors is desirable.  Complete remission is defined as an inability to detect clinical evidence of tumor.  This does not mean that all tumor cells have been removed.  The remaining cells are a source of potential relapse or recurrence of gross tumor.  When relapse occurs during chemotherapy, it implies that the tumor is resistant to the agents being given.

PHARMACOLOGIC PRINCIPLES OF CHEMOTHERAPY

In order to induce remission without harming the patient, anticancer drugs must damage tumor cells to a greater degree than normal cells.  Cytotoxicity refers to the chemotherapeutic action of a drug.  The mechanism of cytotoxicity varies with each drug class.  In general, however, efficacy is greatest against actively cycling cells, and some agents act specifically on cells in certain phases of the cell cycle.  Knowledge of the mechanism of action for each drug will allow the use of drug combinations that may act synergistically, and avoid drugs that may antagonize each other's mechanism of action. 

When a cytotoxic drug is administered to a population of cells, the number of cells killed will not be absolute, but will be a percentage of the total number.  If a tumor containing 109 cells is exposed to a dose of drug that kills 99% of the population, 9.9 x 108 cells will be killed and 107 will remain, but the tumor will now be clinically undetectable.  If the tumor starts at a mass of 100 g, or 1011 cells, 9.9 x 1010 cells will be killed and 109 will survive; the drug has been equally effective but the tumor will remain clinically detectable. 

The cytotoxic action of chemotherapeutic agents is dependent on concentration over time rather than peak plasma levels, whereas peak plasma level often determines adverse effects on normal tissue.  This makes the use of slow infusion techniques desirable for intravenous drugs. 

Dose Response Curve

For all effective drugs, a sigmoid curve can be defined between the dose administered and the effect, such as percentage of cells killed.  This curve exists for normal cells as well as for tumor cells.  An ideal drug has a response curve with a steep slope for tumor cells and a gradual slope for normal cells; furthermore, the therapeutic dose should fall on the linear portion of the curve for tumor cells and at the foot of the curve for normal cells.  Thus a small increase in dose brings about a large increase in tumor response and a small increase in toxicity.  The curve plateaus at a point of maximal effect, beyond which any further increase in dose will not increase the response.

Therapeutic Index

As with other medications, the therapeutic index refers to the ratio of the toxic dose to the effective antitumor dose.  The therapeutic index of most chemotherapeutic agents is relatively low, necessitating careful dosing.  Improvements in therapeutic index can be made by using techniques that either make the drug more effective or protect against toxic effects. 

The optimum dose is at the point on the dose response curve where maximum antitumor effect and acceptable toxicity occur.  It may be necessary to accept some toxicity or some risk of incomplete response, or both.  In practice, the optimum dose in a given circumstance depends on the goal of therapy.  If the goal is cure, toxic risks are likely.  If palliation is the goal, toxicity will be avoided, but incomplete response is likely.

Toxicity from chemotherapeutic agents ranges from mild to life threatening.  Tissues with high growth fractions such as bone marrow and epithelial tissues, including the gastrointestinal tract, are normally most susceptible to toxic side effects.  Some drugs have additional toxic effects on other tissues, such as urinary tract, myocardium, or pancreas.  These effects may be unrelated to the cytotoxic effects and may be idiosyncratic or species specific.  Anaphylaxis is of concern in the use of certain drugs, as a reaction to either the drug itself or the carrier. 

Drug Classes

The major classes of chemotherapy agents are the alkylating agents, antimetabolites, mitotic inhibitors such as plant alkaloids and podophyllotoxins, and antibiotics.  Two additional important agents are the platinum compounds and the enzyme L-asparaginase.  The alkylating agents are the largest and oldest group and are not cell cycle specific.  The antibiotics have a variety of mechanisms of action, and the most commonly used are the anthracyclines

The toxic side effects of some chemotherapy agents can be specifically antagonized or minimized by the use of special administration techniques, such as saline diuresis before administration of cisplatin to minimize renal toxicity, or a second drug, which does not have direct antitumor effect, but does allow the use of higher doses because of an increased therapeutic index.  An example is the use of Mesna to prevent hemorrhagic cystitis caused by ifosfamide. 

Resistance To Chemotherapy

Tumors may be intrinsically resistant to anticancer drugs or they may acquire resistance as a result of exposure.  A tumor cell may be naturally unaffected by the mode of action of a chemotherapeutic agent; the cell may not have receptors or activating enzymes for the drug or may not be reliant on the biochemical process in which the drug interferes.  In addition, some anatomical locations are difficult to treat with chemotherapy because of the inability of the drug to reach the site of the tumor (e.g., blood-brain barrier).  Furthermore, drugs may not reach all cells in a poorly vascularized tumor, and these cells may survive in a quiescent state to reemerge at a later time. 

Acquired resistance develops after tumor cells have been exposed to a drug or similar class of drugs.  Spontaneous mutation is assumed to be ongoing regardless of the presence of any drug and the occurrence of spontaneously resistant cells in a population approximates the rate of mutation.  The rate of spontaneous genetic mutation in both normal and neoplastic cell populations is generally estimated at 10-7-10-5 per mitosis.  If the population is then exposed to the drug, the resistant cell will have a growth advantage.  Many chemotherapy agents are mutagenic and may increase the risk of development of clones that are resistant to one or more drugs.  Thus, the larger the number of cells in a tumor, the more likely it is that spontaneous resistance will occur.  If only a small subset, or clone, has the resistant phenotype, it will eventually become the dominant cell type in the tumor because of the growth advantage conferred by its ability to grow in the presence of a given drug.  This may not be clinically evident if most of the tumor is sensitive until the resistant clone reaches a certain size.  This is one of the mechanisms of relapse. 

Gene amplification is another source of acquired drug resistance that is enhanced by the presence of gradually increasing concentrations of the drug.  Drugs such as mitotic inhibitors which promote a delay in the cell cycle just prior to M phase, are most likely to promote this phenomenon.  A good example of acquired drug resistance by gene amplification is the multiple drug resistance phenotype.  Multiple drug resistance (MDR) is a phenomenon of cross resistance of cells to a variety of agents which are not structurally or functionally related.  These include the antitumor antibiotics, podophyllotoxins, and the plant alkaloids.  MDR is mediated by p-glycoprotein, a cell membrane pump that is present normally on the surface of some epithelial cells.  The protein actively removes drug from the cell, making it resistant to any drugs that are substrates for the pump. 

Chemotherapy Protocols

Combinations and scheduling

Using drugs in combination maximizes therapeutic potential.  The most important criterion for inclusion of a drug into a combination protocol is efficacy as a single agent against the tumor in question.  Using closely related drugs in combination usually does not improve efficacy significantly and may increase toxicity, whereas effective combinations generally consist of drugs that target different metabolic pathways.  Some drugs are synergistic when used in combination, but often the effects are simply additive.  Combinations allow the use of a higher total cytotoxic dose when the toxic effects of the individual drugs are different. 

Scheduling of drug administration can be critical since giving it too late may markedly decrease the antitumor effect of a drug, either because the growth fraction of the tumor has decreased or because a resistant clone has developed.  Also, the scheduling of the various drugs in relation to each other is important.  Differences and similarities in mode of action, toxicities, and mode of resistance should be considered. 

It is critical to avoid overlapping the toxicities of the drugs in combination chemotherapy protocols.  The most commonly encountered example of this is in the use of multiple myelosuppressive agents.  The onset of the neutrophil nadirs of various drugs must be taken into account when planning the sequence and timing of therapy, and since some alkylating agents cause delayed myelosuppression, this may not be readily evident until a second drug is administered. 

Multi-modal therapy

Chemotherapy is often used successfully in combination with other therapeutic modalities, particularly surgery and radiation therapy.  If multi-modal therapy is to be used, the combination should be planned in advance rather than using different modalities one after the other as each one fails.  Preoperative (neoadjuvant) chemotherapy is indicated when a primary tumor is so large that it is inoperable or involves vital structures.  Usually, however, chemotherapy is used postoperatively (adjuvant) after incomplete excision or when micrometastases are expected to be present based on a knowledge of the behavior of a particular tumor.  In theory, adjuvant therapy should be particularly effective since the growth fraction of residual tumor is likely to be relatively large. 

Dose Determination

Because the therapeutic index of chemotherapeutic agents is generally low, accurate dosing is imperative.  Although there are numerous examples in humans where clinical pharmacokinetics have been successfully applied to improve anticancer therapy, most veterinary anticancer drug dosages and regimens are based on human dose extrapolation and empirical trial and error.  It is important, therefore, to realize there are specific species differences in metabolic rates and pathways (e.g., cisplatin-induced fatal pulmonary toxicity in cats, but not in dogs).

Body surface area, an accurate reflection of metabolic rate, has been used to calculate drug dosage in humans.  Most anticancer drugs prescribed in veterinary medicine are dosed on a per body surface area basis rather than a per weight basis for similar reasons.  However, in recent times many veterinary oncologists have become aware of the fact that in doing so, the smaller-sized patients receive a much higher mg/kg dose than do larger-sized patients.  For example, when dosing doxorubicin on a per body surface area basis (30 mg/m2, equivalent to 1 mg/kg), smaller-sized dogs (e.g., 5 kg dog dosed at 30 mg/m2 is given a dose equivalent of 1.74 mg/kg) have higher peak plasma concentrations, greater plasma drug concentrations versus time curves, longer drug elimination half-lives, greater volumes of distribution of the central compartment, more pronounced myelosuppression, and more clinical signs of toxicoses than do larger-sized dogs. 

Although these findings do not imply a carte blanche revision of anticancer drug dosages in veterinary medicine, application of knowledge regarding species variability in drug pathways, coupled with limited veterinary studies and Phase I and II human pharmacokinetic studies should result in improved veterinary therapy compared to empiric trial and error. 

Administration

Anticancer drugs have been given orally, intravenously, subcutaneously, topically, by an intracavitary or intravesicular route, and intra-arterially.  Efficacy and toxicity often vary based on the route of administration chosen.  Care should be given to assure proper administration of all chemotherapy drugs.  Only a few chemotherapy drugs are available in an oral form, but they are widely used in veterinary oncology where frequent office visits for therapy and a perception of the pet's discomfort may deter the client from pursuing other equally or more important forms of treatment.  When chemotherapeutic agents are dispensed for home use, the client must be made aware of the hazards associated with handling the drugs.  Appropriate precautions should be taken to prevent human exposure, especially when children or adults of childbearing age are members of the household. 

The intravenous route is readily accessible in most veterinary patients and is most commonly used.  A few drugs can be extremely irritating if administered perivascularly (e.g., vincristine, doxorubicin), so care must be taken in using these drugs in animals that are difficult to restrain. 

Only a few chemotherapy agents are available for intramuscular and/or subcutaneous administration.  The use of a subcutaneously implanted continuous infusion or absorption devices holds great promise for drugs that are non-irritating.  Some drugs are actually less toxic when given by the subcutaneous or intramuscular route.  L-asparaginase is associated with a much lower rate of anaphylaxis when used intramuscularly than when given intravenously. 

A few drugs are available in topical forms for use in human medicine, however these are generally not useful in veterinary medicine.  Toxicity and poor efficacy have been encountered. 

The use of intracavitary and intravesicular chemotherapy has applications in special cases where the tumor is not bulky, since the drug will only penetrate a few millimeters from the drug/cell interface.  Examples of such tumors may include mesotheliomas, pleural or peritoneal carcinomatosis, and noninvasive transitional cell carcinomas.  The drug used must be nonirritating.  Since systemic absorption is likely, the dose should be within the safe systemic range. 

If a major artery supplying a tumor can be identified and catheterized, some drugs may be given intraarterially to deliver a high concentration of drug to the tumor without exposing the host to an excessively high total body dose. 

CHEMOTHERAPY SAFETY GUIDELINES

Concerns In The Work Place

Health concerns regarding occupational exposure to drugs used in cancer therapy are primarily associated with those drugs referred to as cytotoxic. Beginning in the early 1980's, there have been a series of Technical Assistance Bulletins developed by the American Society of Hospital Pharmacists and recommendations from the Federal Occupational Safety and Health Administration, the National Institutes of Health, the American Medical Association, and others that address the potential health hazards of low dose occupational exposure to cytotoxic anti-cancer drugs. Similar guidelines have been published in the veterinary literature. The potential danger to health care professionals from handling a cytotoxic drug stems from a combination of its inherent toxicity, individual susceptibility, concurrent exposure to known carcinogens, and the level and type of exposure. Exposure may occur through inadvertent ingestion of drug in foodstuffs or cosmetics, inhalation of drug dusts or droplets, or direct skin contact. Health risks from low level occupational exposure must be addressed as a reality, but the word "potential," must be used since there is no conclusive evidence establishing an association between occupational exposure and disease. There is, however, considerable controversy that stems primarily from retrospective studies suggesting that nurses who handle cytotoxic drugs in an unprotected fashion had an increased risk for fetal loss. In addition, some cytotoxic drugs are mutagenic, teratogenic and/or carcinogenic under laboratory or clinical conditions. Given the current level of concern and the need to protect veterinary professionals from potential occupational health risks, many veterinary hospitals have instituted formal procedures for the safe handling of cytotoxic drugs in the work place. Correct preparation and handling technique will prevent dust particles and liquid droplets from escaping into the work place when cytotoxic drugs are being manipulated. Work place contamination can also occur through accidental spills and breakage of drug containers. Although the need for caution and common sense when handling cytotoxic drugs is real, there is no justification for hysteria. Safety equipment and safe handling methods relating to cytotoxic drugs should be taken in the same way that safety equipment and safe technique is accepted when operating x-ray equipment or handling infectious material. All hospital personnel who handle cytotoxic drugs should have training in the procedures and access to information pertaining to their responsibilities. As with other conditions in the work place, "right to know" policies for health care professionals should be followed.

Drug Storage And Preparation

All chemotherapeutic drugs should be clearly identified as potentially hazardous. Chemotherapeutic drugs requiring refrigeration should be stored separately. Store chemotherapeutic drugs in a properly marked zipper closure plastic bag or in a bin designed to contain accidental leaks. A good location for drug preparation is in a side room away from ward traffic and food preparation areas. Windows, doors, and air vents should be closed to eliminate drafts. No other activity should occur in the room during preparation and administration. Read the package insert prior to admixing any chemotherapeutic drug. Have the following materials and supplies readily available in the immediate work area: Plastic-backed diaper, gauze pads, cotton balls, alcohol, gown, gloves, face mask, glasses or goggles, syringes, needles, venting pins, stopcocks, diluent, drug, zipper bags, pen or marker, sharps container, hazard labels. Wash hands thoroughly prior to drug preparation.

Prepare drugs on a working surface at waist level. Use plastic-backed absorbent sheets to line the immediate work surface. During preparation wear a lint free disposable gown made with low permeability fabric. The gown should have a solid front, long sleeves, and snug fitting elastic cuffs. Wear two layers of talc-free latex gloves. Necropsy gloves are appropriate since latex gloves may be less permeable to chemotherapeutic drugs than gloves made from polyvinyl chloride. Torn or punctured gloves should be discarded and not used. When wearing double gloves, one glove should be under the gown cuff and the other one should be placed over it so no skin of the wrist or forearm is exposed. If clothes become contaminated do not wash them. This will potentially expose others. Discard them in a properly marked container for chemotherapeutic waste. Wear a disposable face mask. Wear a pair of safety glasses or splash goggles.

Once the proper diluent and the correct amount have been determined, inject slowly into the chemotherapeutic drug vial. An alcohol dampened 4x4-gauze pad prior to withdrawing the needle from the drug vial should then surround the drug vial stopper. Both needle and syringe should be withdrawn together. Discard the syringe and needle into an appropriate puncture-proof waste container. Do not recap the needle. When withdrawing admixed drugs from a drug vial the syringe should be filled to no more than two-thirds. Avoid large fluctuations between atmospheric pressure and pressure within vials. Venting devices can be useful for capturing aerosolized droplets that have resulted from sudden pressure changes. If multiple syringes are to be filled, the vial should be fitted with a stopcock. Use syringes and IV sets with Leur-lock fittings as a precaution against accidental separation that is possible with standard friction fittings. Aspirating the fluid slowly may reduce air bubbles created in the syringe. Do not tap the syringe to concentrate air bubbles. This increases drug aerosolization. Injecting them into an alcohol moistened cotton ball may safely eliminate air bubbles that are present. 

Do not recap needles. Recapping, crushing, or clipping needles increases the risk of cutaneous or aerosolized drug exposure. Using venting devices to withdraw admixed drug can minimize cutaneous exposure. Discard unused chemotherapeutic drugs into an appropriate chemotherapeutic drug waste container. When breaking an ampule, wear protective gloves. This will reduce the possibility of cutaneous absorption. Place an alcohol dampened 4x4-gauze pad at the neck of the ampule. This will absorb any aerosolized drug. Remove the drug slowly from the ampule to minimize spillage or aerosolization. Inject excess air bubbles into an alcohol moistened cotton ball.

Count tablets and capsule forms of chemotherapeutic drugs on separate counting trays from those used for other hospital drugs. Minimize reducing tablet size for the convenience of smaller sized patients. Reducing tablet size may result in the aerosolization of drug dust.

After preparation has been completed, label all vials and bottles with the date and time. Seal reconstituted drugs that are ready for administration in a properly marked zipper closure bag or leak proof container for transport to the administration area. Place all broken ampules, needles, and other sharp items into a sealed puncture-proof container that is separate from other hospital trash. Clean the preparation area by discarding the plastic-backed absorbable paper liner and then washing the surface with soap and water. Use paper towels to dry this area. All contaminated clothing should be removed prior to leaving the work area. Discard all items in a properly marked waste container. Discard the gown and latex gloves. Thoroughly wash hands with soap and water to remove any possible drug residue. Remember hand washing is not a substitute for wearing gloves and if medication is sent home with the patient, supply the owner with protective latex gloves.

Drug Administration

All drugs should be transported in a properly marked leak proof container or zipper closure bag. Prior to administration, double-check drug selection and dose calculations. All personnel involved in drug administration must wear protective gowns, gloves, and face apparel. When administering IV chemotherapeutic drugs, place a plastic-backed absorbent liner under the patient. Place an alcohol dampened 4x4-gauze pad under and around the IV injection port to prevent aerosolization of the drug. Monitor the administration set carefully for leaks. Administer IV chemotherapeutic drugs through a patent indwelling catheter that has been placed aseptically. Flush IV catheters with a solution that is compatible with the drug prior to and following chemotherapeutic drug administration. This information can be obtained from the drug insert. Cover the needle with a 4x4-gauze pad when removing the needle from the injection port.

Discard contaminated needles and syringes into a puncture-proof container designated only for chemotherapeutic drugs. Dispose of contaminated soft goods such as catheters, IV administrations sets, venosets, gloves, and gowns with other chemotherapeutic drug wastes. Although there is no evidence to date that exposure to urinary or fecal waste from a patient receiving chemotherapeutic drugs is harmful, hospital personnel, as a regular part of the hospital clean hygiene plan, should always wear gloves when handling body wastes from patients. Ward cages or runs housing patients treated with chemotherapeutic drugs should display a warning label to alert hospital personnel. Body waste from chemotherapeutic patients should be disposed of with other biohazardous waste.

Drug Disposal

Written policies regarding the identification, containment, segregation, disposal, and collection of chemotherapeutic drug wastes should be established and posted in the work place. All containers should carry a hazardous drug waste label. Segregate all chemotherapeutic drug contaminated waste containers from other hospital trash and dispose of the waste according to local, state, and federal regulations. Frequently, human hospital pharmacies can be persuaded to accept the small amounts of waste generated by veterinary hospitals.

Accidental Spills

Place an accidental spill kit in the preparation and administration areas. The spill kit should contain an isolation gown made with low permeability fabric, two pairs of latex gloves or necropsy gloves, face mask, shoe covers, eye goggles, cat litter, paper towels or absorbent pads, a hemostat, and a thick resealable plastic bag that carries an appropriate hazardous waste label. If an accidental spill occurs, restrict access to the area immediately and allow some time to pass to allow spilled drug to settle onto surfaces, decreasing the risk of aerosolized exposure. The spill should then be cleaned at once.

If a human or animal has become contaminated by the spill, the contaminated skin should be washed with soap and water and contaminated eyes should be flushed with an eyewash or water based solution for a minimum of five minutes. A physician should be contacted immediately regarding additional emergency medical measures. Contaminated clothing must be removed and discarded with all other contaminated waste. One person should be designated for clean up. Protective apparel must be worn and the spill kit used. Promptly obtain and wear the protective isolation gown, two pairs of latex examination gloves or heavy necropsy gloves, eye goggles, shoe covers, and facemask. Collect broken glass with a broad edge tray or hemostat and place into a separate puncture-proof container. Absorb liquids with disposable towels, pads, or cat litter. Collect powders with a damp disposable towel or pad. Rinse the contaminated surface with water and then clean with detergent. Do not use chemical deactivators. Detergent cleaned surfaces should be cleaned again with water. Clean the spill area once more with soap and water and minimize use of this area for 24 hours. Place all contaminated materials in a resealable disposable thick, plastic bag that carries an appropriate warning label. Wash hands thoroughly after clean up.

Use Common Sense

The previous guidelines should be evaluated for suitability in each individual veterinary hospital. The costs of implementing all of the guidelines maybe considered impractical in some situations. It is recommended that each veterinary hospital adopt some form of safety guidelines for the handling of chemotherapeutic drugs and review these with the hospital staff on a regular basis. Remember, common sense, good techniques and inexpensive safety precautions should eliminate the likelihood of exposure. If you have additional questions, please contact an oncologist or oncology technician in your area.   

MANAGEMENT OF CHEMOTHERAPY SIDE EFFECTS

Prevention

Chemotherapy associated complications should be, and usually are, rare events in veterinary oncology. The single most important method for avoiding chemotherapy toxicity is to know the potential side effects of the drugs you intend to use. Many complications are avoidable and it is imperative that research on utilization of these drugs be performed before use. It is also important to know any synergistic toxicity that may exist if a combination of chemotherapeutic agents (or other medications) is planned. Several texts are available that contain valuable information about chemotherapeutic drug handling and toxicity, and veterinarians are encouraged to consult experienced individuals before using these agents. A complete blood count (CBC), serum biochemical panel, and urinalysis (UA) should be performed prior to the first chemotherapy treatment and these tests should be repeated as necessary depending on the drug administered. With rare exception, treatment with myelosuppressive agents should not be performed if the neutrophil count is less than 2500 cells/µl or the platelet count is less than 100,000/µl (some individuals use 75,000/µl as a guideline for platelets). A urinalysis should be performed to rule out pre-existing cystitis prior to use of drugs such as cyclophosphamide, to identify occult urinary tract infections (UTI), and to identify early renal dysfunction that may impact excretion of chemotherapeutic drugs. Renal dysfunction is an absolute and relative contraindication for use of cisplatin and carboplatin, respectively. Patients receiving doxorubicin should be carefully evaluated for cardiac disease (dog, cat), or renal disease (cat). Some veterinarians perform an ECG prior to each treatment with doxorubicin. Others require thoracic radiography and echocardiography on patients at high risk for cardiomyopathy or congestive heart failure (Boxers, Doberman Pinschers, dogs with heart murmurs and cardiac silhouette/vessel abnormalities on thoracic radiography, or cats with heart murmurs) prior to administration of doxorubicin.

Chemotherapy administration should take place in an area of the hospital that is relatively traffic-free. This ensures full concentration of the staff administering chemotherapy as well as a calm environment for the patient. This may require that chemotherapy treatments be performed at a time of day that is less hectic than usual. You should be sure that all required materials are prepared ahead of time and additional materials are within easy reach. It is important to remember that many chemotherapy agents are dosed using the body surface area method. It is equally important to remember that the m2 charts are used with body weight expressed in kilograms. It is a good practice to have chemotherapy doses determined by two individuals to verify calculations and drug concentrations should be verified to ensure that final drug volumes are appropriate. At times, it is necessary to adjust chemotherapy dosages for individual patients. Doxorubicin and other drugs are sometimes dosed on a mg/kg basis for very small patients. Additionally, dosages should be decreased by 20-25% for those patients who experience side effects of severe GI distress or marked myelosuppression.

Use of premedications varies considerably between those who administer chemotherapeutic drugs routinely. Despite this variation in protocols, there are certain anti-neoplastic agents that always require premedications. It is imperative to administer anti-emetics to dogs prior to use of cisplatin. Butorphanol (0.4 mg/kg SQ or IM 30 minutes before cisplatin) or ondansetron (Zofran, 0.3 mg/kg CRI over 30 minutes just prior to administration of cisplatin) are commonly used for this purpose.

Most chemotherapy drugs have very specific routes of administration and if not properly administered disastrous results may ensue. Complications resulting from extravasation of vesicants, and the requirement for saline diuresis with use of cisplatin are examples. In addition, it important to know the difference in the degree of myelosuppression associated with various routes of administration and dosing schedules of chemotherapy agents. For example, a single subcutaneous dose of cytosine arabinoside will result in less myelosuppression than administration of the same dose as a continuous rate infusion over several hours. In contrast, administration of a single large dose of cyclophosphamide results in a greater degree of myelosuppression than dividing the same dose over several days. Avoid using peripheral veins for phlebotomy when possible. Only highly qualified staff should be responsible for treating chemotherapy patients with drugs that are capable of causing extravasation reactions.

Venipuncture sites should be clipped adequately to allow visualization of the vein and prepared aseptically. Avoid sites of previous venipuncture that have taken place within the prior 24 hours. Aspirate to check for good blood flow and flush the catheter well with at least 5 cc of non-heparinized saline solution prior to administration of the chemotherapeutic drug. After administration of the chemotherapy agent, do not aspirate back into the saline-filled syringe prior to flushing with the saline, as you will contaminate the flush with the chemotherapy drug. Various catheter types are utilized, and are chosen based on the drug to be administered, individual preference level, and patient characteristics. At times it becomes necessary to place venous access ports in order to ensure appropriate administration of intravenous chemotherapy agents. The site of administration should be recorded for each treatment for future reference. 

Histaminic (anaphylactoid) reactions are reported with the use of doxorubicin, L-asparaginase and paclitaxel (Taxol®). This toxicity is rarely observed with use of doxorubicin or L-asparaginase, but prompts some veterinarians to pre-medicate with diphenhydramine (1 mg/kg in cats and 2 mg/kg in dogs SQ or IM 30 minutes prior to administration of chemotherapy drug) and dexamethasone sodium phosphate (dex SP, 0.5 mg/kg IV immediately prior). Pre-medication with these drugs is required when using Taxol due to the high incidence of these reactions, and some oncologists advise administration of oral prednisone the night before treatment in addition to the premedications described above. Histaminic reactions may be characterized by cutaneous erythema, pruritus, wheals, vomiting, vocalization, or cardiovascular collapse (similar in nature and variability to the immune response elicited by bee stings or vaccination reactions). If such a reaction occurs, chemotherapy administration should be discontinued, and treatment with diphenhydramine, dexamethasone SP, +/- epinephrine initiated.

Acute vomiting is a rare side effect unless accompanying a histaminic reaction. One exception is emesis seen routinely following treatment with cisplatin unless pre-treatment with butorphanol or ondansetron is performed as described above. Cimetidine (4 mg/kg IM 30 minutes prior to chemotherapy) is given as an additional premedication when Taxol is administered to avoid vomiting secondary to histaminic gastritis. Other patients may require treatment with anti-emetic medication immediately proceeding or following administration of other anti-neoplastic agents. If a patient has exhibited vomiting as an acute or subacute side effect to drugs such as doxorubicin, administration of metoclopramide immediately preceding chemotherapy and for 1-3 days afterward may be warranted. Some veterinarians advise fasting chemotherapy patients before treatment in an effort to prevent nausea.

Subacute Toxicity

Subacute toxicity syndromes include myelosuppression, gastrointestinal (GI) disturbance, and sterile hemorrhagic cystitis. When highly myelosuppressive agents are administered (usually these drugs are given every 3-4 weeks), a CBC should be obtained at the time of the first expected nadir (usually 10-14 days), to establish the degree of myelosuppression caused by the drug. Subsequent doses should be reduced by 20-25% if the neutrophil count is less than 1000 cells/µl. If the neutrophil count is < 1000 cells/µl, administer prophylactic oral antibiotic therapy (usually trimethoprim-sulfa [22 mg/kg BID] or enrofloxacin [5 mg/kg BID]). Sometimes it is appropriate to instruct the clients to take their dog’s temperature so that they are able to do this at home if the dog feels unwell. If neutropenia and fever or hemorrhagic feces are present simultaneously, then hospitalize the patient for IV antibiotic therapy (cephazolin [22 mg/kg TID-QID], +/- enrofloxacin [5 mg/kg IV SID] +/- metronidazole [7.5-10 mg/kg PO BID]). Intravenous fluids may be administered if GI signs are severe or in an attempt to help diminish a febrile episode; the choice of IV fluids used varies with electrolyte and glucose requirements. Blood glucose levels should be evaluated for suspected septicemic patients. If the patient is suffering from severe lethargy and/or GI distress, a full biochemical profile should be performed to evaluate renal and hepatic function, as well as serum electrolyte levels. Urine should be collected to identify possible UTI and to assess urine specific gravity (prior to initiation of fluid therapy) as a complement to blood urea nitrogen and creatinine to evaluate hydration status and renal function.

Use of granulocyte-colony stimulating factor (hrG-CSF, Neupogen) has become commonplace for neutropenic, febrile patients, though some clinicians reserve this treatment for those cases in which neutrophil rebound does not occur within 24-36 hours, or for those with neutrophil counts less than 500 cells/ul. The dose of hrG-CSF is 5 µg/kg SQ once daily. Daily CBC should be obtained until the neutrophil count is above 2000 cells/ul (usually 1-3 days), at which time treatment with hrG-CSF is discontinued. Occasionally, oncologists will initiate treatment with hrG-CSF at the time of the expected neutrophil nadir if a particularly myelosuppressive chemotherapy protocol is in use. It is important to remember that hrG-CSF should not be administered within the first few days following myelosuppresive therapy as this places stem cells at risk for injury by the chemotherapy agent as they are stimulated to enter the cell cycle.  Neutropenia-associated fever and sepsis is very rare in cats. Chemotherapy-associated anemia is generally mild and self-limiting. Treatment of chemotherapy-induced thrombocytopenia remains supportive in the form of blood transfusions if a bleeding diathesis causes severe anemia. Thrombopoietin (a bone marrow stimulatory factor for platelets) may become commercially available in the future and could prove useful in these patients.

Subacute vomiting is generally mild and self-limiting and the usual recommendations are for fasting or NPO, followed by small, frequent feedings of a bland diet. Use of anti-emetic drugs such as metoclopramide, or chlorpromazine may be initiated for patients with more than one episode of vomiting. It may be necessary to administer these drugs parenterally if the patient is unable to tolerate oral dosing. For refractory cases, butorphanol (0.2-0.4 mg/kg SQ TID-QID) is very effective. Intravenous fluids are required for patients that are intolerant of oral hydration methods. Episodes of diarrhea, and/or hematochezia usually require little more than a bland diet as treatment. For cases that last more than 1-2 days, treatment with loperamide (Imodium A/D®, 0.08-0.2 mg/kg, or 2 mg/25 kg PO q8-12 hours [caution if using for dogs < 10 kg]); 0.08 mg/kg PO q 12-24 hours [cat, with caution]) or diphenoxylate (Lomotil®, 0.05-1.0 mg/kg PO QID [dog]; 0.063 mg/kg or 0.25 mg/cat PO q 8-12 hours [cat]. Sucralfate (Carafate® Ľ gm PO q 8-12 hours) may provide relief from diarrhea in some cats. The diagnosis of sterile hemorrhagic cystitis (SHC) secondary to use of cyclophosphamide is made in the presence of pollakiuria, stranguria, and hematuria without evidence of UTI. This syndrome is generally observed 3-7 days following administration of cyclophosphamide. SHC may occur following the first treatment with cyclophosphamide, or following several doses of the drug. SHC is self-limiting but can be severe and a source of great stress to the patient and the client; cases may last as long as 8-10 weeks in my experience, though most resolve within 1-2 weeks. Attempts at treatment of SHC with corticosteroids and NSAIDS have been generally been unrewarding though there are anecdotal reports of success with anti-spasmodic agents (such as propantheline). It is recommended that a patient with SHC should not be treated with cyclophosphamide (or related agents) again in the future.

Cumulative Or Delayed Toxicity

The classic type of cumulative, delayed toxicity is cardiomyopathy associated with use of doxorubicin. This toxicity is generally avoidable by limiting the lifetime cumulative dose to 180-240 mg/m2 but even with this precaution, cases of cardiomyopathy may occur. Unfortunately, once cardiomyopathy has developed, it is generally irreversible, and fatal congestive heart failure typically ensues within 6 months. Careful pre-screening of patients to rule-out pre-existing myocardial disease is warranted before using doxorubicin. Blood urea nitrogen, creatinine, and urine specific gravity values should be evaluated in these patients prior to each treatment. Chronic use of alkylating agents such as Melphalan and chlorambucil is associated with severe, possibly irreversible myelosuppression, particularly of the platelets. Careful, regular monitoring of trends of peripheral blood cells is vital to prevent such toxicity.

Client Communication

Above all, inform your clients what they may expect and impress upon them the importance of rapid communication with you in the event of ANY and ALL complications, no matter how minor. This information will help you to pre-plan any future treatment adjustments as well as prevent minor complications from becoming major ones. 

CHEMOTHERAPY DOSAGES, INDICATIONS, & ADVERSE REACTIONS

Asparaginase (Elspar)

Dosage:                                   10,000 IU/m2 IM every 1-4weeks

                                                400 IU/kg IM every 1-4weeks

Indications:                             Lymphoma, Leukemia

Adverse Reactions:                 Anaphylaxis

Azothioprine (Immuran)

Dosage:                                   2 mg/kg PO, once daily for 2 weeks; then 0.5 – 1.0 mg/kg PO every 48 hours thereafter

Indications:                             Immune Suppression (IMHA, IMTP, Evan’s Syndrome)

Adverse Reactions:                 Myelosuppression, Nausea

Bleomycin (Bleoxane)

Dosage:                                   2 mg/m2 SQ weekly

Indications:                             Carcinomas, Lymphoma, Leukemias

Adverse Reactions:                 Myelosuppression

Busulfan (Myleran)

Dosage:                                   0.2 mg/kg PO daily

Indications:                             Myeloblastic leukemias

Adverse Reactions:                 Myelosuppression

Carboplatin (Paraplatin)

Dosage:                                   Dogs – 300 mg/m2 IV every 3-4 weeks

                                                Dogs – 90 mg/m2 IV weekly

                                                Cats – 200 mg/m2 IV every 3-4 weeks

Indications:                             Osteosarcoma, Melanoma

Adverse Reactions:                 Myelosuppression, Vomiting

CCNU (Lomustine)

Dosage:                                   60-90 mg/m2 PO every 3 weeks

Indications:                             Relapsed Lymphoma, Mast Cell Tumors, Cutaneous Lymphoma, Mycosis Fungoides

Adverse Reactions:                 Myelosuppression, Vomiting

Chlorambucil (Leukeran)

Dosage:                                   0.2 mg/kg PO daily for 10 days then every 48 hours thereafter

Indications:                             Lymphoma, Leukemias, Soft Tissue Malignancies, Mast Cell Tumors

Adverse Reactions:                 Myelosuppression

Cisplatin (Platinol)

Dosage:                                   70 mg/m2 IV every 3-4 weeks or 30 mg/m2 IV weekly; use a 3-4 hour saline diuresis

Indications:                             Osteosarcoma, Melanoma

Adverse Reactions:                 Myelosuppression, Vomiting, Renal Failure

Cyclophosphamide (Cytoxan)

Dosage:                                   200-350 mg/m2 PO or IV every 1-3 weeks or 50 mg/m2 PO daily for 4 days per week

Indications:                             Lymphoma, Leukemias, Soft Tissue Malignancies

Adverse Reactions:                 Myelosuppression, Hemorrhagic Cystitis

Cyclosporine (Sandimmune)

Dosage:                                   3-10 mg/kg PO daily

Indications:                             Immune Suppression, Atopy

Adverse Reactions:                 Vomiting, Diarrhea, Anorexia

Cytarabine (Cytosar-U)

Dosage:                                   100 mg/m2 SQ TID for 3 days or 10 mg/m2 SQ q12hours until remission occurs

Indications:                             Leukemias

Adverse Reactions:                 Myelosuppression

Dacarbazine (DTIC)

Dosage:                                   200 mg/m2 IV daily for 5 days

Indications:                             Relapse Lymphoma

Adverse Reactions:                 Severe Vomiting, Myelosuppression

Doxorubicin (Adriamycin)

Dosage:                                   > 20 lbs = 30 mg/m2 IV every 2-3 weeks (maximum 5 times)

                                                < 20 lbs = 1 mg/kg IV every 2-3 weeks (maximum 5 time)

Indications:                             Lymphoma, Soft Tissue Tumors

Adverse Reactions:                 Myelosuppression, Anaphylaxis, Vomiting, Cardiomyopathy (do not exceed 180 mg/m2 cumulative administration)

Epirubicin (Pharmorubicin, Ellence)

Dosage:                                   30 mg/m2 IV every 2-3 weeks

Indications:                             Lymphoma, Soft Tissue Malignancies, Carcinomas

Adverse Reactions:                 Myelosuppression, Vomiting, Diarrhea, Acute Hypersensitivity

Fluorouracil (5-FU)

Dosage:                                   50 mg/m2 Intralesionally mixed in sesame oil (10 mg/ml final concentration)

Indications:                             Soft Tissue Malignancies

Adverse Reactions:                 Seizures, Ataxia

Gemcitabine (Gemzar)

Dosage:                                   90-250 mg/m2 IV every 3 weeks

Indications:                             Pancreatic and Hepatocellular Carcinomas

Adverse Reactions:                 Myelosuppression, Vomiting, Anaphylaxis

Hydroxyurea (Hydrea)

Dosage:                                   50 mg/kg PO SID until remission

Indications:                             Leukemias

Adverse Reactions:                 Myelosuppression

Ifosfamide (Ifex)

Dosage:                                   375 mg/m2 diluted to 9.75 mg/kg in saline, IV every 2-3 weeks with concurrent MENSA administration

Indications:                             Soft Tissue Malignancies, Lymphoma, Lung Tumors

Adverse Reactions:                 Hemorrhagic Cystitis (profound), Myelosuppression, Vomiting

Melphalan (Alkeran)

Dosage:                                   0.1 mg/kg PO daily for 10 days then every 48 hours thereafter

Indications:                             Leukemia

Adverse Reactions:                 Myelosuppression

Methotrexate (Methotrexate)

Dosage:                                   0.5 mg/kg IV every 3weeks

Indications:                             Lymphoma, Leukemia

Adverse Reactions:                 Myelosuppression, Vomiting

Mitoxantrone (Novantrone)

Dosage:                                   Dogs – 5-6 mg/m2 IV every 2-3 weeks

                                                Cats – 5-6.5 mg/m2 IV every 3-4 weeks

Indications:                             Lymphoma, Soft Tissue Tumors

Adverse Reactions:                 Myelosuppression, Anaphylaxis, Vomiting

Paclitaxel (Taxol)

Dosage:                                   165 mg/kg, diluted to 0.6 mg/ml in 0.9% saline, given as a continuous IV infusion over at least two hours every 21 days; 5 day premedication with Prednisone, Cimetidine, and Benadryl required.

Indications:                             Lymphoma, Soft Tissue Tumors, Mammary Tumors

Adverse Reactions:                 Anaphylaxis, Vomiting, Diarrhea, Myelosuppression, Alopecia

Piroxicam (Feldene)

Dosage:                                   Dogs – 0.3 mg/kg PO daily or every 48 hours with or without concurrent antacid administration

                                                Cats – 0.3 mg/kg PO every 3-4 days with our without concurrent antacid administration

Indications:                             Transitional Cell Carcinoma, Melanomas, Carcinomas

Adverse Reactions:                 Gastrointestinal Ulceration

Prednisone (Prednisone)

Dosage:                                   40 mg/m2 PO divided BID, SID, or every 48 hours

Indications:                             Lymphomas, Leukemias, Insulinomas

Adverse Reactions:                 Polyuria, Polydypsia

Streptozotocin (Zanosar)

Dosage:                                   500 mg/m2 IV every 3 weeks with concurrent 3 hour saline diuresis

Indications:                             Insulinomas

Adverse Reactions:                 Nephrotoxicity

Tamoxifen (Nolvadex)

Dosage:                                   2.5 – 10 mg PO BID

Indications:                             Mammary Tumors, Brain Tumors, Anticancer Drug Resistant Tumors, Melanomas

Adverse Reactions:                 Vaginal Discharge, Pyometra

Vinblastine (Velban)

Dosage:                                   2 mg/m2 IV slowly every 1-3 weeks

Indications:                             Lymphoma, Leukemias, Mast Cell Tumors, Soft Tissue Tumors

Adverse Reactions:                 Myelosuppression

Vincristine (Oncovin)

Dosage:                                   0.5-0.75 mg/m2 IV every 1-3 weeks

Indications:                             Lymphoma, Leukemias, Mast Cell Tumors, Soft Tissue Tumors

Adverse Reactions:                 Myelosuppression

 

CHEMOTHERAPY DOSAGE CONVERSION CHART

The following values are derived from the equation: m2 = 10.0 (10.1 in cats) x (weight in grams)2/3 / 10000.  Always confirm all dosage calculations before drug admixing and administration! In the chart below, the first column is body weight in kilograms, the second column is body weight in pounds, and the third column is the calculated value in body surface area (in squared meters).

Kg

Lb

m2

Kg

Lb

m2

0.50

1.1

0.06

33

72.6

1.03

1

2.2

0.10

34

74.8

1.05

2

4.4

0.15

35

77.0

1.07

3

6.6

0.20

36

79.2

1.09

4

8.8

0.25

37

81.4

1.11

5

11.0

0.29

38

83.6

1.13

6

13.2

0.33

39

85.8

1.15

7

15.4

0.36

40

88.0

1.17

8

17.6

0.40

41

90.2

1.19

9

19.8

0.43

42

92.4

1.21

10

22.0

0.46

43

94.6

1.23

11

24.2

0.49

44

96.8

1.25

12

26.4

0.52

45

99.0

1.26

13

28.6

0.55

46

101.2

1.28

14

30.8

0.58

47

103.4

1.30

15

33.0

0.60

48

105.6

1.32

16

35.2

0.63

49

107.8

1.34

17

37.4

0.66

50

110.0

1.36

18

39.6

0.69

52

112.2

1.41

19

41.8

0.71

54

114.4

1.44

20

44.0

0.74

56

116.6

1.48

21

46.2

0.76

58

118.8

1.51

22

48.4

0.78

60

121.0

1.55

23

50.6

0.81

62

123.2

1.58

24

52.8

0.83

64

125.4

1.62

25

55.0

0.85

66

127.6

1.65

26

57.2

0.88

68

129.8

1.68

27

59.4

0.90

70

132.0

1.72

28

61.6

0.92

72

134.2

1.75

29

63.8

0.94

74

136.4

1.78

30

66.0

0.96

76

138.6

1.81

31

68.2

0.99

78

140.8

1.84

32

70.4

1.01

80

143.0

1.88

 

Drs. King, Hahn, Freeman, Turner and Carreras are available to consult with your veterinarian on oncology (cancer) cases, or cases where cancer is suspected as the diagnosis.

Please call if we can help:
Phone:
  713-693-1166
Fax:    
713-693-1167

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