Introduction

Chemotherapy is a common treatment modality used in veterinary oncology. Whether used alone or as an adjuvant to surgery or radiation, new drugs, combinations of drugs, or methods of delivery are constantly being explored. In order to successfully use chemotherapy, the clinician must be aware of some basic principles, common potential side effects, and the unique side effects that might occur due to usage of certain drugs. This handout will discuss some basic principles of chemotherapy use, common side effects, and specific drugs commonly used in veterinary medicine for the treatment of cancer.

Indications and uses

Chemotherapy is indicated for a wide variety of hematologic malignancies such as leukemia, lymphoma, pulmonary lymphatoid granulomatosis, and multiple myeloma, as well as highly metastatic malignancies such as osteosarcoma, hemangiosarcoma, transitional cell carcinoma, squamous cell carcinoma, and some mammary gland tumors. Chemotherapy is used to induce remission in hematologic malignancies and maintenance therapy is sometimes recommended. When chemotherapy is used against solid tumors such as osteosarcoma, it is often used in an adjuvant setting after surgery and no maintenance therapy is given.

Principles

Single vs. multiple drugs

The advantages of using single agent treatment are decreased cost, decreased risk of toxicity, and decreased time in hospital. The disadvantages of single drug regimes are less efficacy and possible induction of drug resistance. Multiple drug chemotherapy protocols have the clear advantage of greater efficacy, and drug resistance is slower to develop. The disadvantage of using multiple drug protocols is increased cost, increased risk of toxicity, and increase time spent at the vet. When using multiple drug protocols several “rules” should be followed. Each drug should have some efficacy alone against the tumor targeted. Overlapping toxicities should be avoided or drugs scheduled to compensate for this. Maximal doses should be used when possible. Drugs with different mechanisms of action against neoplastic cells should be combined to maximize cell kill.

Dosing

The dose of any drug used should be the maximum dose possible without causing unacceptable toxicity. Chemotherapy drugs are often dosed on the basis of body surface area (mg/m²), however by using this dosage scheme smaller animals often receive a higher dose than larger animals. This may lead to increased toxicity, though possible increased efficacy as well. The way drugs are metabolized and excreted from the body must also be taken into account as compromised organ function of the liver or kidneys may lead to increased toxicity of certain drugs. An example of this is cyclophosphamide which must be metabolized in the liver in order to be active. Another example is the potential nephrotoxicity of cisplatin indicates that this drug should be avoided in animals with kidney problems.

Timing

The timing of administration of chemotherapy drugs is very important. Ideally drugs should be given to allow for maximum tumor cell death but adequate normal cell recovery (bone marrow, GI tract). The efficacy of a drug is related to the length of time a cell is exposed to the drug, while the toxicity is related to the peak serum concentration. Alternate delivery methods are being devised to increase the time a cell is exposed to a drug and lessen the peak concentrations. Examples of this include sustained release polymer delivery systems, and liposomal encapsulated drugs. Other methods of delivery like intra cavitary or intratumoral administration are designed to give higher concentrations to the tumor cells while decreasing systemic exposure and toxicity.

Resistance

Drug resistance is the reason for ultimate treatment failure and death from disease in most cases of cancer treated with chemotherapy. There are several mechanisms of drug resistance including decreased uptake of drug, altered affinity of drug for the target, increased inactivation of the drug by the body, and increased removal of the drug from the cell. This last mechanism is mediated by p-glycoprotein which is a “pump” that is present on the surface of cells and can actively pump drug out of the cell before it has a chance to do any damage. Methods of blocking this pump are being studied.

Toxicity

Bone Marrow

Neutropenia and thrombocytopenia are the major bone marrow toxicities caused by chemotherapy drugs. Anemia can also occur but is usually slower to develop due to the longer life span of the RBC. Before myelosuppressive chemotherapy agents are given, a CBC should be done to ensure adequate numbers of neutrophils and platelets are present. As a safety margin a good rule of thumb is to have 3000 neutrophils and 100,000 platelets present prior to giving any myelosuppressive drugs. The nadir of a particular drug is when the neutrophil counts are at their lowest and is often 7–10 days after administration, however can be prolonged with certain drugs. Possible life-threatening consequences of bone marrow suppression are sepsis, pneumonia, and bleeding problems. Treatment for chemotherapy induced bone marrow suppression is only given if the animals are clinical for the problem, as most counts will return to normal within a few days. If treatment is necessary, supportive care and antibiotic therapy are often necessary to combat sepsis. Human recombinant colony stimulating factors (GCSF, GMCSF) can be effectively used to increase cell counts. These drugs work well however have the disadvantage of being expensive and human derived, so development of antibodies against them can occur. If significant bone marrow toxicity occurs after chemotherapy administration, the drug dose is usually reduced prior to the next treatment.

Gastrointestinal

Vomiting and diarrhea are the most common GI toxicities seen with chemotherapy. Vomiting occurs due to stimulation of receptors in the chemoreceptor trigger zone (CRTZ) of the brain or by stimulation of the gut enterochromaffin cells. In veterinary patients, vomiting is usually delayed (with the exception of cisplatin) and usually occurs several days after administration of the drug. Antiemetics commonly used in veterinary medicine include metaclopramide, or the serotonin receptor antagonists ondansetron (Zofran) or dolasatron which work very well for chemotherapy induced emesis. Diarrhea can be either small or large bowel, which can include hemorrhagic colitis. Drugs used to combat diarrhea include sulfasalazine and tylosin. Glutamine, an amino acid used preferentially by the gut can also be given to promote GI health and healing.

Allergic reactions

This can occur as a response to the drug itself or the carrier the drug is mixed in. It usually occurs during the time of administration or shortly thereafter and is treated as any other allergic reaction would be. If the patient is still receiving the drug, it is temporarily discontinued and antihistamines with or without steroids are given, as well as any other indicated supported measures such as fluid therapy if anaphylaxis occurs. If the reaction is controlled, drug administration can be reinstituted with careful monitoring and generally is at a slower rate. Drugs associated with allergic reactions include L’asparaginase, doxorubicin, and taxol.

Cardiac

This is a dose dependant, cumulative toxicity that causes damage to the heart muscle and leads to dilated cardiomyopathy. Doxorubicin is the drug most commonly associated with this side effects, as well as less common anthracycline agents, and cumulative doses of 180 to 220 mg/m2 of doxorubicin are felt to be safe. The cat is not as susceptible to this toxicity. Certain factors such as age, preexisting heart disease, and previous radiation are known risk factors to developing chemotherapy induced cardiotoxicity. The first sign of cardiac toxicity is often arrhythmias or tachycardia.

Extravasation

Local skin reactions and cellulitis can occur if some drugs get out of the vein during administration. This reaction can range from mild to severe with resultant full thickness ulceration. Drugs commonly used in veterinary medicine known to cause extravasation reactions include doxorubicin and vincristine. Extravasation can result in nonhealing wounds that have even resulted in the loss of the limb in both people and animals. It can take up to a few weeks to see the full extent of the tissue damage. If drug is known to escape the vein, first withdraw as much as possible from the area, then apply ice for doxorubicin (do not infiltrate the area) or for vincristine, infiltrate the area with saline and apply warmth.

Cystitis

Cyclophosphamide can cause a sterile hemorrhagic cystitis due to irritation of the bladder by the metabolites (primarily acrolein) of the drug. If it occurs the drug must be discontinued. The risk of this side effect can be lessened by ensuring adequate hydration and allowing animals ample opportunity to empty the bladder after cyclophosphamide is given. If cystitis occurs antiinflammatories such as piroxicam can be used to lessen the effect. Most cases resolve within 4–6 weeks.

Alopecia

hair loss associated with chemotherapy is rare and breed dependant, however regrowth of hair previously shaved from surgical sites can be slow. Breeds susceptible to alopecia include poodles, Old English sheep dogs and some terriers. Cats can loose facial whiskers.

Drugs

Cyclophosphamide (Cytoxan)

 IV, oral

 200–250 mg/m² q 3 weeks

 Bone marrow suppressions, alopecia, GI toxicity

 Cystitis (sterile, hemorrhagic)

 LSA, MGT, MCT, sarcomas

Chlorambucil (Leukeran)

 Oral

 2–8mg/m² daily to every other day

 slow onset of action

 bone marrow suppression

 LSA, CLL, MCT

Melphalan (Alkeran)

 Oral, (IV in humans)

 Several dose schemes used

 0.05mg/kg to 0.1mg/kg orally daily until remission then every other day

 bone marrow suppression

 multiple myeloma

Lomustine (CCNU)

 Oral

 80mg/m² q three weeks

 bone marrow suppression

 LSA, MCT

Cytosine arabinoside (Ara-C)

 IV, SQ – short half life, given CRI or pulsed

 Several dose schemes used

 600mg/m² divided, given q 12 hours for 4 doses, q 3 weeks,

 600mg/m² given as CRI for 48 hours

 10mg/m² SQ daily

 Crosses blood brain barrier

 Bone marrow suppression, alopecia, GI toxicity

 LSA, GME

Doxorubicin (Adriamycin)

 IV

 30mg/m², 1mg/kg if less than 10 kg q 3 weeks

 bone marrow suppression, alopecia, GI (colitis)

 cardiotoxicity (dogs), renal (cats)

 LSA, OA, HAS, sarcomas, MGT, thyroid

Mitoxantrone (Novantrone)

 IV

 5.5mg/m² dog, 6.5 mg/m² cat, q 3 weeks

 bone marrow suppression, alopecia, GI

 LSA, TCC, SCC

Actinomycin D (Dactinomycin,)

 IV

 0.7–1mg/m² q 3 weeks

 bone marrow suppression, alopecia, GI

 LSA, sarcomas

Vincristine (Oncovin)

 IV

 0.5–0.75mg/m² weekly for induction then as protocol dictates

 alopecia, GI, minimal bone marrow suppression

 peripheral neuropathy

 LSA, TVT, leukemias

Vinblastine (Velbane)

 IV

 2mg/m² weekly

 bone marrow suppression, alopecia, GI

 peripheral neuropathy

 LSA, MCT

L’asparaginase

 IM, IP, SQ

 10,000 IU/m², weekly

 anaphylaxis, pancreatitis, DIC

 LSA, MCT

Cisplatin

 IV, intracavitary

 50–70mg/m², q 3 weeks

 bone marrow suppression, alopecia, GI

 nephrotoxicity

 pulmonary in cats (FATAL, do not use)

 OSA, TCC, nasal, SCC, testicular, ovarian

Carboplatin

 IV

 300mg/m² dogs, 180–200 mg/m² cats

 bone marrow suppression, alopecia, GI,

 minimal renal toxicity

 OSA, TCC, carcinomas