The use of chemotherapy drugs in practice (Proceedings)

Chemotherapy is an essential component in the treatment of cancer patients. Clients are always somewhat reluctance to treat pets with chemotherapy because of the horror stories that circulate about the use of chemotherapy in people. The clients need to be reassured that quality of life is the major concern in veterinary oncology and that most protocols used produce acceptable toxicity for a short period of time after treatment. For conditions such as lymphoma there are well-established protocols that will produce good quality of life for a year or more. After informing the client about expected duration of remission, toxic effects and cost an informed decision can be made about chemotherapy.

A major concern about chemotherapy in practice is the safety of the clinician and the staff. Many of the chemotherapy drugs are carcinogenic and teratogenic which creates significant liability problems. All personnel involved with chemotherapy need to be aware of potential hazards and be trained to handle the drugs safely. Pregnant women should not be handling chemotherapy drugs. Chemotherapy can be safely done without a biological safety cabinet when only a few chemotherapies a week are done. Most exposure to chemotherapy drugs is by inhalation of aerosolized drug, absorption of drug through the skin or ingestion of the drug. The chemotherapy drugs should be mixed in a quiet area free of draft. There should be no eating or drinking allowed in the room and refrigerators used for chemotherapy drugs should not be used for food storage. Latex gloves and impermeable gowns should be worn when mixing or administering drugs to avoid skin contamination. Hands should be washed thoroughly before eating or smoking. When mixing drugs outside of a safety cabinet, goggles should be worn to avoid eye exposure. An industrial type mist and dust respirator can be used to further reduce potential inhalation. To prevent inhalation, tablets such as cyclophosphamide, CytoxanR should not be split. Removing air from a syringe containing a chemotherapy drug has the potential to aerosolize the drug. Only Luer-lok syringes should be used for chemotherapy to avoid the needle coming off the syringe during administration. Chemotherapy safety pins are very useful to remove drugs safety from vials. The Chemo Dispensing Pins can be obtained from B. Braun Medical in Bethelehem, PA 18018. When drugs are mixed, the vials need to be de-pressurized before the needle is removed. Excess air in the syringe can be expelled into an alcohol soaked cotton ball to avoid aerosolization. Drugs should be carried in plastic zip-lock type bags and used syringes; empty vials and gloves should be put into special chemotherapy disposal containers. The mixing of drugs should be done on a plastic backed, absorbant pad. Most of the necessary safety equipment can be purchased from Chemo Safety Systems, 8380 Camino Santa Fe, San Diego, CA 92121. Stool and urine from treated dogs should be considered contaminated and handled with gloves. When the routine is established and the equipment is available, the administration of chemotherapy becomes a comfortable and safe procedure.

Chemotherapy is used mainly in systemic tumors such as lymphomas and multiple myelomas. Chemotherapy can also be used in an adjuvant mode in dogs with hemangiosarcomas and osteosarcomas after splenectomy or amputation. In over 90% of these dogs, there will be metastases even though no evidence of tumor was seen at the time of surgery. Chemotherapy can be used in a neoadjuvant manner in tumors such as vaccine induced sarcomas to try to reduce the size of the tumor to allow curative surgery. Chemotherapy can also be used to try to reduce tumor growth in tumors that are not operable or treatable with radiation therapy. This treatment is not expected to cure the animal but only to improve the quality of life and prolong survival time.

There are a number of chemotherapy principles that guide the use of these drugs. Chemotherapy is most effective in fast replicating cells. Large tumors that have hypoxic centers and many cells in a resting phase are unlikely to respond well to chemotherapy. Normal tissues such as bone marrow and intestinal epithelium have fast replicating cells that are killed by chemotherapy drugs. This produces neutropenia and thrombocytopenia as well as anorexia, nausea, vomiting and diarrhea after some chemotherapy drugs.

Chemotherapy drugs are given at the maximum tolerated dose to achieve the best response without producing excessive toxicity. Some toxicity is expected which indicates that you are giving the maximal tolerated dose. There is a very narrow margin between toxic doses and therapeutic doses therefore drug doses should be calculated carefully and the dose recheck if you are not routinely using a drug. Route of excretion or metabolism of the drug must be considered. Doses of carboplatin must be reduced in animals with renal dysfunction because of its renal excretion. Doxorubicin and vincristine doses must be reduced in patients with significant hepatic disease.

Combinations of chemotherapy drugs that destroy cells through different mechanisms are generally more effective that single agent therapy. Drugs that have different toxicity are advantageous in that the toxic effects are reduced while the drugs are still effective against the tumor. Some drugs such as doxorubicin are very effective as a single drug because they kill tumor cells through different mechanisms.

The most commonly used chemotherapy drugs are: doxorubicin, vincristine, cyclophosphamide, l-asparaginase, cisplatin and carboplatin. There are many chemotherapy protocols that utilize these drugs.

Doxorubicin has a broad spectrum of activity against lymphomas, sarcomas and some carcinomas. It is very caustic outside the vein and must be given intravenously through a catheter. The dose in dogs over 25 pounds is 30mg/M2 and 1 mg/kg in small dogs and cats. Because of allergic reactions, premedicate with antihistamines. It is given every three weeks if the hemogram is acceptable. I feel comfortable if the neutrophil count is above 3,500 cells/uL and there are at least 150,000 platelets. If blood values are too low, delay chemotherapy for 4-7 days to allow bone marrow rebound. Gastrointestinal toxicity is seen in the first 3 or 4 days and neutropenia at 7 to 9 days after treatment. In dogs, cumulative doses above 180 mg/M2 are likely to produce cardiomyopathy. Dosing large dogs every 2 weeks rather than every 3 weeks enhances the likelihood of cardiomyopathy. Certain breeds of dogs have mutations in the multiple drug resistance (MDR) gene. This is the same abnormality that causes severe adverse responses to ivermectin. Collies and Shelties need to be tested for MDR abnormalities before giving them either doxorubicin or vincristine.

Vincristine is a very useful drug because it produces minimal bone marrow suppression or gastrointestinal toxicity. It is included in most lymphoma protocols. It is also caustic outside the vein. Vincristine can be given to dogs at 0.7mg/M2 and to cats at 0.5 mg/M2. It is helpful in the treatment of immune mediated thrombocytopenia.

Cyclophosphamide is an old drug that remains a part of many chemotherapy protocols. It can be given orally or intravenously. It is usually used in combination with other drugs. It is an alkylating agent that needs to be handled carefully. It is bone marrow suppressive and can produce a hemorrhagic cystitis.

L-asparaginase is an enzyme that destroys the amino acid asparagine that is necessary for some lymphoma cells but normal cells can manufacture their own asparagine. This gives the drug a special advantage because it is not toxic to the bone marrow or the intestinal tract. It can cause anaphylactic reactions and has been linked to some cases of pancreatitis. Intramuscular administration greatly reduces the likelihood of anaphylaxis but premedicate with antihistamines.

The platinum compounds, cisplatin and carboplatin are effective drugs in the treatment of osteosarcoma and some carcinomas. Cisplatin is nephrotoxic and causes vomiting at the time of administration. Fluid diuresis must be done with cisplatin to avoid serious renal damage. Because of these problems and the reduced price of carboplatin, carboplatin has become the drug of choice in the platinum group. Carboplatin has much less renal toxicity but it can produce bone marrow suppression.

These drugs are generally well tolerated but life-threatening neutropenia can occur with most of the chemotherapy agents. Neutrophil counts below 1,000 cells/UL will allow entry of bacteria from the gut, skin and mouth into the circulation causing a septicemia. The neutropenia usually resolves in 48 hours. Intravenous electrolyte solutions to maintain hydration and broad-spectrum bacteriocidal antibiotics given for 5 days are usually adequate to treat the septicemia. The animal must have good supportive care until the septicemia resolves.

The small animal clinician can treat many of the common cancer patients. There is little treatment information about many of the less common tumors and these tumors need to be referred to an oncologist.