Angela E. Frimberger, VMD, DACVIM (Oncology)
Although most tumour cells are in active phases of the cell cycle and susceptible to chemotherapy, most normal cells are not. Chemotherapy toxicity is most common in renewing tissues - haematopoietic cells, mucosa, epidermis, gametes, and foetal tissues. This is important for both patient side effects and for client and practice staff safety.
Many clients are concerned about side effects in their pets. Taking a proactive approach is important in both preventing side effects and managing them when they occur. The first step in preventing chemotherapy side effects is careful dosing, discussed in Part 1. Prophylactic measures prevent many side effects. When side effects occur, they usually resolve with supportive care; and dose reductions in future cycles of the same treatment will usually avoid repeat occurrences.
Myelosuppression is bone marrow toxicity. The nadir of peripheral counts occurs about 5–10 days post-treatment. Haematopoietic stem cells are also largely non-proliferating and so are relatively chemoresistant, but are stimulated to divide by myelosuppression; so further chemotherapy during this time can cause stem cell destruction. The usual interval between myelosuppressive drug administrations is every 2 to 3 weeks, but some drugs may have delayed or prolonged nadirs, and their intertreatment intervals are longer.
A complete blood count (CBC) including platelet count should be checked at the expected neutrophil nadir, usually 7 days after administration. The absolute neutrophil count (not the percentage, or the total leukocyte count) should be evaluated. A count of < 1.0 x 109/L indicates dose reduction of that myelosuppressive drug by 25% even if no complications occur.
In addition, a CBC should be evaluated immediately prior to each potentially myelosuppressive chemotherapy, and treatment delayed if the neutrophil count is < 3.0 x 109/L.
Neutropenia itself is asymptomatic and poses no quality of life problem. The potential complication of concern is sepsis / febrile neutropenia, as this is potentially life-threatening if untreated. Nonetheless, most neutropenia in veterinary chemotherapy patients is self-limiting and uncomplicated. Giving prophylactic antibiotics after the first administration of a potentially myelosuppressive treatment (and with every doxorubicin) reduces the risk further. However animals with an absolute neutrophil count of < 1.0 x 109/L are considered at risk and these animals should be treated aggressively if signs occur. A fever or any other sign of sepsis after chemotherapy should be treated as an emergency and the veterinarian should provide aggressive support including intravenous fluids and parenteral broad-spectrum antibiotics.
Thrombocytopenia rarely causes clinical signs, however at counts of < 50 x 109/L the risk of bleeding increases. Myelosuppressive chemotherapy should not be administered if the platelet count is < 100 x 109/L.
Gastrointestinal toxicity may cause inappetance, nausea, vomiting or diarrhoea, with management depending on the severity of signs. Significant vomiting requires hospitalization for supportive care, but mild nausea can usually be managed at home with antiemetics. Significant vomiting is not acceptable and is largely preventable. Mild diarrhoea is usually manageable with dietary modifications but severe or haemorrhagic diarrhoea may require hospitalization for supportive care.
Cardiotoxicity in veterinary oncology is only a clinical problem for dogs receiving doxorubicin. Chronic cardiotoxicity is related to lifetime cumulative dose of doxorubicin, and the end result resembles dilated cardiomyopathy. Cardiotoxicity is most frequent above 180 mg/m2, and doxorubicin should not be given above this level without extreme caution and careful consideration of relative risks. Breeds susceptible to dilated cardiomyopathy, particularly Dobermans, are more sensitive to this toxicity and some clinicians will not administer doxorubicin to these dogs even with pre-screening.
Nephrotoxicity is the primary dose-limiting toxicity of cisplatin. It is partially ameliorated by administering with appropriate diuresis. Cisplatin should not be administered if the serum creatinine is above the normal range or the dog is otherwise at risk for renal disease (and should never be administered to cats under any circumstances).
Doxorubicin has been associated with cumulative nephrotoxicity in cats and should not be administered to cats with pre-existing renal disease. It is important to check the serum creatinine level before each doxorubicin treatment in cats.
Urothelial toxicity (sterile hemorrhagic cystitis) is mainly associated with cyclophosphamide administration. Clinical signs vary in severity but can be severe and prolonged. Secondary urinary tract infection can occur, so culture and sensitivity should be performed.
Hypersensitivity reactions may occur during rapid doxorubicin administration, but rarely if the drug is given over 15 to 20 minutes. True anaphylaxis may follow L-asparaginase administration, but very rarely following intramuscular or subcutaneous administration. If anaphylaxis occurs, treatment with corticosteroids and antihistamines plus other supportive measures as necessary should be instituted immediately, and the patient should never receive further L-asparaginase.
Safe Chemotherapy Handling
Most chemotherapeutic agents are both toxic and mutagenic. Alkylating agents have been associated with the highest risks to handlers. Organ damage and increased risk of fetal loss have been reported in persons handling and administering chemotherapy with inadequate attention to personal safety.1
In the US, the Occupational Safety and Health Administration (OSHA) published guidelines describing the equipment, garments, and work practices needed to protect pharmacists and nurses from exposure to cytotoxic agents in 1986.2 However further have shown that even following those guidelines and using biological safety cabinets, drug residues on work surfaces remain a potential significant source of worker exposure3 and 1 review found that despite the use of precautions cyclophosphamide was present in the urine of health care workers in 11 of 12 studies4.
Regulatory guidelines for employers whose workers are handling hazardous drugs including cytotoxic chemotherapeutics have been discussed and determined to some extent around the world, however in large part they are not legally binding. Overall, precautions are similar in any geographic location, but veterinarians are encouraged to check the specific guidelines and regulations for their location to ensure they are in compliance with any relevant regulations.
In the US, the relevant regulatory instruction is found in the OSHA Technical Manual, Section VI: Health-Care Facilities, Chapter 2. Controlling Occupational Exposure to Hazardous Drugs; which can be found online at: www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html #5. While the OSHA guidelines are not in themselves law, they can be enforced under the general duty clause in the Code of Federal Regulations (CFR) which requires that employers provide a safe or healthful employment and places of employment, should OSHA be called in investigate a complaint. In addition, the Hazard Communication Standard is a federal regulation that requires employers to inform employees of the risks of all hazardous materials in their workplace; and the Access to Employee Exposure and Medical Records standard requires that employees who work with toxic substances have access to workplace monitoring records as well as their employee medical records. Additional very useful and more recent, voluntary, guidelines are in NIOSH Publication No. 2004-165: Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings (www.cdc.gov/niosh/docs/2004-165/). While other specific requirements may exist, the OSHA and NOSH publications can also provide useful guidance for veterinary practitioners in other countries.
In addition, any cytotoxic-contaminated waste must be disposed of according to any regulations. In the US, the Environmental Protection Agency (EPA) regulates the management of hazardous wastes, including several chemotherapy drugs according to the Resource Conservation and Recovery Act (RCRA). Two relevant EPA publications are Managing Hazardous Waste: A Guide for Small Businesses [EPA 2001] and RCRA Hazardous Waste Regulations [40 CFR Parts 260–279].
Safe Chemotherapy handling
There are 3 basic systems for safe chemotherapy handling:
1. The traditional gold standard is to use a vertical laminar flow biological safety cabinet (BSC). However, BSCs should not be relied on solely. "Chemo-pins" (or the PhaSeal system) (both below) are used for preparing injectable chemotherapeutics in the hood; and a disposable gown with closed-cuff sleeves and chemotherapy gloves should be worn.
2. A newer approach that appears to offer equivalent or better safety and better convenience is to use a closed system drug transfer device, as suggested by the NIOSH guidelines 2004. Several commercial systems are on the market but the best developed and documented is the PhaSeal system, a component-based closed system drug transfer device that mechanically prohibits the escape of drug aerosols.4-6
3. A third option is to work in a low traffic area using eye shield, respirator mask, disposable gown with closed-cuff sleeves and gloves for preparation and administration. When preparing injectable chemotherapeutics, "Chemo Dispensing Pin" hydrophobic filters that insert into drug vials should be used to prevent aerosolisation. This option is only appropriate when chemotherapy is used very infrequently.
Chemotherapy can be performed successfully in veterinary private practice. Achieving this requires careful attention to prevention and management of side effects in patients, and specific safety procedures for staff and clients.7
1. Polovich M. Online J Iss Nurs 2004;9:5.E-pub.
2. McDevitt JJ, et al. J Occup Med 1993;35:57.
3. Sessink PJM, et al. Drug Safety 1999;20:347.
4. Harrison BR, et al. Am J Health Syst Pharm 2006;63:1736.
5. Sessink PJ, et al. J Oncol Pharm Pract 2010;Epub ahead of print
6. Siderov J, et al. J Oncol Pharm Pract 2010;Epub ahead of print.
7. Frimberger A, Moore A. Chemotherapy preparation & administration safety issues in veterinary medicine. The Veterinarian March 2011.