"All things are poison. Nothing is without poison. Only the dose permits something not to be a poison." Taracelsus (1493–1541)
Chemotherapy can be a poison. After chemotherapy is given, normal cells often would receive various degrees of damage from the cytotoxic agents. Therefore, one should know how to manage common side effects associated with chemotherapy when using these drugs.
Most chemotherapeutic agents will unselectively cause damage to the rapidly growing/dividing cells such as cells in the bone marrow, the gastrointestinal epithelial cells and hair follicle cells, whereas cells with slower turnover (e.g., spinal cord, muscle and more) are generally very resistant to most chemotherapeutic drugs.
Practitioners must keep in mind that most side effects of chemotherapy are self-limiting and resolve with minimal veterinary intervention. However, some toxicity needs to be addressed immediately in order to maintain patient quality of life (QOL) and client's motivation to keep treating their animals with cancer. In this lecture, the mechanisms and the managements of the following chemotherapy-induced side effects will be discussed.
1. Bone Marrow Suppression
Many antitumor drugs cause a decrease in the number of peripheral blood cells days to weeks after administration. Neutropenia and thrombocytopenia are the early signs of bone marrow suppression. Anemia may develop later because red blood cells have a longer life span, hence longer cell turnover.
Most dogs and cats have a low risk of infection if their neutrophils count remains > 1,500/μl. It is important to remember that treatment decisions should be made based on absolute neutrophil count, not total while blood cell count. A neutrophil nadir in dogs is most commonly seen 5–10 days (14 days for carboplatin) after the administration of most chemotherapeutic agents.
Bright and alert animals without fever and with neutropenia can usually be managed as outpatients. Treatment may be a 5–7 day course of a broad-spectrum oral prophylactic antibiotic such as cephalosporin (25 mg/kg PO TID) or enrofloxacin (5 mg/kg PO q24h). We usually instruct the owner to monitor the patient's TPR twice daily at home and to call our hospital if the temperature exceeds 39.2°C.
Febrile or systemically ill patients should be hospitalized for 24-h observation and care. Intravenous fluid therapy and intravenous antibiotic treatment are the treatment of choice for these animals. Intravenous coverage for both gram-positive and gram-negative bacteria should be used.
2. Gastrointestinal (GI) Toxicity
Most commonly, gastrointestinal side effects are delayed, usually 2–5 days following chemotherapy administration. Clinical signs can range from mild loss of appetite and slightly soft feces to severe vomiting or large amounts of watery or bloody diarrhea. Many animals with mild signs would respond to symptomatic treatment including brief withholding of food and water followed by a bland, high-fiber diet over a short period of time. Antiemetic medications such as metoclopramide (0.2–0.4 mg/kg q6–8h PO, SC or IM or CRI as 1–2 mg/kg/day), ondansetron (0.1–0.2 mg/kg q8–12h), or maropitant (1–2 mg/kg q24h) can be administered orally if patients are bright and alert or parentally if they are not able to take oral medications. Oral medications for diarrhea such as loperamide, metronidazole, and/or tylosin may be prescribed as well. Dehydrated, weak and/or lethargic animals should be hospitalized for intravenous fluid therapy. These animals should be kept without food and water until vomiting resolves, and parental antinausea medications can be administered. If animals have no vomiting for 12–24 hours, small amount of water followed by bland diet can be started. It takes 24–72 hours for the intestinal cells to regenerate and usually their clinical signs should be resolved within that period. When vomiting persists longer than 72 hours, clinicians should look for other causes such as pancreatitis, foreign body, or tumor spread to the digestive tract.
3. Extravasation
Several chemotherapeutic drugs including doxorubicin, vincristine, and vinblastine can cause tissue damage if extravasation occurs. Administration of these drugs needs to be given with perfectly placed intravenous catheter. Patients undergoing infusions of these tissue-irritant agents should be constantly monitored until completion of the infusion to ensure that the catheter remains functional and in place.
If doxorubicin has been extravasated:
1. Stop the delivery
2. Aspirate back through the catheter as much drug as possible
3. Remove the catheter
4. Apply cold pack for 10 minutes every 60 minutes for the first 24 hours
5. Consider surgical treatment including immediate surgical removal of the affected tissue. Dexrazoxane (Zinecard, Pfizer), a free-radical-scavenging drug, may help minimize doxorubicin tissue damage. Intravenous administration of dexrazoxane at 10 times the dose of doxorubicin within 3 hours, and repeated 24 hours after extravasation, may significantly reduce local tissue injury.
4. Cystitis
Cyclophosphamide and ifosfamide have been reported to cause sterile chemical cystitis in dogs. Clinical signs include stranguria, hematuria, and dysuria. Both drugs, metabolized to their active forms as well as to compounds, can cause urothelial damage (acrolein) in the liver. Since prolonged contact time between the bladder wall and acrolein results in hemorrhagic cystitis, it is important for the dogs to void urine as much as possible. Cyclophosphamide should preferably be administered in the morning rather than late in the day to allow dogs a maximum opportunity to urinate during the day. Furosemide given as a single dose (2 mg/kg PO) at the time of cyclophosphamide administration or MESNA, a drug binding to acrolein in urine and avoiding the toxicity, can be used to prevent these side effects, although MESNA usually limits its use to dogs receiving ifosfamide due to high cost and the complicated protocol. Treatments of cystitis include 1. discontinuing cyclophosphamide and replacing with chlorambucil, 2. managing secondary infections with appropriate antibiotics, and 3. decreasing discomfort associated the cystitis with NSAIDs such as piroxicam (0.3 mg/kg PO q24–48h) if renal function is normal. Most cases resolve with time, but may take several weeks to months to subside.
5. Hypersensitivity
L-asparaginase can result in severe anaphylaxis, usually within 60 minutes of administration. Therefore, animals should be monitored in the hospital for signs of anaphylaxis for 60 minutes following drug administration. The likelihood of these reactions increases with multiple L-asparaginase injections. Clinical signs include facial swelling; development of hives; and, occasionally, severe, acute collapse.
If a mild or moderate hypersensitivity reaction occurs, administer diphenhydramine (3–4 mg/kg IM) and dexamethasone (0.5–1.0 mg/kg IV). For very severe, life-threatening hypersensitivity reactions, epinephrine (0.001–0.01 mg/kg IV) may need to be administered.
6. Cardiac Toxicity Associated with Doxorubicin
Doxorubicin has been reported to induce dose-dependent dilated cardiomyopathy and transient dysrhythmias during administration in dogs. For this reason, it is important to limit the cumulative dose of doxorubicin to 180 mg/m2 (6 treatments if doxorubicin given at 30 mg/m2) during a dog's lifetime. Routine echocardiograms and electrocardiograms should be conducted on dogs, where we usually measure a fractional shortening (FS) by echocardiograms prior to the 1st doxorubicin (base line), 4th, and 6th dose of doxorubicin (the cumulative dose of doxorubicin at 120 mg/m2 and 180 mg/m2). Doxorubicin should be given with great caution in breeds that are predisposed to cardiomyopathy.
The author recommends using the consensus documents: "Common Terminology Criteria for Adverse Events (VCOG-CTCAE) Following Chemotherapy or Biologic Antineoplastic Therapy in Dogs and Cats v1.1". This document is used for the purpose of standardizing the reporting and analysis of chemotherapy-induced side effects.
References
1. Chemotherapy: properties, uses, and patient management. In: Ogilvie GK, Moore AS, eds. Managing the Canine Cancer Patient. Columbus, OH: Veterinary Learning Systems; 2006.
2. Management of chemotherapy side effects. In: Crump K, Thamm DH, eds. Cancer Chemotherapy. Chichester, West Sussex, UK: John Wiley & Sons Ltd.; 2011.
3. Veterinary cooperative oncology group - common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Vet Comp Oncol. 2011 Jul 20. doi: 10.1111/j.1476-5829.2011.00283.x.