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Doxorubicin: An Overview
As in human medicine, the veterinary “nurse” is a jack of all trades. A veterinary technician’s role in the oncology world is not only to have excellent technical skills but also to also be warm and compassionate, be a patient advocate, and make connections with and educate clients. Treating patients with chemotherapeutics requires a thorough understanding of the risks and handling of these agents. In addition, in the face of a chemotherapeutic spill or extravasation, it is necessary to know and act on the immediate response protocol.
Doxorubicin is one of the most dangerous chemotherapeutics used in veterinary oncology. However, it is also one of the most common and efficacious treatments for several types of canine and feline malignancies (see DOXORUBICIN IN THE TREATMENT OF SPECIFIC CANCERS1–12).
Sometimes referred to as the “red death,” doxorubicin is red in color and originates from a product of a fungus (Streptomyces). It is considered part of the anthracycline antitumor antibiotic class of chemotherapeutics. Its antitumor properties were first discovered more than 45 years ago, when it was being used as an antibiotic and tested on tumor-bearing mice; early dosing and frequency studies were performed on dogs.13 Cardiotoxic effects were first noted during human testing in the late 1960s. Fourteen children died during the study; 7 had cardiopulmonary complications.13
Veterinary studies of doxorubicin were first published in the late 1970s. Hundreds of published studies have since investigated its use. Clinically relevant cardiotoxicity is uncommon in cats when appropriate doses are used, but the cardiotoxic effects noted in humans have been observed in dogs (FIGURE 1). Several mechanisms for these effects have been proposed, but the most studied theory is that doxorubicin interacts and releases iron from storage proteins, causing the creation of reactive superoxide molecules, or oxidative free radicals.14 The exact mechanism of iron and free radical damage as it relates to cardiotoxicity secondary to doxorubicin is unknown. Cardiac side effects of doxorubicin are cumulative and irreversible. They can occur at any time during the treatment protocol, even during administration if doxorubicin is given too quickly.15 Extreme caution should be used when cumulative doses reach 180 to 240 mg/m2.
A few measures can be taken to help reduce the risks of doxorubicin-induced cardiomyopathy, including evaluation by a cardiologist before treatment. The cardiologist will perform such tests as echocardiography and electrocardiography (ECG) to search for any evidence of myocardial dysfunction. This is especially recommended for breeds that are known to be prone to dilated cardiomyopathy (BOX 1). It is recommended that any patient that develops heart murmurs or arrhythmias while on doxorubicin chemotherapy be evaluated by a cardiologist.6 Echocardiography and ECG are also recommended when a patient requires doses beyond the lifetime margin of safety of 180 to 240 mg/m2. A small study of the side effects of doxorubicin in cats showed that echocardiographic changes consistent with doxorubicin-induced cardiomyopathy occurred in 4 of 6 cats after cumulative doses of 170 to 240 mg/m2 were given.16 Because doxorubicin is usually dosed at 25 mg/m2 or less for cats, and most protocols only include 4 to 5 treatments, this is not usually a clinical concern in this species.
Dexrazoxane (Zinecard; pfizer.com) is a cardioprotectant intravenous drug that chelates to iron ions, thus reducing the number of ions that are available for doxorubicin to release and consequently decreasing the formation of superoxide radicals. Although this sounds like a solution to the toxic properties of doxorubicin, dexrazoxane is very expensive, and high doses need to be given to adequately protect the heart—10 times those of doxorubicin (eg, a 30 kg/0.976 m2 dog would need almost 300 mg)—making it difficult for some owners to afford.17
Dexrazoxane is available in 250 and 500 mg sterile vials and is reconstituted with sodium lactate to a concentration of 10 mg/mL.18 The patient dose is then further diluted with sterile 0.9% NaCl or 5% dextrose solution to a concentration of 1.3 to 5 mg/mL.19 The infusion is given intravenously over 15 minutes, and doxorubicin administration should follow within 30 minutes of finishing the infusion.
Doxorubicin must always be administered through a clean, “one stick” intravenous catheter. The vein being used should be intact and should not have been used within the 24 to 48 hours before doxorubicin administration. Doxorubicin is diluted with sterile 0.9% sodium chloride or 5% dextrose solution; the dilution ratio may vary by hospital. The vein should be continually monitored for any sign of extravasation, and blood drawback confirmation is necessary before every push of doxorubicin. Institutions administering doxorubicin must have an extravasation protocol and easy access to the supplies needed to carry it out, including dexrazoxane.
To avoid acute adverse effects, doxorubicin is administered as a carefully controlled slow infusion, generally over 15 to 20 minutes. Adverse effects can include acute vomiting, nausea, hives, blood pressure changes, and arrhythmias and are attributed to an anaphylactic response and a release of histamine. During doxorubicin administration, it is the veterinary technician’s responsibility to be alert and in tune with the patient’s demeanor. Noticing a change in the patient’s behavior during administration could mean catching an acute side effect before it manifests and reversing it. Patients experiencing acute side effects may hypersalivate; become restless or lethargic; have pale or injected mucous membranes; develop hives, facial swelling, or wheals; or vomit. A general guideline for veterinary technicians administering doxorubicin is to know the patient and be alert to any changes during doxorubicin administration. If an anaphylactic response is suspected, the administration of doxorubicin should be paused. Administration of an antihistamine (diphenhydramine 3–4 mg/kg IM), and a corticosteroid (dexamethasone sodium phosphate 0.5–1 mg/kg IV) is recommended.17 The doxorubicin administration can be finished, at a much slower rate, when the patient’s clinical signs subside. When doxorubicin is administered at a slow rate, acute adverse effects are infrequent.
Before initiation of doxorubicin treatment, baseline staging tests such as a complete blood cell count, serum chemistry, and urinalysis should be performed. Doxorubicin should be used with caution in feline patients with known renal dysfunction.16 Doses can be reduced in these patients, but judicious monitoring of renal values and urine concentration is recommended, ideally before administration of each dose.
Doxorubicin tissue extravasation has the potential to be catastrophic. This is one of the main reasons that only trained personnel should handle doxorubicin. Extravasation, or leaking of a drug outside of a vein, of some chemotherapeutics can cause mild to moderate tissue irritation, but doxorubicin can cause tissue sloughing, necrosis, and wounds that can take months to heal and may require amputation.
Veterinary technicians who handle doxorubicin must understand the emergency procedures necessary in the event of extravasation, including the dose, proper administration, and availability of dexrazoxane. If extravasation is suspected, the doxorubicin infusion should be terminated and every attempt made to draw back as much of the doxorubicin product from the catheter as possible before the catheter is removed. Application of a cold compress promotes vasoconstriction and decreases diffusion of doxorubicin into the surrounding tissues. The dosing and dilution ratio of dexrazoxane are the same as if it is being used for its cardioprotective properties.
In a small study of 4 dogs with doxorubicin extravasation, 3 patients showed resolution of lesions with medical management alone after the extravasation was treated with dexrazoxane within 2 hours.20 Repeated doses at 24 and 48 hours after the event may also improve outcome. To prevent additional trauma that will perpetuate the wound, an Elizabethan collar is advised. Administration of NSAIDs and pain medications should be considered. Application of a cold compress to the area for periods of 15 minutes multiple times during the first 24 hours may also help mitigate the effects of doxorubicin extravasation.
The benefits of applying topical dimethyl sulfoxide (DMSO) to the area of extravasation are unclear. However, DMSO is recommended by many oncologists in the event of an extravasation for the following reasons20:
- It decreases pain by blocking nerve conduction fibers.
- It reduces inflammation and swelling.
- It improves blood supply and oxygen delivery via its vasodilation properties.
- It is one of the most potent free radical scavengers.
BOX 2 provides an example of an extravasation protocol.
Doxorubicin has the potential to cause some of the most severe delayed adverse effects of any drug in veterinary oncology. In general, delayed effects can be grouped into gastrointestinal, hematologic, organ toxicosis, and other. Most adverse effects can be handled with ancillary medications that the owners can give at home. In fact, <5% of patients have side effects so severe that they need to be hospitalized. In an effort to help veterinary oncologists quantify chemotherapy toxicities, or adverse events, the Veterinary Cooperative Oncology Group (VCOG) has established grading criteria for different types of adverse events (TABLE 1).21 This grading system helps the veterinary oncology team work with owners to decide the severity of the event (eg, vomiting, diarrhea, inappetence) and helps oncologists make treatment recommendations and decisions.
TABLE 1 Gastrointestinal Adverse Events Associated With Chemotherapy
|ADL, activities of daily living (eating, sleeping, urinating, defecating); LLN, lower limit of normal; PPN, partial parenteral nutrition; TPN, total parenteral nutrition.
Adapted with permission from 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 doi: 10.1111/j.1476-5829.2011.00283.x.
|Neutropenia||1500 uL to <LLN||1000–1499 uL||500–999 uL||<500 uL||Death|
|Anorexia: Disorder characterized by loss of appetite||Coaxing or dietary change required to maintain appetite||Oral intake altered (≤3 days) without significant weight loss; oral nutritional supplements/appetite stimulants may be indicated||Of >3 days’ duration; associated with significant weight loss (≥10%) or malnutrition; IV fluids, tube feeding, or force feeding indicated||Life-threatening consequences; TPN indicated; >5 days’ duration||Death|
|Diarrhea: Disorder characterized by frequent, watery bowel movements||Increase of up to 2 stools per day over baseline; no increase in frequency; however, consistency decreased over baseline||Increase of 3–6 stools per day over baseline; medications indicated; parenteral (IV or SC) fluids indicated ≤48 h; not interfering with ADL||Increase of >6 stools per day over baseline; incontinence >48 h; IV fluids >48 h; hospitalization; interfering with ADL||Life-threatening (eg, hemodynamic collapse)||Death|
|Nausea/ptyalism: Disorder characterized by hypersalivation and sensation or urge to vomit; difficult to assess in companion species||Loss of appetite without alteration in eating habits||Salivation or lip smacking <3 days’ duration, grade 2 anorexia||Salivation or lip smacking >3–5 days’ duration, grade 3 anorexia||Salivation or lip smacking >5 days’
duration, grade 4 anorexia
|Vomiting: Disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth||<3 episodes in 24 h; medical intervention not indicated||3–10 episodes in 24 h; <5 episodes/day for ≤48 h; parenteral fluids (IV or SC) indicated ≤48 h; medications indicated||Multiple episodes >48 h and IV fluids or PPN/TPN indicated >48 h||Life-threatening (eg, hemodynamic collapse)||Death|
The gastrointestinal tract is lined with rapidly dividing cells, much like those of malignant tumors. Doxorubicin, like most chemotherapeutics, is designed to target such cells, leaving the gastrointestinal tract open to its effects. Vomiting, nausea, inappetence, and diarrhea are among the gastrointestinal side effects associated with doxorubicin administration. They usually occur anywhere from 2 to 5 days after administration. The addition of maropitant (Cerenia; zoetis.com) to the ancillary medications regimen after doxorubicin administration has been shown to decrease the number of patients that experience vomiting and diarrhea, and to lessen the severity of these effects in patients that do experience them.22 Patients in this study received maropitant (2 mg/kg) orally for 5 consecutive days after doxorubicin administration. Alternatively, maropitant can be given orally or subcutaneously before doxorubicin administration, followed by 4 consecutive daily doses at home. This is simpler because of the way maropitant is packaged. Fasting patients before treatment with doxorubicin has also been shown to reduce the incidence of vomiting after treatment.23
Diarrhea is another known adverse effect of doxorubicin that can manifest in the first week after administration. Metronidazole can be used to help these patients at doses as low as 10 mg/kg PO every 12 hours as needed for soft stool or diarrhea.19 If soft stool or diarrhea does not respond to metronidazole therapy, alternative options include tylosin and probiotics. Veterinary oncology technicians should be well versed in adverse gastrointestinal effects and recommended therapy so that they can accurately discuss these details with owners.
Doxorubicin’s myelosuppressive effects, which are described as mild to moderate, are one of its many dose-limiting toxicities; the established dose of doxorubicin is based on the increased rate of myelosuppression at higher doses. A complete blood cell count with differentials should be performed 7 to 10 days after doxorubicin administration to monitor for white blood cell (specifically neutrophil) nadirs. The nadir is defined as the anticipated lowest cell count in a patient after chemotherapy. Neutropenia after doxorubicin administration can be dangerous because of the potential for simultaneous adverse gastrointestinal effects. Vomiting and/or diarrhea can cause translocation of bacteria, and if a patient’s immune response is compromised, sepsis may occur.17 Other, less common hematologic effects of doxorubicin include anemia and thrombocytopenia.
Prophylactic antibiotics may be considered after a patient’s first dose of doxorubicin. In dogs, sulfamethoxazole–trimethoprim is a broad-spectrum, cost-effective, relatively safe antibiotic that is gentle on the gastrointestinal tract. It can be started 3 days after doxorubicin infusion and continued for 7 days, or longer as needed (15–30 mg/kg PO BID).19 Doxorubicin-associated neutropenia is less common in cats, and client administration of oral medications to cats can decrease quality of life for both client and patient, so a prophylactic antibiotic can be spared in feline patients.
Most veterinary patients do not experience the same chemotherapy-induced alopecia as human patients, but patchy alopecia may be seen in breeds with continually growing hair (eg, Maltese, golden retrievers, poodles). It mostly affects the hair around the muzzle and eyes, but severe cases of hair loss can occur (FIGURE 2). To help prevent painful matting of the fur, it is recommended to keep patients undergoing chemotherapy well groomed. Hyperpigmentation of the skin of shaved and thinly haired areas can occur (FIGURE 3). Radiation recall dermatitis (RRD) is a phenomenon in humans in which the dermal side effects of radiation return if certain chemotherapeutic agents are administered shortly after radiation therapy is completed. Cases of RRD have been reported up to 2 decades after radiation therapy.24 This phenomenon is not reported in veterinary patients, but many believe it can occur.
Although doxorubicin poses significant risks in administration and toxicity, it is one of the most effective chemotherapeutic agents in veterinary medicine. Its effects help patients achieve lengthy and good quality of life remission and survival times for many types of malignancies. Doxorubicin’s potential benefits almost always outweigh the risks of its adverse effects. Doxorubicin is a drug that requires meticulous attention to detail and exceptional technical skills. Staff members handling doxorubicin should be well versed in the potential adverse effects to be able to comfort and educate owners of pets going through chemotherapy.
- Postorino NC, Susaneck SJ, Withrow SJ, et al. Single agent therapy with adriamycin for canine lymphosarcoma. JAAHA 1989;25:221.
- Vail DM. Hematopoietic tumors. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 6th ed. St. Louis, MO: Elsevier; 2005.
- Milner RJ, Peyton J, Cooke K, et al. Response rates and survival times for cats with lymphoma treated with the University of Wisconsin-Madison chemotherapy protocol: 38 cases (1996-2003). JAVMA 2005;227(7):118-122.
- MacVean DW, Monlux AW, Anderson PS, et al. Frequency of canine and feline tumors in a defined population. Vet Pathol 1978;145:700-715.
- Ogilvie GK, Powers BE, Mallinckrodt CH, et al. Surgery and doxorubicin in dogs with hemangiosarcoma. J Vet Intern Med 1996;10:379-384.
- Withrow SJ, Vail DM, Page RL. Cancer chemotherapy. In: Small Animal Clinical Oncology. 5th ed. St. Louis: Elsevier Saunders; 2013:157-173.
- Bergman PJ, MacEwen EG, Kurzman ID, et al. Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases (1991 to 1993). J Vet Intern Med 1996;10(2):76-81.
- Berg J, Weinstein MJ, Springfield DS, Rand WM. Results of surgery and doxorubicin chemotherapy in dogs with osteosarcoma. JAVMA 1995;206(10):1555-1560.
- Theilen GH, Madewell BR. Tumors of the skin and subcutaneous tissues. In: Theilen GH, Madewell BR, eds. Veterinary Cancer Medicine. Philadelphia, PA: Lea & Febiger; 1979.
- Kuntz CA, Dernell WS, Powers BE, et al. Prognostic factors for surgical treatment of soft-tissue sarcomas in dogs: 75 cases (1986-1996). JAVMA 1997;21:1147-1151.
- Selting KA, Powers BE, Thompson LJ, et al. Outcome of dogs with high-grade soft tissue sarcomas treated with and without adjuvant doxorubicin chemotherapy: 39 cases (1996-2004). JAVMA 2005;227:1442-1448.
- Moe L. Population-based incidence of mammary tumours in some dog breeds. J Reprod Fertil Suppl 2001;57:429-443.
- Tan C, Tasake H, Yu K, et al. Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Cancer 1967;20(3):333-353.
- Young RC, Ozols RF, Myers CE. The anthracycline antineoplastic drugs. N Engl J Med. 1981;305(3):139-153.
- Eschalier A, Lavarenne J, Burtin C, et al. Study of histamine release induced by acute administration of antitumor agents in dogs. Cancer Chemother Pharmacol 1988;21:246-250.
- O’Keefe DA, Sisson DD, Gelberg HB, et al. Systemic toxicity associated with doxorubicin administration in cats. J Vet Intern Med 1993;7(5):309-317.
- Thamm DH, Vail DM. Aftershocks of cancer chemotherapy: managing adverse events. JAAHA 2007;43(1):1-7.
- Pharmacia & Upjohn. Dexrazoxane [package insert]. New York; 2012.
- Plumb DC. Plumb’s Veterinary Drug Handbook. 8th ed. Stockholm: PharmaVet Inc; 2015:1345-1349.
- Venable R, Saba C, Endicott M, Northrup N. Dexrazoxane treatment of doxorubicin extravasation injury in four dogs. JAVMA 2012;240(3):304-307.
- 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. doi: 10.1111/j.1476-5829.2011.00283.x.
- Rau SE, Barber LG, Burgess KE. Efficacy of maropitant in the prevention of delayed vomiting associated with administration of doxorubicin to dogs. J Vet Intern Med 2012;24(6):1452-1457
- Withers SS, Hass PH, Rodriguez CO, et al. Fasting reduces the incidence of delayed-type vomiting associated with doxorubicin treatment in dogs with lymphoma. Transl Oncol 2014;7(3):377-383.
- Haas RLM, Klerk G. An illustrated case of doxorubicin-induced radiation recall dermatitis and a review of the literature. Neth J Med 2011;69(2):72-75.
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- Doxorubicin is a member of which class of drug?
- Alkylating agents
- Vinca alkaloids
- Doxorubicin can be used safely in many veterinary patients, but it might it be used more cautiously in _______ due to the potential for cardiotoxicity.
- Labrador retrievers
- In veterinary oncology, dexrazoxane is used for
- antibiotic therapy.
- b and c.
- Acute adverse effects of doxorubicin include all of the following except
- cardiac arrhythmias.
- True or false: Fasting patients before doxorubicin administration has been shown to reduce gastrointestinal adverse effects.
- The expected neutrophil nadir occurs ____ days after doxorubicin administration.
- 3 to 5
- 7 to 10
- 14 to 21
- There is no expected nadir after doxorubicin administration.
- After an extravasation event, which of the following should be performed?
- Removal of IV catheter
- Cold compress on the affected area
- Elizabethan collar
- All of the above
- What is the recommended dose for dexrazoxane when used for its cardioprotective properties?
- 2.2 mg/kg
- 5× the dose of doxorubicin
- 7.5× the dose of doxorubicin
- 10× the dose of doxorubicin
- Which of the following is not a class of tumor?
- Round cell
- Cats generally do not experience the cardiotoxic effects of doxorubicin. Which effect are they more sensitive to?
- Renal toxicosis
- Severe thrombocytopenia
- Liver toxicosis
- Pulmonary toxicosis