Oncologic Emergencies: Chemotherapy-Related Side Effects
ACVIM 2008
Craig Clifford, DVM, MS, DACVIM (Oncology); Louis-Philippe de Lorimier, DVM, DACVIM (Oncology)
Red Bank, NJ, USA; Brossard, QC, Canada

Introduction

Cancer is a common diagnosis in older companion animals, and an increasing number of pet owners are willing to seek therapeutic options and advanced care once a diagnosis has been confirmed. Since the administration of chemotherapy is now commonplace not only in referral institutions, but also in general practices, it is important to understand potential accompanying toxicities resulting in therapy related emergencies. This presentation will outline supportive measures for patients presenting on an emergency basis from side effects associated with chemotherapy and the specific therapeutic interventions necessary for treatment of such patients.

Chemotherapy-Related Side Effects

The most common chemotherapy related side effects include hematologic, gastrointestinal, urologic, cardiac, neurologic, hypersensitivity reactions and acute tumor lysis syndrome. Another side effect of note with certain vesicant drugs is tissue damage following extravasation. The toxicities associated with damage to rapidly dividing cells, including myelosuppression, alopecia, and certain gastrointestinal side effects, may be observed with nearly all cytotoxic agents, while certain side effects such as neurotoxicity, hypersensitivity reactions, and urologic toxicity which is often limited to specific drugs.

Acute Tumor Lysis Syndrome (ATLS)

Rarely encountered, ATLS could develop when newly diagnosed chemosensitive high-grade lymphomas with large tumor burden are treated with potent chemotherapy drugs (e.g., vincristine + L-Asparaginase). Massive cancer cell death releases cellular components, leading to potentially life-threatening hyperkalemia, with hyperphosphatemia, hypocalcemia, and hyperuricemia0. Clinical signs may include lethargy, vomiting, collapse, and death. Treatment involves aggressive IV fluid therapy aiming to correct electrolyte disturbances, and monitoring with ECG. This syndrome generally occurs in the 48 hours following therapy.

Hypersensitivity Reactions

Hypersensitivity reactions, though uncommon, generally develop within minutes of administration. Clinical signs may include urticaria, intense pruritus, facial swelling, cutaneous hyperemia, vomiting, hypotension, restlessness, head shaking and loss of consciousness. An IgE-mediated anaphylaxis can be observed with L-Asparaginase, especially with multiple dosages as this is a foreign protein. The IV route clearly results in a higher risk of anaphylaxis than IM or SQ, and is therefore not recommended. Anaphylactoid reactions may also be observed with certain drugs such as doxorubicin (believed to be a result of histamine release), and paclitaxel, in which cremaphor (the vehicle for this drug) is at cause. Diphenhydramine along with a corticosteroid are often used as a premedication to decrease the risk of developing or when a reaction hypersensitivity reaction is encountered. Slowing the infusion rate of drugs such as doxorubicin and paclitaxel may also help decrease the risk of anaphylactoid reactions.

Hematologic Toxicity

Myelosuppression often follows cytotoxic therapy, and is the dose-limiting toxicity of most chemotherapy agents used in veterinary oncology. While certain drugs are considered as causing mild to no myelosuppression (corticosteroids, L-Asparaginase, chlorambucil, bleomycin, cisplatin), others are moderately myelosuppressive (vincristine, vinblastine, cyclophosphamide, melphalan), or highly myelosuppressive (lomustine, carboplatin, doxorubicin, mitoxantrone). Logically, most drugs can be more or less myelosuppressive depending on the dosage administered. Having shorter circulating lifespan and bone marrow transit times, platelets and neutrophils are at highest risk for cytopenias. Though it varies between agents and patients, nadirs are typically observed 6-10 days following administration. With moderate (<1,000/uL) to severe (<500/uL) neutropenia, the risk of life-threatening complications such as sepsis from bacterial translocation or pneumonia increases. With acute and severe thrombocytopenia, signs of bruising and mucosal bleeding may present. In addition to the CBC performed during the nadir window, patients should be evaluated with a TPR and complete physical examination. As a rough guide:

 With neutrophil count <2,500/uL, no fever or clinical signs (lethargy, anorexia), delay therapy for 2-4 days and repeat CBC prior to chemotherapy.

 With neutrophil count <1,500/uL, no fever or clinical signs (lethargy, anorexia), delay therapy for 7 days, administer prophylactic broad spectrum antibiotics, and repeat CBC prior to chemotherapy. Subsequent drug dosage may be decreased by 10-20%.

 With neutrophil count <1,500/uL and fever or signs consistent with sepsis, hospitalize and treat appropriately. For febrile animals, assume sepsis is present and treat with broad-spectrum intravenous antibiotics covering gram-positives (for skin bacteria), gram-negatives (for gastrointestinal bacteria), and anaerobes (for oral bacteria). The use of recombinant human colony-stimulating factors (Neupogen®) is occasionally considered in select cases. Death from chemotherapy-induced sepsis is low especially with early and aggressive therapy. Owners must therefore be educated to recognize the signs of illness and advised as to the urgency of seeking treatment for a fever, especially when a highly myelosuppressive agent has been administered. Subsequent drug dosage should be decreased by 20-25%.

 Chemotherapy should be delayed when the platelet count is <50,000 to 100,000/uL. Patients should be monitored for signs of mucosal bleeding when the count is <30,000/uL.

Gastrointestinal Toxicity

Gastrointestinal (GI) side effects can manifest as acute or delayed. Acute manifestations (emesis) occur within minutes to a few hours of chemotherapy administration, and are most frequent with cisplatin, dacarbazine or doxorubicin. Acute emesis appears to result from direct stimulation of the vomiting center within the brain. It can often be prevented with antiemetics administered prior to chemotherapy. In contrast, the more common delayed GI side effects are observed 2 to 5 days following treatment, and may manifest as inappetence (nausea), vomiting or diarrhea. Many cytotoxic agents cause direct damage to intestinal crypt cells, resulting in a delayed onset of clinical signs. The onset of diarrhea is typically 3-5 days after therapy, paralleling the time taken by cells to migrate from the crypts to the villi. Vomiting develops following triggering of the chemoreceptor trigger zone, either through stimulation of gut vagal efferents or via centrally mediated events. Chemotherapy agents may be classified as having a potential for GI related side effects that is high (cisplatin, dacarbazine, mustargen, streptozotocin), moderate (doxorubicin, dactinomycin, vincristine, mitoxantrone, carboplatin, procarbazine), or low (chlorambucil, cyclophosphamide, CCNU, vinblastine, cytosine arabinoside). Patients receiving agents with a moderate to high potential of GI side effects should be dispensed oral antiemetics (Table 1). Most side effects are self limiting and can be treated supportively by withholding food and water then performing a water/food trial, use of bland diets, oral or SQ antiemetics, probiotics, or antibiotics with severe diarrhea. In more severe cases, hospitalization is required to rehydrate and prevent further losses (IV antiemetics, IV antibiotics). Usually, even such patients will respond within 1-2 days.

Table 1. Drugs used to control chemotherapy-induced nausea and vomiting.

Drug name

Drug class

Dosage

Frequency

Route

Prochlorperazine

Phenothiazine

Variable

Variable

PO/SQ/IM

Chlorpromazine

Phenothiazine

Variable

Variable

PO/SQ/IM

Metoclopramide

Prokinetic, dopamine antagonist, 5-HT3 blockade at high dosage

0.2-0.4 mg/kg

q6-8h

PO/SQ/IV

1-2 mg/kg/d

CRI

CRI

Dexamethasone

Corticosteroid

0.1-0.2 mg/kg

q24-72h

PO/SQ/IM/IV

Butorphanol

Opioid

0.2-0.4 mg/kg

Once, 30 minutes prior to cisplatin

IM

Ondansetron

5-HT3 receptor antagonist

0.3-1.0 mg/kg

q12-24h

PO/SQ/IM/IV

Dolasetron

5-HT3 receptor antagonist

0.5-1.0 mg/kg

q12-24h

PO/SQ/IM/IV

Maropitant* (Cerenia®)

Neurokinin-1 receptor antagonist

1 mg/kg

q24h

SQ

2 mg/kg

q24h

PO

Mirtazapine

Various, including 5-HT3 receptor antagonism

Not well established

q24h

PO

*Dosage approved for prevention and treatment of acute vomiting in dogs

Cardiotoxicity

Cumulative cardiotoxicity is an uncommon manifestation of doxorubicin administration and oftentimes manifests after the course of chemotherapy has been completed. The generation of iron-based free radicals that damage cardiac myocytes is the currently accepted proposed main mechanism of toxicity. Cardiac muscle, unlike other tissues, has relatively low levels of specific free radical scavenger capacities, and this is thought to contribute to the susceptibility of myocardial tissue to anthracyclines. Clinical features of cumulative doxorubicin cardiotoxicity include non dose-dependent electrocardiographic abnormalities and cumulative clinical congestive heart failure (CHF) associated with decreased contractility. In dogs, the accepted maximum cumulative dose is between 180mg/m2 and 240mg/m2, although cardiotoxicity has been described to occur with lower doses and other dogs have received higher doses with minimal effects. ECG abnormalities include ventricular premature complexes, supraventricular arrhythmias and R wave amplitude changes. Unfortunately, ECG and echocardiography are relatively insensitive indicators of cardiotoxicity. However, it is prudent to offer a base line ECG or echocardiogram prior to initiation of this drug to rule out pre-existing cardiac abnormalities (especially for certain breeds of dogs or in dogs with suspect cardiac dysfunction, i.e., heart murmur or an arrhythmia). The breeds of dogs predisposed to certain types of cardiomyopathy appear to be at increased risk for this cumulative cardiotoxicity, and caution should be exercised. In doubt, or when maximum cumulative doses are approached, alternatives should be considered, including the use of other drugs, a different formulation of doxorubicin (liposome-encapsulated), or the coadministration of the iron chelator dexrazoxane. An acute cardiotoxicity also exists with doxorubicin, in the form of transient premature ventricular complexes during administration, but is not clinically significant. A slower infusion rate decreases the incidence of these arrhythmias.

Urologic Toxicities

Nephrotoxicity is a relatively uncommon chemotherapy-related side effect and is most often associated with cisplatin administration. The cellular and molecular mechanisms of cisplatin-induced nephrotoxicity are still not completely understood. The risk of nephrotoxicity with cisplatin can be significantly reduced with aggressive saline diuresis. Saline is administered at a rate of 18-20 ml/kg/hr for 4 hours, then the cisplatin is given over 20 min in 7-8 ml/kg of saline (one third the hourly fluid rate), followed by an additional 1-2 hours of saline diuresis at the initial rate. All patients should have a urinalysis performed prior to the administration of cisplatin, and cisplatin is only administered if the USG is > 1.030, and granular casts are not present in increased numbers. All patients on NSAIDs, independent of the Cox-2 selectivity, should be taken off the NSAID 2-3 days prior to and until 2-3 days post cisplatin administration. Another chemotherapy agent requiring saline diuresis to prevent nephrotoxicity is streptozotocin, a drug used specifically to treat insulinomas.

Cyclophosphamide and ifosfamide can both cause a sterile hemorrhagic cystitis (SHC) after a single high dose or after prolonged therapy, via direct urothelial toxicity by the metabolite acrolein. There is no antidote to SHC, but the likelihood of it developing can be abrogated through simple precautionary measures such as providing free access to fresh water, having the patient urinate frequently for 48 hours after drug administration, or administering cyclophosphamide concurrently with a dose of furosemide &/or prednisone. Clinical signs include stranguria, hematuria and dysuria. Treatment of this side effect includes the use of a steroid or nonsteroidal, antispasmodic and replacing the cyclophosphamide with a different alkylating agent (e.g., chlorambucil) to prevent further irritation. Antibiotics may be indicated because the irregular bladder lining is susceptible to infection. Amelioration of clinical signs can occasionally be achieved with administration of oxybutanin (anti-spasmodic agent) at 0.2 to 0.3 mg/kg BID or TID. The use of intravesicular instillation of dilute 1% formalin or a formulation of dimethyl sulfoxide (DMSO) has been described, however, these authors caution against such use. Most cases resolve with time (4-6 weeks). Because of a higher risk of SHC with ifosfamide, the acrolein-binding Mesna (2-mercaptoethanoesulfonate) is always concurrently administered for prevention.

Extravasation

Certain chemotherapy agents are vesicants, can cause significant tissue damage when perivenous extravasation occurs, and include vincristine, vinblastine, dactinomycin, doxorubicin, and mustargen. Prevention, with the use of a clean-stick catheter in a vein that has not been punctured for over 72 hours, is mandatory. If extravasation occurs with doxorubicin, prompt action is required to decrease the risk of severe tissue damage. Though various methods have been described, none has proven to be of repeatable value, short of the administration of the iron chelator dexrazoxane, at 10 times the dosage of doxorubicin, administered IV in the 2-4 hours following the extravasation event (and repeated once or twice). If vincristine extravasation was to occur, hyaluronidase is an antidote that, if available, could decrease the severity of tissue damage.

Cats and Chemotherapy

Though the information herein discussed applies to both dogs and cats, certain peculiarities with regards to chemotherapy and cats are worth mentioning. For example, cats may develop constipation with vincristine chemotherapy, occasionally prompting substitution by vinblastine in lymphoma protocols when this side effect is observed. Cats also appear to have a higher incidence of unpredictable nadirs (prolonged, delayed, double) with carboplatin administration, further supporting an individualized schedule of treatment, based on sequential CBCs. Doxorubicin is considered nephrotoxic in cats, but a more appropriate dosing range (20 to 25 mg/m2) seems to markedly reduce this risk, though caution remains warranted in presence of renal insufficiency. While lomustine is known to cause hepatotoxicity in dogs, it has yet to be reported in cats, despite an increasing use of this drug in recent years. A high-dose pulse chlorambucil protocol provides good clinical responses and survival times for cats with small cell GI lymphoma, but may uncommonly lead to certain neurologic side effects such as myoclonus. Cats have an increased tendency to shed whiskers during chemotherapy, when compared to dogs. Finally, toxicities with cisplatin (pulmonary) and 5-fluorouracil (neurologic) are lethal to cats and these drugs are therefore absolutely contraindicated in this species.

Summary

Cytotoxic chemotherapeutic agents are being used with an increasing frequency in cancer-bearing dogs and cats. Though multiple toxicities can develop from their use, certain precautions and an early recognition with appropriate therapeutic intervention can minimize their frequency, severity, and negative impact on the quality of life of our patients. A better understanding of these drugs used to treat common veterinary cancers helps to ensure that the benefits associated with their use far outweigh the risks.

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Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Craig Clifford, DVM, MS, DACVIM (Oncology)
Red Bank Veterinary Hospital
Tinton Falls, NJ

Louis-Philippe de Lorimier, DVM, DACVIM (Oncology)
Hopital Veterinaire Rive-Sud
Brossard, Canada


MAIN : ACVIM Oncology Generalist : Oncology Emergencies
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