Treatment of Adverse Effects from Cancer Therapy

Chapter 72


Treatment of Adverse Effects from Cancer Therapy



One of the primary goals of cancer treatment in veterinary patients is to preserve quality of life. Every effort is made to minimize adverse effects of chemotherapy, but it is not possible to eliminate them completely. Chemotherapy is unique in that dosages are based on toxicity rather than efficacy. Dose-response curves tend to be very steep for most cancers, and to minimize treatment failures drugs are administered at the highest possible dosages that are tolerated by most patients. Some risk of toxicity has to be accepted; anticipation, early recognition, and prompt intervention can help minimize adverse effects and maintain patient quality of life.



Chemotherapy Dosages


Most chemotherapy dosages are based on body surface area (BSA) because it is thought that this parameter predicts biologic functions more closely than body weight; however, there is no direct evidence that BSA predicts drug absorption, distribution, metabolism, or excretion. Additionally, when chemotherapy drugs are dosed based on BSA, smaller patients receive a larger dose on a milligrams-per-kilogram basis. Doxorubicin (DOX), cisplatin, carboplatin, and melphalan all are associated with an increased prevalence of adverse effects in small dogs when dosed based on BSA. Consequently, melphalan often is dosed on a milligrams-per-kilogram basis for dogs of all sizes. For the other drugs listed, lower BSA-based dosages or milligrams-per-kilogram dosing schemes often are used in smaller dogs (usually <10 to 15 kg). In cats a carboplatin dosing equation has been derived based on patient glomerular filtration rate that predicts toxicity more accurately than dosing based on BSA.


A polymorphism in the gene that encodes the membrane-associated pump ABCB1 (adenosine triphosphate–binding cassette, subfamily B, member 1; also called MDR-1 [multidrug resistance protein 1] and P-glycoprotein) increases the risk of adverse effects with drugs that are substrates of the pump (Mealey et al, 2008). The collie, Australian shepherd, long-haired whippet, McNab, and silken windhound are among the most commonly affected breeds. Dogs homozygous for the ABCB1-1Δ polymorphism experience a higher incidence of vincristine-associated neutropenia and thrombocytopenia, and computer-based pharmacokinetic modeling predicts that they cannot receive therapeutic dosages of DOX without unacceptable gastrointestinal (GI) toxicity. Other chemotherapy drugs that are substrates of ABCB1 are vinblastine, vinorelbine, mitoxantrone, dactinomycin, docetaxel, paclitaxel, and etoposide. Alkylating agents, antimetabolites, and platinum chemotherapy drugs are not impacted by ABCB1. Genetic testing for the ABCB1-1Δ polymorphism is available through Washington State University (www.vetmed.wsu.edu/depts-VCPL/index.aspx).



Management of Adverse Events



Hematologic Toxicity


One of the most common adverse effects associated with chemotherapy is myelosuppression, a decrease in blood cell counts. This should be distinguished from immunosuppression, inhibition of immune system function. Neutropenia is the most common manifestation of myelosuppression, followed by thrombocytopenia. Severe anemia is uncommon because of the prolonged life span of red blood cells, although a slow decline in hematocrit can be observed over the course of a protocol.


Bone marrow aspiration with cytologic evaluation should be considered before starting chemotherapy in patients with cancers that can infiltrate the marrow, such as lymphoma and leukemias, especially if the baseline complete blood count (CBC) shows abnormal cells in circulation or normal cell line cytopenias. Patients with substantial marrow involvement (>50% effacement) are at higher risk of chemotherapy-associated cytopenias, and occasionally it is necessary to administer chemotherapy when they are cytopenic. Using less myelosuppressive drugs (such as l-asparaginase) at the start of treatment in these patients is preferable whenever possible, and prophylactic antibiotic therapy should be considered.


A CBC should be performed on the day of each chemotherapy treatment. In a patient with a relatively healthy bone marrow, the neutrophil count should be at least 1500 to 2500/µl and platelet counts should be 50,000 to 100,000/µl or more on the day of treatment. If a patient is too cytopenic, chemotherapy treatment should be delayed by 3 to 7 days. A CBC should be repeated to ensure that the cytopenias have improved before treatment is resumed.


CBCs should be performed to assess blood cell counts at their nadirs (low points). With most drugs, nadirs typically occur around 5 to 10 days after treatment, and a CBC should be performed 1 week after the first treatment. Notable exceptions include carboplatin, which can cause neutropenia or thrombocytopenia anywhere from 7 to 14 days after treatment in dogs and neutropenia anywhere from 7 to 21 days after treatment in cats, and lomustine (CCNU), which can cause neutropenia anywhere from 7 to 28 days after treatment in cats. For these drugs, CBCs should be performed weekly to ensure that the nadir is identified accurately. Measurement of nadir CBCs is essential after the first dose of any myelosuppressive chemotherapy drug. Measurement of subsequent nadir CBCs is indicated only if severe cytopenias are identified that result in a dosage reduction.


Nadir neutrophil counts of 1000/µl or higher typically do not require any intervention. Patients with fewer than 1000 neutrophils/µl are at increased risk of systemic infections. Prophylactic treatment with antibiotics is recommended. Common choices include amoxicillin/clavulanic acid (13.75 mg/kg q12h PO), enrofloxacin (dogs: 10 mg/kg q24h PO; cats: 2.5 to 5.0 mg/kg q24h PO; high-dose treatment not recommended), or trimethoprim/sulfamethoxazole (15 mg/kg q12h PO). The dosage of the causative drug should be decreased by 10% to 25% in subsequent treatments, regardless of whether or not the patient develops an infection. The most common causative agents for systemic infections in neutropenic patients are normal gut and skin flora; however, neutropenic dogs and cats also should avoid groomers, pet stores, kennels, and public parks while their counts remain low. In most dogs and cats, the neutrophil count recovers within 3 to 5 days, although in the author’s experience severe neutropenias can be slower to recover in cats.


Signs of systemic infection most commonly are acute-onset lethargy and anorexia. Vomiting and diarrhea occasionally are seen as well. Most patients are febrile, although this is not always the case since white blood cells are one of the primary sources of the inflammatory cytokines that cause fever (interleukin-1, tumor necrosis factor). A patient with a neutrophil count of less than 1000/µl that is systemically ill should be considered to have a systemic infection until proven otherwise. Systemic infections require prompt treatment with intravenous fluids and intravenous antibiotics. Common choices are ampicillin/sulbactam (30 mg/kg q8h IV) or a combination of ampicillin (22 mg/kg q8h IV) or cefazolin (22 mg/kg q8h IV) with enrofloxacin (dogs: 10 mg/kg q24h IV; cats: 2.5 to 5.0 mg/kg q24h IV). If needed, additional treatment for signs of septic shock (hypotension, hypoglycemia) should be implemented. In patients with uncomplicated systemic infections the fever should break within 24 hours, and temperature usually returns to the normal range within 24 to 48 hours of initiation of therapy. After temperature has been within normal limits for 24 hours, patients can be switched to the oral equivalents of their intravenous antibiotics and discharged from the hospital. If clinical signs do not improve, imaging of the thorax or abdomen should be considered to search for a nidus of infection. Blood cultures are not routinely performed; in most patients the infection is under control before results are available.


Thrombocytopenia is seen most commonly with carboplatin, lomustine, dacarbazine, melphalan, and occasionally DOX. It usually is not clinically significant, but patients with fewer than 25,000 to 50,000 platelets/µl should avoid trauma and be monitored for petechiae, ecchymoses, epistaxis, or GI bleeding. Also, lomustine and melphalan can be associated with cumulative and often irreversible thrombocytopenia. These drugs should be discontinued in patients with persistent platelet counts below 75,000 to 100,000/µl.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Treatment of Adverse Effects from Cancer Therapy

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