Hematological and Selected Serum Biochemical Changes Associated with Cancer Chemotherapeutics in Small Animals—An Overview  

Alexandra Sahora, DVM; Nicole Northrup, DVM; Bruce E. LeRoy, DVM, PhD

Animal Clinical Investigation, LLC, PO Box 42535, Washington, DC 20015 (Sahora), Departments of Small Animal Medicine and Surgery (Northrup) and Pathology (LeRoy), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388

Introduction

Chemicals have been used to kill cancer cells since the 1940s. Most chemotherapeutics affect all rapidly dividing cells, whether they are cancerous or not, which is the basis of many side effects of these compounds. In spite of side effects, chemotherapy is a mainstay in the treatment of cancer as it provides improved survival and higher quality of life. Many of the chemotherapy-related side effects (vomiting, diarrhea, lethargy, and malaise) commonly experienced in human cancer patients are somewhat less severe in dogs and cats. ^{8, 9} However, these toxicities still occur in dogs and cats and may be the limiting factor in the treatment of an individual’s neoplastic process. ³

Cancer results in disruption of the normal checks and balances of cellular growth and proliferation leading to uncontrolled cell growth and subsequent tumor formation. Most neoplastic cells have an increased rate of cell division and are able to avoid growth inhibitory signals. Additionally, many cancer cells are able to avoid programmed cell death (apoptosis). Most chemotherapeutics prevent cell division by targeting nucleic acid replication, synthesis, and repair mechanisms. ⁸ Topoisomerase activity, microtubule formation, and protein synthesis may also be impaired. 8 However, non-neoplastic host cells (such as hematopoietic cells, the gastrointestinal tract, and other epithelial cells) that also have a rapid proliferation rate are also affected by many of these drugs. 9 Hematological and gastrointestinal complications associated with chemotherapy are common, but their presentation and severity may vary greatly depending on the drug used, the dosage, and the individual patient. 9 Occasionally, other organ systems (cardiovascular, nervous) may also be affected by cancer chemotherapeutics. In light of these potential complications, it can be difficult to determine whether abnormalities noted on routine blood tests are due to chemotherapy or instead reflect a worsening of a patient’s health status due to progression of the underlying disease. In order to help resolve this diagnostic dilemma, the following is a summary of some of the abnormalities seen on complete blood counts (CBC) and serum biochemical profiles often associated with chemotherapy.  

Abnormalities Reflected in the Complete Blood Count (CBC):

Erythrocytes : Anemia is uncommon due to chemotherapy but can be seen with chronic treatment lasting more than 3 months. Anemia may arise as a potential complication from hydroxyurea administration for the therapy of polycythemia vera or chronic granulocytic leukemia. ^{3, 9, 22, 28} Anemia in a cancer patient may also be due to the anemia of chronic/inflammatory disease, hemorrhage, immune-mediated mechanisms, iron deficiency, or possible myelophthisis secondary to neoplastic infiltration of the bone marrow. ⁵

Chemotherapy may occasionally result in alterations in red blood cell morphology. Poikilocytosis (a generic term referring to abnormally-shaped red blood cells) has been documented in dogs, cats, and human beings treated with the antitumor antibiotic doxorubicin. ^3,22 In cats, specific morphologic abnormalities present on blood smears following doxorubicin administration included ovalocytes, echinocytes, schistocytes, acanthocytes, and keratocytes. ²⁶ The underlying mechanisms are unknown but may include disruptions in sodium-potassium ATPase ion pumps, free radical-induced damage, and dysregulation of calcium transport. Vinca alkaloids (vincristine and vinblastine) have been associated with dysplastic changes in canine erythroid cells. Reported findings include binucleated metarubricytes, nuclear blebbing of both myeloid and erythroid cells, and bone marrow anisocytosis. ³

Leukocytes : Neutropenia is the most common and often the dose-limiting hematological toxicity encountered in cancer patients. Neutrophils are usually the first cells to manifest the antiproliferative effects of chemotherapy due to their rapid rate of cell division, short circulating half life (t ½= 10 hours) and extended bone marrow transit time (~ 5 days). ¹⁹ The maximum decrease in the neutrophil concentration, or nadir, most commonly occurs on the CBC approximately 5-10 days post-treatment. ⁸ Cisplatin may produce a bimodal nadir on both day 6 and day 15 following administration. ^3,28 However, marrow stem cells are usually unaffected by these drugs and neutrophil counts begin to rebound quickly and generally normalize within 2-3 weeks post-treatment. ^12,26

Severely neutropenic animals have an increased risk of infection. Neutrophil concentrations below 2000 cells/ul may increase the risk of sepsis. ⁹ Neutrophils from septic animals usually exhibit toxic changes (basophilic cytoplasm, Dohle bodies, cytoplasmic vacuolation, and toxic granulation). Septic animals may also be hypoglycemic, hypoalbuminemic, and have elevations in serum alkaline phosphatase. ^2,10,19

The degree of neutropenia depends upon many factors, such as the type of chemotherapeutic(s) given, the individual’s response to the therapy, and the dosage used. Severe myelosuppression can occur following doxorubicin, cyclophosphamide, and vinblastine, while moderate effects are generally seen with chlorambucil, cisplatin and vincristine. ^1,11,12 In contrast, prednisone (see below) and L-asparaginase are not known to induce neutropenia. ^22,27 However, compounds that individually have minimal effect on neutrophil counts can induce dramatic neutropenias once combined. For instance, L-asparaginase and vincristine may induce a severe neutropenia when administered together. ²⁴ Lomustine (CCNU) can cause delayed and cumulative neutropenia, in addition to thrombocytopenia and hepatotoxicity. ⁸

Glucocorticoids commonly cause characteristic alterations in the white blood cell differential count. Most typically, in dogs there is a leukocytosis characterized by a mature neutrophilia, lymphopenia, eosinopenia, and a monocytosis, which indicates a glucocorticoid-induced “stress leukogram.” ^{3, 19, 20} However, it is rare for all of these changes to be present on every CBC. For instance, chronic administration of prednisone may cause a mature neutrophilia with no other differential changes. ²⁰

Platelets: Like neutrophils, platelets have a relatively short circulating half life (t ½= 5-10 days) and a bone marrow transit time of 4-6 days. ⁹ Thrombocytopenia occurs frequently in cancer patients but is not a common cause of clinically significant coagulopathies. Generally, the risk of spontaneous bleeding usually occurs below 30,000/ul. ¹⁵ Chemotherapy-induced thrombocytopenia usually does not reduce platelet concentrations below 50,000/ul. 9 Busulfan may cause thrombocytopenia by direct damage to megakaryocytes. ³ Doxorubicin may cause a mild reduction in platelet counts followed by a rebound thrombocytosis. ²⁶ Carboplatin and cisplatin may occasionally cause severe thrombocytopenia. ^3,12,13 Vincristine and vinblastine are often used to increase release of platelets from the bone marrow and result in thrombocytosis. ⁸

Abnormalities Reflected on the Serum Biochemical Profile

Electrolytes: Chemotherapy-induced gastrointestinal disturbances often disrupt electrolyte homeostasis. Vomiting, diarrhea, and anorexia may result in hyponatremia, hypokalemia, and hypochloremia. Metabolic alkalosis is also possible if there is prolonged vomiting of gastric contents but may not result in alkalemia if metabolic acidosis secondary to dehydration is present. ¹⁶

Acute tumor lysis syndrome (ATLS) may occur following treatment of large-volume tumors with a high proliferation rate that are very sensitive to chemotherapy (such as lymphoma and acute lymphoblastic leukemia). The combination of hyperuricemia, hyperphosphatemia, hyperkalemia, metabolic acidosis, and hypocalcemia with or without azotemia indicate the presence of ATLS. ^6,9,18,23,30 Risk factors include pre-existing renal insufficiency, elevations in serum alkaline phosphatase (ALP), and elevations in serum lactate dehydrogenase. ^6,9

The pathogenesis of ATLS is related to the rapid destruction of large numbers of cancer cells which exceeds the body’s capability to excrete their cytoplasmic contents. Marked hyperkalemia (occurs ~ 12 hours post chemotherapy treatment) and hyperphosphatemia (occurs ~ 48- 96 hours post treatment) are noted on serum biochemistry. ⁶ Tumor cells that are rapidly dividing contain approximately 4x the concentration of phosphorus as normal cells. ^{7, 18} As these tumor cells are lysed, the serum phosphorus concentration may increase dramatically and bind with serum calcium forming precipitates of calcium phosphate and possibly causing hypocalcemia. ⁷ If the calcium x phosphorus product > 70 is increased, there may be nephrocalcinosis leading to renal failure. Additional renal damage occurs with the release of intracellular purines. These nucleic acids are converted into uric acid 6 which is normally resorbed in the proximal tubules and converted to non-toxic allatoin by the liver. ¹⁸ However in ATLS, uric acid may result in an obstructive nephropathy and renal azotemia secondary to crystallization of uric acid into urates. ^6,18 Increased lactate concentration may result in a high anion gap titrational metabolic acidosis. ATLS is an emergency and can result in bradycardia (secondary to hyperkalemia, hypocalcemia, and metabolic acidosis), shock, and death. ^7,23

Vincristine has been associated with hyponatremia due to the syndrome of inappropriate ADH secretion.

As mentioned earlier, serum biochemical profile abnormalities that may be found with sepsis include hypoalbuminemia, hypoglycemia, and an elevated serum alkaline phosphatase activity. Other alterations include electrolyte derangements, azotemia, and acid-base disturbances. ^2,10,16

Lipase and amylase: Increased activity of these enzymes, possibly secondary to pancreatic damage, has been described in cancer patients receiving corticosteroids, azathioprine, L-asparaginase, and cytosine arabinoside, but may occur with any chemotherapeutic protocol. ^9,21,22 Hypersensitivity to these medications is suspected to be the etiology for this complication. ^14,21,27

The highest risk for developing azathioprine-related pancreatitis occurs after 3-4 weeks but may also occur after more chronic treatment. ²¹ L-asparaginase can cause an acute hemorrhagic necrotizing pancreatitis after first time administration or, more often, after repeated dosages. ¹⁴ The mechanism is unknown but may involve direct cytotoxicity to the pancreatic parenchyma.

Common biochemical changes seen with pancreatitis include: pre-renal azotemia, mild-moderate increases in liver enzyme activity, hypocalcemia if fat saponification has occurred, electrolyte abnormalities (i.e. hyponatremia, hypochloremia) associated with vomiting/diarrhea/anorexia, and marked elevations in serum lipase and amylase activities. ⁴ Currently, pancreatic lipase immunoreactivity is considered the test of choice for accurate diagnosis of pancreatitis. Interestingly, patients treated with L-asparaginase may not exhibit increased lipase and amylase activities because of the drug’s interference with protein synthesis. ^14,27

Hepatocellular enzymes: Elevations in ALT (alanine aminotransferase), ALP (alkaline phosphatase) and/or AST (aspartate aminotransferase) activity may indicate hepatotoxicity. Prednisone is the most common chemotherapeutic agent associated with hepatocellular dysfunction and cholestasis. Mild elevations in ALT and AST are common, and in dogs a moderate to marked increases in the corticosteroid isoenzyme of ALP often results from chronic glucocorticoid administration. Specific induction of the glucocorticoid isoenzyme of alkaline phosphatase may be identified by resistance to levamisole suppression. ^2,20

In addition to prednisone therapy, hepatotoxicity can occur secondary to the administration of methotrexate and may cause acute hepatic necrosis/cirrhosis. CCNU has also been associated with a delayed hepatotoxicity. Elevations in liver enzyme activity (ALT, ALP, AST, GGT) and abnormal liver function tests (serum bile acids, BUN, albumin) have all been documented with long-term therapy with CCNU. High cumulative dosages with CCNU may cause damage directly to the hepatocytes and/or induce cholestasis, resulting in irreversible changes. ¹⁷ Other agents associated with hepatotoxicity include dacarbazine (hepatic necrosis) and azathioprine. ^9,22

Veterinarians treating animals with cancer should be aware of complications and laboratory abnormalities associated with chemotherapy. Routine CBC and serum biochemical panels may be early indicators of chemotherapy-related toxicities. Additionally, laboratory testing is recommended to help guide therapy and aid dosage adjustments in order to maintain the balance between effective chemotherapeutic treatment and untoward side effects.

References

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