Acute tumor lysis syndrome (ATLS), although

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1 ACUTE TUMOR LYSIS SYNDROME Michele Cohen, DVM, DACVIM (Oncology) College of Veterinary Medicine Auburn University Auburn, Alabama Acute tumor lysis syndrome (ATLS), although uncommon, can be a serious and occasionally fatal complication of cancer treatment. ATLS results from the rapid lysis of tumor cells, which causes the release of intracellular contents into the circulation. The release of large amounts of purines, lactate, and uric acid from tumor cells can overwhelm the metabolic and excretory capabilities of the kidneys and liver. When the clearance of these waste products is slowed or inhibited, ATLS occurs. This syndrome is classically categorized by hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia. Metabolic acidosis and azotemia have also been reported. Clinical signs can result from any of these metabolic abnormalities; if left untreated, they can lead to acute renal failure or death. In humans, ATLS is most commonly associated with highly proliferative hemolymphatic tumors, such as high-grade lymphomas and acute leukemias, although some reports of solid tumors exist. ATLS has been reported in dogs with advanced lymphoma (stages IV and V) and in one cat with lymphoma. DIAGNOSTIC CRITERIA Historical Information Gender Predisposition: No gender predisposition has been identified. Age Predisposition: No age predisposition has been identified for the development of ATLS. Middle-aged to older dogs are most commonly affected with lymphoma. Breed Predisposition: Breed predilection for ATLS is unknown because of a lack of reported cases. Chronic liver and renal disease are known risk factors for ATLS in humans, so presumably dogs with these diseases would be at increased risk. Dalmatians are at risk for KEY TO COSTS $ indicates relative costs of any diagnostic and treatment regimens listed. $ costs under $250 $$ costs between $250 $500 $$$ costs between $500 $1000 $$$$ costs over $1000 hyperuricemia because they lack uricase, which is needed to convert uric acid to allantoin. Therefore, dalmatians may also be at increased risk for ATLS. Owner Observations: Owners may notice nausea, vomiting, anorexia, lethargy, weakness, muscle fasciculations, spasmodic movements, tetanic seizures, or even sudden death typically within 4 days after treatment. Other Historical Considerations/Predispositions (Table 1): Renal disease results in decreased clearance of uric acid, phosphorus, and potassium. Extensive tumor burden or tumors that are rapidly growing and are very sensitive to chemotherapy or radiation predispose patients to acute tumor lysis. Dogs with stage IV and V lymphoma are at increased risk. Preexisting hypercalcemia predisposes the patient to form calcium phosphorus complexes, which contribute to renal failure. Patients with severe liver disease have a diminished ability to metabolize waste products from tumor cells. Rapid tumor necrosis after chemotherapy or radiation therapy overwhelms the ability of the liver and kidneys to metabolize waste products. Physical Examination Findings The clinical presentation of ATLS varies depending on the time of presentation in the course of the crisis. Typically, animals with ATLS will have had a very rapid and measurable response to the cancer therapy (i.e., rapid reduction in the size of enlarged lymph nodes, resolution of circulating lymphocytosis). Physical examination findings can be vague and include signs such as weakness, lethargy, shock, or bradycardia or can be referable to the metabolic abnormalities. Signs of hyperuricemia include oliguric renal failure and related symptoms. Signs of hypocalcemia include anorexia, lethargy, vomiting, pruritus, muscle tremors, tetany, and seizures. Signs of hyperkalemia include weakness, cardiac arrhythmias, and neuromuscular abnormalities. 7

2 TABLE 1 Risk Factors for Acute Tumor Lysis Syndrome The risk factors for ATLS can best be remembered with the mnemonic REDHEN: Renal disease Extensive tumor burden Dalmatians Hypercalcemia (pre-existing, i.e., associated with lymphoma) End-stage liver disease Necrosis (rapid tumor necrosis after treatment) Laboratory Findings Hyperphosphatemia is the most common metabolic abnormality of ATLS in dogs. Lymphoblasts have four times the amount of phosphorus as lymphocytes. Lysis of tumor cells results in the release of enormous amounts of phosphorus into the blood and urine. Occasionally, triple phosphate crystals can be seen in the urine. Hypocalcemia often accompanies hyperphosphatemia via the formation of calcium phosphate complexes. These complexes can precipitate in the renal tubules and ultimately lead to renal failure. Hyperuricemia results from the release of purines into the circulation. Through a series of steps (Figure 1), the purines are metabolized into uric acid by xanthine oxidase in the liver. The excessive serum uric acid (hyperuricemia) and urine levels that result can lead to precipitation in the renal tubules, thereby contributing to renal failure. Unlike humans, dogs have the enzyme uricase, which converts uric acid into allantoin; therefore, they may be at decreased risk for developing hyperuricemia. Dalmatians, which lack uricase, and dogs with liver disease that have diminished or impaired uricase, may be at an increased risk. Hyperkalemia results from the release of intracellular potassium into the circulation and usually is seen within 12 to 48 hours following chemotherapy. Hyperkalemia is not a consistent laboratory finding in dogs with ATLS, unless it is associated with acute renal failure. Purines Hypoxanthine Xanthine Uric Acid Allantoin Azotemia can occur as a result of any of the reasons mentioned above. Metabolic acidosis often occurs as the result of lactic acidosis. Tumor cells such as lymphoblasts preferentially use anaerobic metabolism, and lactate is produced as the result of glycolysis. Other Diagnostic Findings Electrocardiography Continuous ECG monitoring of patients with ATLS is essential to identify abnormalities associated with metabolic disturbances. Cardiac changes can occur with serum potassium levels greater than 6.5 meq/l. Typical ECG changes associated with hyperkalemia include tall peaked T waves, wide QRS complexes, a prolonged PR interval, bradycardia, atrial standstill, ventricular fibrillation, or asystole. Hypocalcemia can cause tachycardia or prolonged QT intervals. $ Urinary Catheter Placement Urinary catheter placement is recommended if there is evidence of impending oliguric or anuric renal failure. The catheter will allow quantification of urine production and provide assistance in diuresis. $ Central Venous Pressure Monitoring Placing a central venous catheter is important if there is evidence of renal failure. Monitoring central venous pressure is crucial in patients with acute renal failure to prevent fluid overload. $ Blood Pressure Monitoring Blood pressure monitoring is important in critical care patients. Alterations in blood pressure can result from various mechanisms during ATLS, including metabolic abnormalities, renal failure, and shock. $ Body Weight Monitoring Monitoring of central venous pressure, blood pressure, and urine output should be coupled with frequent measurement of body weight. Increases in body weight support an increase in body fluid either rehydration or fluid retention. Decreases in body weight suggest inadequate fluid support and potential dehydration. Xanthine oxidase Xanthine oxidase Uricase Abdominal Radiography/Ultrasonography May be useful to look for mineralization of the kidneys or ureteral obstruction. $ FIGURE 1 Metabolism of Purines Allopurinol Thoracic Radiographs Useful to look for evidence of fluid overload if the patient is in oliguric renal failure. $ 8 S E P T E M B E R V O L U M E 5. 8

3 Summary of Diagnostic Criteria History of cancer treatment within the last 96 hours in an animal with a large tumor burden (typically advanced lymphoma). Clinical signs may include: Vomiting. Anorexia. Weakness. Muscle fasciculations. Tetany. Seizures. Sudden death. Physical examination findings typically include signs referable to the metabolic abnormalities of ATLS: Weakness. Muscle fasciculations. Cardiac arrhythmias. Laboratory findings: BUN, creatinine, and urinalysis indicate renal dysfunction. Hypocalcemia, hyperphosphatemia, and hyperkalemia are the hallmark metabolic abnormalities. Lactic acidosis may be seen. ECG monitoring may document changes referable to one of the following: Hyperkalemia (peaked T waves, wide QRS complex, prolonged PR interval progressing to bradycardia, atrial standstill, ventricular fibrillation, or asystole). Hypocalcemia (tachycardia or prolonged QT intervals). If renal failure occurs, tests/procedures that may be useful include urinary catheter placement to measure urine production, central venous catheter placement to measure central venous pressure, abdominal radiography and/or ultrasonography to check for mineralization or obstruction, and thoracic radiography to check for fluid overload. Differential Diagnoses ATLS can present with signs similar to renal failure, the causes of which include chemotherapy drug toxicity, acute pyelonephritis, tumor metastasis/ invasion into the kidneys, and lower urinary tract obstruction. Hypoadrenal crisis should also be considered. The clinical signs of chemotoxicity or radiation toxicity (half or whole body) are similar to those of ATLS lethargy, diarrhea, vomiting, and anorexia. While treatment toxicity is usually noticed either shortly after therapy (i.e., emesis following cisplatin administration) or several days following treatment, signs from gastrointestinal insult, ON THE NEWS FRONT Urate oxidase has been recently approved by the FDA for use in human patients to decrease uric acid load. Urate oxidase converts uric acid to allantoin, which is water soluble and easily excreted. In humans with ATLS, uric oxidase appears to be useful in decreasing hyperuricemia. and, rarely, neutropenia can occur as early as 3 to 5 days after treatment. Complete blood count and serum chemistry profile will differentiate treatment toxicity from ATLS. Pseudohyperkalemia is a laboratory error that results from lysis of cells during collection or processing of blood samples and should be ruled out. It typically occurs in samples with very high white blood cell or platelet numbers, which release large quantities of potassium when lysed. The red blood cells of Akitas have very high concentrations of potassium, which can result in pseudohyperkalemia during blood sampling. TREATMENT RECOMMENDATIONS Prophylactic Therapy Preventive measures should be instituted in all patients considered at risk for developing ATLS. Human cancer patients at risk for ATLS receive prophylactic therapy 24 to 48 hours before treatment. These treatments include aggressive fluid diuresis, administration of allopurinol, and alkalinization of the urine. Allopurinol, 7 to 10 mg/kg PO tid, inhibits xanthine oxidase, which converts hypoxanthine to xanthine and xanthine to uric acid. Sodium bicarbonate can be given as a bolus of 2 to 3 meq/kg IV over 30 minutes for the treatment of hyperkalemia. It can also be added to the intravenous fluids to alkalinize the urine (optimum ph 7 to 7.5), which results in increased solubility of uric acid and decreased precipitation in the renal tubules. Alkalinization of the urine in dogs is not recommended because it can promote phosphate deposition in the tubules. Diuresis for 12 to 24 hours before chemotherapy or radiation therapy and for 24 to 48 hours after therapy may be advisable in at-risk veterinary patients. Decreasing the induction chemotherapy dose or altering the administration of multiple drugs may be another consideration for at-risk dogs. Initial Treatment The most critical step in the treatment of ATLS is diuresis. Aggressive fluid diuresis with at least two to three times daily maintenance requirements (40 to 60 ml/kg/day) after fluid deficits have been 9

4 TABLE 2 Treatment of Metabolic Abnormalities of ATLS Drug Dosing Instructions Mechanism of Action Hyperkalemia: Treatment is warranted if serum potassium >6.5 meq/l and/or ECG changes are present Furosemide 2 mg/kg IV Promotes potassium and phosphorus excretion by inhibiting reabsorption of sodium and chloride; use with caution in renal failure Regular insulin 5 U/kg/hr IV with 2 g dextrose/u of Causes immediate intracellular influx of potassium and dextrose insulin; discontinue infusion when normokalemic Sodium bicarbonate 2 3 meq/kg IV over 30 min Causes alkalosis, which causes intracellular influx of potassium Calcium gluconate If potassium >8 meq/l, give Indicated in cases of hyperkalemia-induced ml/kg of a 10% calcium gluconate cardiac arrhythmias to reestablish cardiac solution IV over min while excitability monitoring ECG Hyperphosphatemia Aluminum hydroxide mg/kg PO sid tid Decreases intestinal absorption of phosphorus Hyperuricemia: Not typically a significant problem in dogs, but allopurinol can be administered if clinically apparent Allopurinol 7 10 mg/kg PO tid Inhibits xanthine oxidase Urate oxidase Dose not established for dogs Converts uric acid to allantoin Hypocalcemia Calcium gluconate Give mg/kg ( ml/kg) Replaces calcium deficit of a 10% calcium gluconate solution via slow IV over 20 min; stop infusion if bradycardia develops; after bolus, give ml/kg over 24 hr; continue until hypocalcemia resolves or switch to calcium lactate g/day PO replaced will promote excretion of the excess potassium, phosphorus, and uric acid in the body. Rehydration and diuresis will also help to resolve the lactic acidosis that has developed. While the type of fluid administered is not that crucial, a fluid with low potassium content such as 0.9% NaCl (0 meq/l), Ringer s solution (4 meq/l), or Normosol R (5 meq/l) should be chosen. If the patient is hypocalcemic, 0.9% NaCl may not be an appropriate choice because it promotes calciuresis. A solution with supplemental calcium should be considered, such as lactated Ringer s solution, which contains 4.5 meq/l of calcium. Some clinicians believe that lactate-containing fluids may be a suboptimal choice for treating ATLS because these animals are already hyperlactemic. This is primarily a theoretical rather than a practical concern. Additional therapy depends on the metabolic derangement present (Table 2). Alternative/Optional Treatments/ Therapy If the metabolic derangements and/or acute renal failure cannot be controlled with conservative medical therapy, peritoneal dialysis or hemodialysis may be necessary. Supportive Treatment Discontinue cancer therapy temporarily until ATLS is resolved. Ensure adequate caloric intake. Patient Monitoring Monitor ECG for arrhythmias. Monitor electrolytes frequently. Monitor creatinine and BUN frequently. Monitor urine production. Monitor central venous pressure. 10 S E P T E M B E R V O L U M E 5. 8

5 Home Management Patients with ATLS should not be sent home until all physical examination findings and clinicopathologic parameters are improved. Any patient at risk for developing ATLS should be hospitalized for 24 to 48 hours after therapy for appropriate management and monitoring. All clients should be informed of the signs of ATLS and should be instructed to seek medical attention immediately. Milestones/Recovery Time Frames If ATLS is identified early in the crisis (i.e., if blood work reveals abnormalities before clinical signs become apparent), the metabolic abnormalities can typically be improved with fluid diuresis prior to any evidence of problems. Restoration of severe metabolic derangements typically takes 24 to 48 hours. Renal function usually improves if there is mild compromise; however, permanent renal damage can occur. Treatment Contraindications Chemotherapy or radiation therapy should be discontinued temporarily until the syndrome has resolved. Avoid fluids that contain excessive potassium. Avoid anesthesia to minimize renal compromise. Avoid nephrotoxic drugs. PROGNOSIS Because there are so few reports of ATLS in animals, prognosis is difficult. Early identification of affected patients brings a greater likelihood of successful outcome. If ATLS is allowed to progress, the metabolic abnormalities can lead to such complications as cardiac arrhythmias, renal failure, and death. RECOMMENDED READING Brooks DG: Acute tumor lysis syndrome in dogs. Compend Contin Educ Pract Vet 7(9): , Calia CM, Hohenhaus AE, Fox PR, Meleo KM: Tumor lysis syndrome in a cat. J Vet Intern Med 10(6): , DiBartola SP: Fluid Therapy in Small Animal Practice, 2 nd ed. Philadelphia, Lea & Febiger, 2000, pp Ezzone SA: Tumor lysis syndrome. Semin Oncol Nurs 15(3): , Laing EJ, Carter RF: Acute tumor lysis syndrome following treatment of canine lymphoma. JAAHA 24: , Plumb DC: Veterinary Drug Handbook, ed 4. Ames, Iowa State Press, Wetzein GA: Tumor lysis syndrome: A treatment guide. Oncol Special Edition 4: ,