Drug Criteria & Outcomes

Tumor lysis syndrome: An ounce of prevention is worth a pound of cure

By Jon Case, PharmD, Pharmacy Practice Resident, Huntsville Hospital, Huntsville, AL

Tumor lysis syndrome (TLS) is a serious and life-threatening complication that is frequently seen following initiation of chemotherapy. It is most commonly associated with the treatment of lymphoproliferative malignancies such as acute lymphocytic leukemias and non-Hodgkin lymphomas. Risk factors include rapidly proliferative bulky tumors, tumors with high sensitivity to chemotherapy, extensive bone marrow involvement, and lactate dehydrogenase levels > 1,500 IU.

Metabolic disturbances

The condition is characterized by metabolic disturbances that include hyperkalemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia. These metabolic disturbances result from release of intracellular contents (i.e., ions and metabolic by-products) into the systemic circulation due to rapid killing of neoplastic cells and are usually seen within 48-72 hours after starting chemotherapy with hyperkalemia often appearing first.

Acute renal failure, which often develops due to calcium-phosphate and uric acid crystal depositions in the renal tubules, is another concern with TLS. Also, because the kidney is the main organ involved in the clearance of potassium, phosphate, and uric acid, pre-existing renal impairment or intravascular volume depletion puts the patient at significantly more risk of developing TLS and acute renal failure.

Identification of patients at high risk for developing TLS is of key importance, as delay in recognizing TLS and initiating treatment can be life-threatening. The treatment strategy should include adequate hydration and management of metabolic disturbances. Intravenous hydration, with continuous infusion as high as 4-5 L/day, should be started 24-48 hours before beginning chemotherapy and continue 48-72 hours after chemotherapy is complete unless otherwise contraindicated.

Management, treatment, prevention

There are various approaches to management of the metabolic disturbances associated with TLS. In the case of acute renal failure, hemodialysis may prove the most appropriate method of managing the associated metabolic abnormalities. Management of hyperkalemia and hyperphosphatemia should be aggressive and include careful monitoring. Management of hyperuricemia includes the option to alkalinize the urine through the use of intravenous sodium bicarbonate with the goal to achieve a urinary pH close to.7 Because uric acid is more soluble in alkaline environments, urine alkalinization may reduce the amount of uric acid crystallization in the renal tubules. The danger associated with urinary alkalinization is that it may promote calcium-phosphate precipitation in the renal tubules.

Another option for the prevention/treatment of hyperuricemia is the use of a uric acid-lowering agent (i.e., allopurinol or rasburicase). Allopurinol inhibits xanthine oxidase, the enzyme responsible for the formation of uric acid. The recommended dosage of allopurinol is 600-800 mg PO daily for 2-3 days or 200-400 mg/m2/day IV (maximum of 600 mg/m2/day IV) as a continuous infusion or in equally divided infusions at 6-, 8-, or 12-hour intervals. It is recommended that the final concentration not exceed 6 mg/mL.

Rasburicase is a recombinant urate oxidase, which metabolizes uric acid to a more soluble metabolite (allantoin) and is not naturally found in humans. Rasburicase presents a good choice in the treatment of baseline hyperuricemia in that it can break down existing uric acid whereas allopurinol cannot. The recommended dosage of rasburicase is 0.15 mg/kg or 0.2 mg/kg as a single IV infusion over 30 minutes for up to five doses given no more frequently than daily. After one dose, there is often a dramatic decrease in serum uric acid and further doses may not be needed. Monitoring electrolytes, hydration status, and uric acid concentrations should be used to identify the need for additional doses of rasburicase.

The safety of rasburicase has been established only for a single course of therapy. Gastrointestinal symptoms along with hypersensitivity reactions are the most commonly reported adverse events. Because breakdown of uric acid by rasburicase causes the formation of hydrogen peroxide, patients with documented glucose-6-phosphate dehydrogenase deficiency should not be given rasburicase due to the increased risk of hemolysis. Also, known hypersensitivity (anaphylaxis) or hematologic (hemolysis, methemoglobinemia) reaction to rasburicase or any of its components is a contraindication for the use of this drug. Serious hypersensitivity reactions (e.g., urticarial rash, Stevens-Johnson syndrome, toxic epidermal necrolysis) to allopurinol have been reported and should be monitored for in patients receiving this drug.

Both allopurinol and rasburicase are effective in managing elevations of uric acid levels in patients. The choice of one drug over the other should be based on patient-specific factors and drug cost considerations.

Cost comparison

The drug acquisition cost of allopurinol is much lower, especially if oral administration is possible, compared to rasburicase (one day of therapy, adult dose calculated as 70 kg or BSA 1.73 m2: rasburicase = $3,500; IV allopurinol = $800.00; oral allopurinol = $0.32). Due to the increased cost, rasburicase should be reserved for patients that are at high-risk for developing TLS and hyperuricemia with impaired renal function, patients that need a rapid reduction in uric acid levels, patients that have a history of a serious adverse drug reaction to allopurinol, or patients who are not responding to allopurinol therapy.

Conclusion

Tumor lysis syndrome presents a significant clinical problem in which early detection and initiation of treatment is important to the outcome of the patient. The treatment strategy for TLS should include adequate hydration, management of electrolyte disturbances, and correction of uric acid levels. The currently available uric acid-lowering agents, allopurinol and rasburicase, can both provide a significant clinical benefit in a patient with TLS when used appropriately.

Resources

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  2. Davidson MB, Thakkar S, Hix JK, et al. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med 2004;116:546-554.
  3. Ikeda AK, Sakamoto K. Tumor lysis syndrome. Available at www.emedicine.com/ped/topic2328.htm. Accessed Dec. 26, 2006.
  4. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001;97:2998-3003.
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