Some cancer centers have given IV fluids containing sodium bicarbonate to increase uric acid solubility and decrease urate crystal formation. This is somewhat controversial, as the resulting increase in urine pH may result in higher serum phosphorus levels and increased formation of calcium phosphate crystals. Clinical evidence either for or against the use of sodium bicarbonate IV fluids is not strong, and phosphorus should be monitored closely in patients receiving sodium bicarbonate IV fluids.1
Allopurinol (Lopurin, Zyloprim, generics) Allopurinol inhibits xanthine oxidase, the enzyme responsible for uric acid formation. Xanthine oxidase converts hypoxanthine to uric acid via a two-step process. Allopurinol blocks both steps, decreasing production of new uric acid. It does not, however, break down uric acid that is already formed.
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Allopurinol is considered a safe and effective method of minimizing uric acid levels in oncology patients at risk of developing hyperuricemia and TLS. One of the first published reports using allopurinol in patients with leukemia and lymphoma showed a reduction in serum uric acid in 74 of 75 patients. The one patient that did not respond had both renal insufficiency and intestinal obstruction, which may have limited the effectiveness of allopurinol.14
The oral form of allopurinol is dosed between 600 to 800 mg/day in two to three divided doses. The maximum dose of the IV formulation is 600 mg/day. Patients should be monitored for potential drug-drug interactions between allopurinol and some chemotherapy drugs.13 For example, allopurinol inhibits the metabolism of mercaptopurine and azathioprine.15 Pharmacists should review the patient’s chemotherapy and medications to detect these drug-drug interactions.
Rasburicase (Elitek) The human body does not break down uric acid into a more easily excreted compound. Other organisms naturally produce urate oxidase, which breaks uric acid down into allantoin, a compound that is more easily excreted. Recombinant technology has made the manufacture of a therapeutic formulation of urate oxidase (rasburicase) possible. Rasburicase is a potent agent used to eliminate circulating uric acid. The FDA approved rasburicase for the management of uric acid levels in both adult and pediatric patients at risk of developing TLS.16
Rasburicase has been shown to reduce serum uric acid levels faster than allopurinol, and to a higher degree. In a study by Goldman and colleagues, pediatric patients treated with rasburicase had an average uric acid reduction of 86%, versus a 12% reduction for patients treated with allopurinol. A reduction in the uric acid area under the curve (AUC) of 61% was also seen in the rasburicase group. This indicates that the response was sustained over several days.17
The labeled dose of rasburicase is 0.2 mg/kg daily for up to 5 days; however, alternate dosing strategies have been studied.15 The Detroit Medical Center reported administering a single dose of 0.15 mg/kg of rasburicase to patients at high risk of developing TLS.18 Even 96 hours later, all eight patients had a serum uric acid level below 4 mg/dL. The authors estimate that using a single dose, instead of repeated daily doses, saved their institution more than $100,000 (2003 dollars) on the treatment of those eight patients alone.18
Other institutions have used single-dose regimens of rasburicase at lower, fixed (not weight-based) doses. Studies have evaluated one-time doses of 3 to 7.5 mg for adult patients at high risk of developing TLS. These have been shown effective at reducing serum uric acid concentration to safe levels. The responses have also been long-lasting for most patients. Single 3-mg doses of rasburicase have been shown to achieve and maintain normal serum uric acid levels (less than 8 mg/dL) for 48 hours.19-22 As such, many adult patients are treated with fixed doses of 3 to 6 mg.13
A few precautions related to the use of rasburicase should be noted. Because it is a biologic product, patients may develop antibodies against it. These antibodies can trigger an allergic reaction or limit the effectiveness of rasburicase. In addition, rasburicase should not be given to patients with a glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD is needed to eliminate the hydrogen peroxide produced when rasburicase converts uric acid to allantoin. Patients with insufficient G6PD are at risk of developing methemoglobinemia and hemolysis. Patients of Asian or African descent are at higher risk for G6PD deficiency. Screening these patients for G6PD is recommended prior to treatment with rasburicase. The biologic has caused fetal damage in animal models, so should only be given to pregnant women if the benefit to the mother outweighs the potential risk to the fetus.1,2,8
Rasburicase will continue to break down uric acid in the blood, even after the blood sample is drawn from the patient. Therefore, blood samples drawn from a patient treated with rasburicase should be put on ice immediately and analyzed within 4 hours of collection.17 Chilling the blood sample reduces the activity of rasburicase. Samples not put on ice will return a falsely low uric acid level.
PROPHYLACTIC RECOMMENDATIONS BY RISK LEVEL
Low risk The initial prophylaxis and monitoring plan depends on the risk of developing TLS. For patients at low risk, adequate hydration to maintain target urine output is usually effective. Allopurinol can be considered for these patients. Monitoring for changes in potassium, phosphorus, uric acid, calcium, and serum creatinine levels should be performed every day, and more frequently if symptomatically indicated.1,2
Intermediate risk Patients at intermediate risk for TLS should receive the same aggressive hydration, plus allopurinol. Allopurinol should be started 2 to 3 days prior to chemotherapy, if possible, and continued for 10 to 14 days.13 Intermediate-risk patients should have their serum calcium, creatinine, phosphorus, potassium, and uric acid levels monitored every 8 to 12 hours initially. Laboratory monitoring can be performed less frequently once the patient has completed 2 days of chemotherapy.1,2
High risk Hydration and urine output goals for patients at high risk of developing TLS are the same as for patients at lower risk. Patients at high risk for TLS should receive a single prophylactic dose of rasburicase. The prophylactic dose can be repeated if repeat uric acid levels are elevated. High-risk patients should have their serum calcium, creatinine, phosphorus, potassium, and uric acid levels checked every 4 to 6 hours for the first 2 days of chemotherapy. Laboratory monitoring may be performed less frequently once the patient has completed 2 days of chemotherapy.1,2
Some clinicians choose to treat high-risk patients with a prephase to lessen the risk of TLS. A prephase can consist of steroid monotherapy or lower doses of the chemotherapy that will be used to treat the cancer. Prephase treatments may last 5 to 7 days.23,24 The rationale for a prephase is that the lower-intensity treatment will kill cancer cells more slowly than typical chemotherapy regimens, releasing cell contents more slowly with less chance of TLS developing.1
Patients who develop laboratory TLS, regardless of their initial risk level, should be treated proactively. Intravenous hydration should be continued at 2.5 to 3 L/m2/day, if tolerated. Hyperkalemia, hyperphosphatemia, hypocalcemia, and other electrolyte abnormalities should be managed per institutional guidelines. A pharmacist should be consulted to evaluate the patient’s medications to determine if any other medications are contributing to the electrolyte disturbances (eg, medications that contain potassium). Patients who develop hyperuricemia, regardless of initial risk stratum, should be treated with rasburicase at the same dose used for prophylactic dosing. In the event of acute kidney injury, patients may require hemodialysis. TLS can worsen rapidly if left uncorrected, so the threshold for initiating hemodialysis may be lower in patients with TLS than in other patient populations.1
CONCLUSION
Tumor lysis syndrome is a serious, potentially fatal complication of cancer treatment. The possible complications of this syndrome can be minimized by proactive risk stratification, prophylactic therapies, and vigilant monitoring. Prevention and treatment of TLS requires frequent assessment of electro-lytes and clinical symptoms, as well as administration of fluids and medications. Oncology nurses are vital to the early detection and proper management of TLS. ONA
Kevin Curler is an oncology pharmacy practice resident at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado. Lisa Thompson is assistant professor, Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.
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