New guidelines issued for tumor lysis syndrome
Tumor lysis syndrome is a group of metabolic abnormalities that arise from tumor breakdown that exceeds the body’s ability to excrete the excess metabolic by-products. Characteristics of tumor lysis syndrome include hyperuricemia, impaired renal function, hyperkalemia, hyperphosphatemia and hypocalcemia. Recently, a group of researchers published comprehensive guidelines in the prevention and treatment of tumor lysis syndrome.
Tumor lysis syndrome is more common in patient care situations where there is a faster production and lysis of tumor cells. This includes tumors that have a high proliferation rate, are highly sensitive to chemotherapy or radiation therapy, and have a large tumor size or burden. Tumor lysis syndrome has been described most commonly with acute myeloid leukemia, acute lymphoid leukemia and moderate- to high-grade lymphomas, including Burkitt’s lymphoma. Tumor lysis syndrome is most common with the first cycle of chemotherapy and with the first few days of therapy. In addition, patients with pre-existing dehydration, poor urine output, renal impairment or pre-existing hyperuricemia are at higher risk for tumor lysis syndrome. The investigators who wrote the new guidelines have grouped patients at high, intermediate and low risk (see table 1.)
Hyperuricemia is caused by the breakdown of nucleic acids from tumor cells faster than the kidney can excrete the uric acid. Uric acid is poorly soluble in the urine and, if the solubility is exceeded, it can crystallize in the kidneys and cause acute kidney injury.
Vigorous IV hydration with diuresis has long been the cornerstone to prevention and treatment of tumor lysis syndrome (to achieve urine output of 80 mL/m2 per hour to 100 mL/m2 per hour.) By increasing intravascular volume and urine output, it increases the renal excretion of uric acid and phosphate. Alkalization of the urine with administration of sodium bicarbonate, although long employed in an effort to improve the solubility of uric acid in the filtered urine, is not currently recommended due to the lack of supporting evidence and potential for enhancing the precipitation of xanthine in the urine.
Allopurinol works to lower serum uric acid levels by reducing the production of uric acid from purine precursors by inhibiting xanthine oxidase. Because it does not alter the uric acid already formed, it works best when initiated one to three days prior to chemotherapy. It is generally well tolerated, but can cause skin rash, increased liver function tests and also exhibits drug interactions, notably with warfarin, mercaptopurine and azathioprine. It can be given orally or intravenously and the dose should be adjusted for pre-existing renal impairment.
More recently, rasburicase has been introduced to prevent or treat hyperuricemia. Rasburicase is recombinant urate oxidase and works to degrade preformed uric acid. It works quickly and profoundly, often dropping the uric acid level to levels less than normal in a few hours. However it should be noted that rasburicase continues to degrade uric acid after blood samples have been taken, and spuriously low uric acid levels can be seen if the sample is not placed on ice and analyzed immediately. Although contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency, it is well tolerated. The traditional recommended dosage is 0.15 mg/kg per dose to 0.2 mg/kg per dose IV daily for up to seven days.
The researchers recommend the use of rasburicase in the initial management of high-risk patients and as backup therapy for moderate-risk therapy for those patients who go on to develop hyperuricemia despite allopurinol and hydration (see table 2.)
Lower rasburicase doses
Unfortunately, rasburicase is expensive and cannot be recommended for use in all patients. Recently, other researchers have studied the use of lower, fixed dosage rasburicase in adult patients. These dosages range from 3 mg to 6 mg and are substantially lower than 0.15 mg/kg per dose to 0.2 mg/kg per dose. These regimens also employ only one to two daily doses instead of the five to seven doses otherwise recommended. These researchers have found that these lower dose, shorter course regimens adequately lower the uric acid levels in adult patients. These alternative regimens substantially lower the cost of rasburicase treatment and make it available to more patients.
The guideline researchers recommend higher doses of rasburicase for high-risk patients (if uric acid level <7.5 mg/dL, 0.2 mg/kg per dose) intermediate dose for intermediate-risk patients (if uric acid level >7.5 mg/dL, 0.15 mg/kg per dose) and low dose for low-risk patients (if uric acid level <7.5 mg/dL, 0.1 mg/kg per dose) with treatment courses ranging from one to seven days based on uric acid levels and clinical judgment. Further therapy with rasburicase is not needed when the uric acid levels have fallen to very low levels or are undetectable.
Hyperkalemia in tumor lysis syndrome is caused by release of intracellular contents faster than the kidney can excrete the excess. This places the patient at risk for cardiac arrhythmias and cardiac arrest, as well as muscle cramps and paresthesias. To prevent hyperkalemia, potassium should be withheld from IV fluids. Aggressive hydration and loop diuretics, already employed to lower uric acid levels, will help excrete potassium as well. Treatment of hyperkalemia includes sodium polystyrene, insulin/glucose infusions, calcium gluconate and potentially sodium bicarbonate. Hemodialysis or other renal replacement therapies may be necessary for life-threatening hyperkalemia.
Hyperphosphatemia is also caused by rapid release of intracellular contents in tumor lysis syndrome, and inability of the kidney to excrete the overload. Hyperphosphatemia can lead to renal impairment, nausea/vomiting and seizures. Treatment of hyperphosphatemia includes oral administration of phosphate binders (calcium acetate, calcium carbonate, sevelamer, aluminum hydroxide) or moderately elevated levels, or hemodialysis in severe cases.
Hypocalcemia in tumor lysis syndrome is due to deposition of phosphate-calcium complexes prompted by hyperphosphatemia. Hypocalcemia can manifest as cardiac arrhythmias, muscle cramps and tetany. Because further calcium administration can exacerbate this precipitation, correction of the calcium levels is not recommended unless the patient is symptomatic. In these cases, judicious use of IV calcium gluconate is recommended.
Supportive care of the patient at risk for tumor lysis syndrome includes eliminating medications that could exacerbate one of the component conditions (eg, thiazides, diuretics, potassium supplements and potassium sparing diuretics), careful monitoring of intake and output and use of loop diuretics when needed, and careful monitoring of serum electrolytes and renal function. This new guideline on the prevention and treatment of tumor lysis syndrome can help guide the use of specific therapies.
Lisa Lohr, PharmD, BCPS, BCOP, is a Clinical Pharmacist in Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center and is a HemOnc Today Editorial Board member.
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