eMedicine Specialties > Oncology > Special Topics in Oncology
Tumor Lysis Syndrome: Treatment & Medication
Updated: Mar 11, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
The identification of patients at risk for the development of tumor lysis syndrome is the most important aspect of management, as prophylactic measures may be initiated before the initiation of therapy. Most of the complications can be readily managed when they are recognized early; however, delay in recognition and initiation of treatment of tumor lysis syndrome can be life-threatening.
Guidelines for management of pediatric and adult tumor lysis syndrome have recently been published.19 Tumor lysis syndrome management20,21 requires initiation of preventive measures in high-risk patients prior to cancer treatment as well as prompt initiation of supportive care for patients who develop acute tumor lysis syndrome during treatment. Patients with evidence of pretreatment acute tumor lysis syndrome should be started immediately on tumor lysis syndrome treatment, withholding cancer therapy if possible until all parameters are corrected. Identify high-risk patients before treatment by assessing the extent of tumor burden, histopathologic findings, and renal function.
Conservative management and prevention of tumor lysis syndrome are similar and are discussed together.
- Hospital setting
- Cancer patients with acute manifestations of tumor lysis syndrome or those at high risk should be treated by personnel who are experienced with tumor lysis syndrome complications and treatment. An oncology unit or ICU with readily available continuous cardiac monitoring and hemodialysis capabilities is preferable.22
- If basic supportive care measures are ineffective in controlling electrolyte disturbances or renal function, nephrology and critical care consultants should be accessible to assist in further management.
- Laboratory turnover time must be rapid so that metabolic derangements can be addressed before life-threatening problems arise.
- Surveillance
- Severe manifestations of tumor lysis syndrome can be prevented only through meticulous laboratory monitoring and careful clinical observation. Necessary cardiac studies include baseline ECG with follow-up studies or continuous cardiac monitoring during treatment. Appropriate renal surveillance and fluid status determinations require baseline and daily weights, regular vital sign checks, and frequent measurements of both fluid intake and urine output.
- Patients at high risk and those with evidence of tumor lysis syndrome should have at least thrice-daily laboratory monitoring of BUN, creatinine, uric acid, potassium, calcium, phosphate, and LDH. Monitoring should continue for the first 48-72 hours after chemotherapy initiation.
- Control of hyperuricemia23
- Allopurinol is a xanthine oxidase inhibitor and is given to reduce the conversion of nucleic acid byproducts to uric acid in order to prevent urate nephropathy and subsequent oliguric renal failure. It is usually given orally as 600 mg/d for prophylaxis and 600-900 mg/d (up to a maximum of 500 mg/m2/d) for treatment of tumor lysis syndrome. Patients unable to take oral medications can be given intravenous allopurinol. Adverse effects include mild-to-severe rash, xanthine stone-induced urolithiasis, acute interstitial nephritis, pneumopathy, fever, and eosinophilia. Dose reduction is necessary in renal insufficiency; dose reduction is also necessary if given concomitantly with mercaptopurine, 6-thioguanine, or azathioprine, since allopurinol interferes with the metabolism of these agents.
- Rasburicase (recombinant urate oxidase) is a newer therapy that can be used when the uric acid levels cannot be lowered sufficiently by standard approaches.24 Rasburicase is useful in cases of hyperuricemia. Humans do not express urate oxidase; urate oxidase catalyses the conversion of poorly soluble uric acid to soluble allantoin. By converting uric acid to water-soluble metabolites, it effectively decreases plasma and urinary uric acid levels. Unlike allopurinol, uricase does not increase excretion of xanthine and other purine metabolites; therefore, it does not increase tubule crystallization of these compounds. It is administered by intramuscular injection or intravenous infusion at dosages ranging from 50-100 U/kg/d. It is contraindicated in glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and pregnancy.
- In G-6-PD deficiency, as rasburicase breaks down uric acid and accelerates catabolism of its precursors xanthine and hypoxanthine, excess hydrogen peroxide accumulates from G-6-PD deficiency, placing patients at risk for both hemolytic anemia and methemoglobinemias.25 Some authorities recommend screening for G-6-PD deficiency prior to administration of the drug.
- Studies are underway to establish safety and efficacy in those populations at highest risk for developing tumor lysis syndrome. It is approved by the U.S. Food and Drug Administration (FDA) for the prevention and treatment of hyperuricemia and tumor lysis syndrome in pediatric patients with leukemia, lymphoma, or solid organ malignancy receiving chemotherapy. It is also indicated in treatment of adults in countries like Australia, Canada, and in parts of Europe.
- Since humans do not express urate oxidase, rasburicase can potentially elicit an immune response.
- Hydration
- Volume depletion is a major risk factor for tumor lysis syndrome and must be corrected vigorously. Aggressive intravenous hydration not only helps correct electrolyte disturbances by diluting extracellular fluid, but it also increases intravascular volume. Increased volume enhances renal blood flow, glomerular filtration rate, and urine volume to decrease the concentration of solutes in the distal nephron and medullary microcirculation.
- Ideally, intravenous hydration in high-risk patients should begin 24-48 hours prior to initiation of cancer therapy and continue for 48-72 hours after completion of chemotherapy.
- Continuous infusion rates as high as 4-5 L/d (or 3 L/m2/d) yielding urine volumes of at least 3 L/d should be given unless the patient's cardiovascular status indicates impending volume overload.
- Urinary alkalinization
- Use of isotonic sodium bicarbonate solutions intravenously to promote alkaline diuresis has the potential benefits of solubilizing, and thus minimizing, intratubular precipitation of uric acid. The goal is to increase urinary pH to 7.0 to maximize uric acid solubility in renal tubules and vessels.
- Drawbacks to systemic alkaline therapy include magnification of clinical hypocalcemia by shifting ionized calcium to its nonionized form. Increased likelihood of calcium phosphate precipitation in renal tubules is an additional drawback. For these reasons, routine urine alkalinization is controversial, and if it is employed, it must include close monitoring of urinary pH, serum bicarbonate, and uric acid levels to both guide therapy and avoid overzealous alkalinization. Consider withdrawing sodium bicarbonate from intravenous fluid solutions once serum bicarbonate levels reach 30 mEq/L, urinary pH exceeds 7.5, or serum uric acid levels have normalized.
- If urinary alkalinization is not achieved with exogenous bicarbonate solutions despite increasing serum bicarbonate levels, intravenous acetazolamide at doses of 250-500 mg/d (5 mg/kg/d) may be added to decrease proximal tubule bicarbonate reabsorption, thereby increasing urinary pH.
- Diuretics
- Use of furosemide or mannitol for osmotic diuresis has not proven to be beneficial as front-line therapy. In fact, these modalities may contribute to uric acid or calcium phosphate precipitation in renal tubules in a volume-contracted patient.
- Diuretics should be reserved for well-hydrated patients with insufficient diuresis, and furosemide alone should be considered for the normovolemic patient with hyperkalemia or for the patient with evidence of fluid overload.
- Control of electrolyte disturbances
- Aggressively treat and monitor hyperkalemia. Immediately restrict dietary potassium and remove potassium from intravenous fluids. Acute treatment modalities include intravenous infusion of glucose plus insulin to promote redistribution of potassium from the extracellular to intracellular space, and intravenous calcium gluconate as cardioprotection for potassium levels greater than 6.5 mmol/L or for those with ECG alterations. Intravenous hydration with alkaline fluid as already described can also increase intracellular uptake of potassium. Potassium-wasting diuretics may be employed with caution since these may worsen renal precipitation in the volume-contracted patient. Long-term therapy such as oral potassium-exchange resins should be given immediately because of the transient effectiveness of acute treatment modalities. If these measures fail to control serum potassium, dialysis should be initiated promptly.
- Hyperphosphatemia is managed with oral phosphate binders and the same solution of glucose plus insulin used for control of hyperkalemia. Hyperphosphatemia may lead to hypocalcemia, which usually resolves as phosphate levels are corrected. In some cases, depressed serum 1,25-dihydroxycholecalciferol levels contribute to hypocalcemia, and administration of calcitriol may correct calcium levels. Such therapy, however, should not be undertaken until serum phosphate levels have normalized to avoid metastatic calcium phosphate calcifications. As a rule, do not correct hypocalcemia unless evidence of neuromuscular irritability exists, as indicated by a positive Chvostek or Trousseau sign.
- Dialysis
- If the previously mentioned methods fail, consider early initiation of dialysis. Dialysis prevents irreversible renal failure and other life-threatening complications. Indications for dialysis include persistent hyperkalemia or hyperphosphatemia despite treatment, volume overload, uremia, symptomatic hypocalcemia, and hyperuricemia.
- Hemodialysis is preferred over peritoneal dialysis because of better phosphate and uric acid clearance rates. Continuous hemofiltration also has been used and is effective in correcting electrolyte abnormalities and fluid overload.
- Because hyperkalemia can recur after dialysis is initiated and because of the high phosphate burden in some patients with tumor lysis syndrome, electrolyte levels must be monitored frequently and dialysis repeated as needed.
Consultations
- If initial supportive care measures fail to control electrolyte disturbances or renal failure, nephrology and critical care consultations are important for assistance in further management.
- Should dialysis become necessary, consultation with a surgeon to place an appropriate vascular access device is required.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Uricosurics
These agents control hyperuricemia and attempt to prevent urate nephropathy and subsequent oliguric renal failure.
Allopurinol (Zyloprim)
Inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine. Reduces synthesis of uric acid without disrupting biosynthesis of vital purines. Response measured by serum uric acid levels assessed at 48 h after initiation of therapy; dosage adjustments made prn.
Adult
600-800 mg/d PO, not to exceed 800 mg/d; alternatively, 200-400 mg/m2/d IV; not to exceed 600 mg/d
Pediatric
<6 years: 150 mg/d PO divided bid/tid, not to exceed 800 mg/d
6-10 years: 300 mg/d PO
IV: 200 mg/m2/d
>10 years: Administer as in adults
Alcohol decreases effects; ampicillin and amoxicillin increase incidence of skin rash; large amounts of vitamin C acidify urine and may cause kidney stone formation; inhibits metabolism of azathioprine and mercaptopurine (reduce dose of mercaptopurine or azathioprine to one third to one fourth the dose necessary to avoid toxicity); prolongs half-life of warfarin (monitor PT time); uricosuric agents increase urinary excretion of uric acid; thiazides may increase toxicity (monitor renal function if taken concomitantly); may increase half-life of chlorpropamide, increasing risk for hypoglycemia; may increase cyclosporine levels (adjust dose of cyclosporine when coadministered)
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Not for use in asymptomatic hyperuricemia; reduce dose in renal insufficiency; monitor liver function and perform complete blood counts before initiating therapy and periodically thereafter; potential increased risk for formation of xanthine calculi (slightly alkaline urine and sufficient fluid intake to yield urine output of at least 2 L/d recommended)
Rasburicase (Elitek)
A recombinant form (derived from Saccharomyces cerevisiae -synthesized, Aspergillus flavus) of the enzyme urate oxidase, which oxidizes uric acid to allantoin. Indicated for treatment and prophylaxis of severe hyperuricemia associated with the treatment of malignancy. Hyperuricemia causes a precipitant in the kidneys, which leads to ARF. Unlike uric acid, allantoin is soluble and easily excreted by the kidneys. Elimination half-life is 18 h.
Adult
0.15-0.2 mg/kg/d IV infused over 30 min for 5 d; dilute in 50 mL 0.9% NaCl
Pediatric
Administer as in adults
None reported
Documented hypersensitivity; G-6-PD deficiency; pregnancy
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause hemolytic anemia secondary to hydrogen peroxide produced during uric acid oxidation; may cause methemoglobinemia; other adverse effects include fever, nausea, or vomiting; children <2 y may experience more vomiting, diarrhea, fever, and rash; avoid shaking or vortexing during product reconstitution; highly antigenic, multiple administration may produce allergic reaction, anaphylaxis, or death; produces false low uric acid levels, accurate levels obtained by collecting blood into prechilled, heparin-containing tubes kept at 4°C and centrifuged at that temperature, maintain resultant plasma at 4°C and analyze within 4 h of collection
Alkalinizing agents
These agents may prevent the crystallization of uric acid.
Acetazolamide (Diamox)
Carbonic anhydrase inhibitor. May be added to decrease proximal tubule bicarbonate reabsorption, thereby increasing urinary pH.
Adult
250-500 mg/d IV (5 mg/kg/d)
Pediatric
Not established
Can decrease therapeutic levels of lithium and alter excretion of drugs (eg, amphetamines, quinidine, phenobarbital, salicylates) by alkalinizing urine
Documented hypersensitivity; hepatic disease; severe renal disease; adrenocortical insufficiency; severe pulmonary obstruction
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Patients with impaired hepatic function may go into coma; may cause substantial increase in blood glucose in some diabetic patients
Sodium bicarbonate (Neut)
Used IV to alkalinize urine. Promotes alkaline diuresis with potential benefits of solubilizing, and thus minimizing, intratubular precipitation of uric acid. Goal is to increase urinary pH to 7 to maximize uric acid solubility in renal tubules and vessels. Routine urine alkalinization is controversial, and if employed must include close monitoring of urinary pH, serum bicarbonate, and uric acid levels. Consider withdrawing sodium bicarbonate from IVF solutions once serum bicarbonate levels reach 30 mEq/L, urinary pH >7.5, or serum uric acid levels have normalized.
Adult
1 ampule (44 mEq) of sodium bicarbonate is added to 1 L of 0.45% isotonic saline and infused at 100 cc/h IV
Pediatric
1.9 mEq/kg IV q1-2h prn
Urinary alkalinization, induced by increased sodium bicarbonate concentrations, may decrease levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine
Documented hypersensitivity; alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; abdominal pain of unknown cause
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Can cause alkalosis, decreased plasma potassium, hypocalcemia and hypernatremia; caution in electrolyte imbalances (eg, patients with CHF, cirrhosis, edema, corticosteroid use, renal failure); when administering, avoid extravasation since can cause tissue necrosis
Electrolytes
These agents are used to prevent and treat hyperkalemia and restore electrolyte balance.
Dextrose (D-glucose) plus insulin
Promotes redistribution of potassium from extracellular to intracellular space. Stimulates cellular uptake of potassium within 20-30 min. Glucose should be administered along with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.
Adult
Suggested dosing:
10 U IV and 50 mL D50W bolus or 500 mL D10W over 1 h
Pediatric
Not established
Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone
Documented hypersensitivity; hypoglycemia
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Hyperthyroidism may increase renal clearance of insulin, increasing need for insulin to treat hyperkalemia; hypothyroidism may delay insulin turnover, decreasing need for insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments of insulin may be necessary in patients diagnosed with renal or hepatic dysfunction
Calcium gluconate (Kalcinate)
Used for cardioprotection for potassium levels >6.5 mmol/L or for patients with ECG alterations. Moderates nerve and muscle performance, and facilitates normal cardiac function.
Adult
100-300 mg elemental calcium IV diluted in 150 mL D5W over 10 min; initial rate of infusion should be 0.3-2 mg of elemental calcium/kg/h
Pediatric
2 mg/kg of elemental calcium IV (about 20 mg/kg of calcium gluconate 10%)
May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil; large intakes of dietary fiber may decrease absorption and levels
Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in digitalized patients, respiratory failure, acidosis, or severe hyperphosphatemia
Diuretics
These agents should be reserved for well-hydrated patients with insufficient diuresis.
Furosemide (Lasix)
Increases excretion of water by interfering with chloride-binding cotransport system that in turn inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Not proven to be beneficial as front-line therapy in TLS. May contribute to uric acid or calcium phosphate precipitation in renal tubules in volume-contracted patients.
Adult
20-80 mg/d PO/IV/IM
Pediatric
1-2 mg/kg/dose PO; not to exceed 6 mg/kg/dose; do not administer more frequently than q6h
1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg
Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; aminoglycosides increase auditory toxicity—hearing loss of varying degrees may occur; may increase anticoagulant activity of warfarin; may increase plasma lithium levels and toxicity
Documented hypersensitivity; hepatic coma; anuria; severe electrolyte depletion
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Perform frequent serum electrolyte, CO2, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter
More on Tumor Lysis Syndrome |
| Overview: Tumor Lysis Syndrome |
| Differential Diagnoses & Workup: Tumor Lysis Syndrome |
 Treatment & Medication: Tumor Lysis Syndrome |
| Follow-up: Tumor Lysis Syndrome |
| References |
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References
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Further Reading
Keywords
tumor lysis syndrome, TLS, acute tumor lysis syndrome, ATLS, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, acute renal failure, ARF, malignancy-associated hyperuricemia, acute leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, Burkitt's lymphoma, malignancy, anticancer treatment, cancer treatment, acute hyperphosphatemia, cardiac arrhythmia, metabolic acidosis, rapid tumor cell turnover, metabolic derangements, rapid cell lysis
