Important: This is NOT complete and total information on this subject. This is just standard/general information with standard recommendations; it is imperative that you know how to handle TLS and that you do your own due diligence to stay up on the latest information.

In tumor lysis syndrome, a constellation of clinical symptoms may develop prior to the initiation of or within 72 hours after the administration of cytotoxic therapy. Inquiries should be made with regard to the following:

• Time of onset of symptoms of malignancy
• Presence of abdominal pain and distension
• Presence of urinary symptoms - Such as dysuria, oliguria, flank pain, and hematuria
• Occurrence of any symptoms of hypocalcemia - Such as anorexia, vomiting, cramps, seizures, spasms, altered mental status, and tetany
• Symptoms of hyperkalemia - Such as weakness and paralysis

Other symptoms of tumor lysis syndrome include the following:

• Lethargy
• Edema
• Fluid overload
• Congestive heart failure
• Cardiac dysrhythmias
• Syncope
• Sudden death

International Occurrence

The incidence of tumor lysis syndrome is unknown. The prevalence varies among different malignancies; bulky, aggressive, treatment-sensitive tumors are associated with higher frequencies of tumor lysis syndrome. In studies of frequency in patients with intermediate-grade or high-grade non-Hodgkin lymphomas, laboratory evidence of tumor lysis syndrome (42%) occurred much more frequently than the symptomatic clinical syndrome (6%). In children with acute leukemia receiving induction chemotherapy, silent laboratory evidence of tumor lysis syndrome occurred in 70% of cases, but clinically significant tumor lysis syndrome occurred in only 3% of cases.

As advances are made in cancer treatment and as high-dose regimens become more common place, tumor lysis syndrome incidence may increase and the syndrome may emerge in a broader spectrum of malignancies.

Age-related Demographics

Although tumor lysis syndrome occurs in all age groups, advanced age leading to impaired renal function may predispose patients to clinically significant tumor lysis syndrome owing to a decreased ability to dispose of tumor lysis byproducts.

Prognosis

Early recognition of signs and symptoms of patients at risk for tumor lysis syndrome, including identification of abnormal clinical and laboratory values, can lead to successful prevention of the otherwise life-threatening complications of the condition.

Potential complications of tumor lysis syndrome include uremia and oliguric renal failure due to tubule precipitation of uric acid, calcium phosphate, or hypoxanthine.

Severe electrolyte disturbances, such as hyperkalemia and hypocalcemia, predispose patients to cardiac arrhythmia and seizures.

Iatrogenic complications, such as pulmonary edema from overly vigorous hydration or metabolic alkalosis from excess exogenous administration of bicarbonate, can also occur and are life threatening if not immediately addressed.

Acute Renal Failure

Renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine causes acute renal failure. This is often oliguric (< 400 mL daily) in nature, leading to volume overload and complications of hypertension and pulmonary edema.

High blood urea nitrogen (BUN) levels due to increased protein catabolism and renal impairment can be severe enough to result in pericarditis, platelet dysfunction, and defective cellular immunity. Renal dysfunction can be severe enough to require dialysis, but with prompt supportive measures, it is usually reversible.

Cardiac Arrhythmia

Hyperkalemia can lead to electrocardiographic changes and life-threatening cardiac arrhythmia, including asystole. Severe potassium elevation can cause electrocardiographic alterations such as peaked T waves, flattened P waves, prolonged PR interval, widened QRS complexes, deep S wave, and sine waves. Hypocalcemia can lead to QT interval lengthening, which predisposes patients to ventricular arrhythmia.

Metabolic Acidosis

Acute renal failure and the liberation of large amounts of endogenous intracellular acids from cellular catabolism result in acidemia. This acidemia causes a decrease in serum bicarbonate concentration and a high anion gap acidosis (see the Anion Gap calculator).

Acidemia states can worsen the many electrolyte imbalances already present in tumor lysis syndrome; intracellular uptake of potassium is hindered, uric acid solubility is decreased, and extracellular shift of phosphate is promoted. Calcium phosphate solubility, however, improves in acidic conditions. The myriad of metabolic disorders must be assessed and treated rapidly. Proper fluid management, alkalinization of the urine, correction of acidosis, and attention to infections are the mainstays of therapy.

History

In tumor lysis syndrome, a constellation of clinical symptoms may develop prior to the initiation of chemotherapy or, more commonly, within 72 hours after administration of cytotoxic therapy. Inquiries should be made with regard to the following:

• Time of onset of symptoms of malignancy
• Presence of abdominal pain and distension
• Presence of urinary symptoms - Such as dysuria, oliguria, flank pain, and hematuria
• Occurrence of any symptoms of hypocalcemia - Such as anorexia, vomiting, cramps, seizures, spasms, altered mental status, and tetany
• Symptoms of hyperkalemia - Such as weakness and paralysis

Other symptoms of tumor lysis syndrome include the following:

• Lethargy
• Edema
• Fluid overload
• Congestive heart failure
• Cardiac dysrhythmias
• Syncope
• Sudden death

Physical Examination

Symptoms reflect the severity of underlying metabolic abnormalities. Hyperkalemia can cause paresthesia, weakness, and fatal cardiac arrhythmias.

Severe hypocalcemia can lead to the following symptoms:

• Paresthesia and tetany with positive Chvostek and Trousseau signs
• Anxiety
• Carpal and pedal spasms
• Bronchospasm
• Seizures
• Cardiac arrest

Deposition of calcium phosphate in various tissues may be responsible for the following symptoms:

• Pruritus
• Gangrenous changes of the skin
• Iritis
• Arthritis

Uremia can produce the following symptoms:

• Fatigue
• Weakness
• Malaise
• Nausea
• Vomiting
• Anorexia
• Metallic taste
• Hiccups
• Neuromuscular irritability
• Difficulty concentrating
• Pruritus
• Restless legs
• Ecchymoses

As uremia progresses, paresthesia and evidence of pericarditis may develop, as well as signs of drug toxicity for administered medications eliminated by the kidney. Features of volume overload, such as dyspnea, pulmonary rales, edema, and hypertension, may develop.

Elevated uric acid levels may present with lethargy, nausea, and vomiting. Rapidly increasing uric acid levels may lead to arthralgia and renal colic.

• Differential Diagnoses
• Acute Renal Failure

Blood Chemistry

High-risk patients should have laboratory monitoring (BUN, creatinine, phosphate, uric acid, and calcium levels) prior to therapy and for 48-72 hours after treatment induction. Follow measurements at least three times per day, or more often if evidence of tumor lysis syndrome develops. Lactate dehydrogenase should be checked at least on diagnosis and prior to treatment, as elevated values can reflect the potential for progressing to tumor lysis syndrome with the initiation of chemotherapy.

Most patients with tumor lysis syndrome have laboratory derangements in lactate dehydrogenase, potassium, phosphate, calcium, and uric acid, as well as abnormal renal functions, occurring 1-3 days after chemotherapy initiation. Hyperkalemia is often the first life-threatening abnormality.

Approach Considerations

Tumor lysis syndrome management requires the initiation of preventive measures in high-risk patients prior to cancer treatment, as well as the prompt initiation of supportive care for patients who develop acute tumor lysis syndrome during treatment. (Conservative management and prevention of tumor lysis syndrome is similar.) Identify high-risk patients before treatment by assessing the extent of tumor burden, histopathologic findings, and renal function.

Patients with evidence of pretreatment acute tumor lysis syndrome should be started immediately on therapy for it, with cancer treatment withheld if possible until all parameters are corrected.

Cancer patients with acute manifestations of tumor lysis syndrome or those at high risk should be treated by personnel who are experienced with the condition’s complications and treatment. An oncology unit or intensive care unit (ICU) with readily available, continuous cardiac monitoring and hemodialysis capabilities is preferable.

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.

Surgical Care

Patients with tumor lysis syndrome may need surgical intervention for central venous line placement or for the placement of a dialysis catheter in cases of extreme hyperkalemia or renal failure.

Diet

Dietary restrictions are highly dependent on the status of the individual patient. However, patients who are not restricted to a nothing-by-mouth diet could theoretically benefit from restriction of intake of foods that contain high levels of potassium, phosphorus, or uric acid.

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. If dialysis becomes necessary, consultation with a surgeon to place an appropriate vascular access device is required.

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 laboratory monitoring at least 3 times daily of BUN, creatinine, uric acid, potassium, calcium, phosphate, and lactate dehydrogenase. Monitoring should continue for the first 48-72 hours after cytotoxic therapy initiation. Some patients may need to be placed on dialysis prior to the initiation of therapy.

Control of Hyperuricemia

Allopurinol

Allopurinol is a xanthine oxidase inhibitor; it is administered 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 at 600 mg daily for prophylaxis and 600-900 mg daily (up to a maximum of 500 mg/m2 daily) for treatment of tumor lysis syndrome. Patients unable to take oral medications can be given IV allopurinol.

Adverse effects include mild-to-severe rash, xanthine stone-induced urolithiasis, acute interstitial nephritis, pneumopathy, fever, and eosinophilia. Moreover, the inhibition of uric acid synthesis promotes an increase of xanthine in plasma and the renal system; although reported to be rare, xanthine has the capacity to precipitate in the renal tubules.

Dose reduction is necessary in renal insufficiency or if the medication is given concomitantly with mercaptopurine, 6-thioguanine, or azathioprine (since allopurinol interferes with the metabolism of these agents).

Rasburicase

Rasburicase (recombinant urate oxidase) can be used when uric acid levels cannot be lowered sufficiently by standard approaches. Rasburicase is useful in cases of hyperuricemia and has been shown to be safe and effective in pediatric patients, as well as in adults. It also has a more rapid onset of action than allopurinol. Humans do not express urate oxidase, which catalyze the conversion of poorly soluble uric acid to soluble allantoin. By converting uric acid to water-soluble metabolites, urate oxidase 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 IV infusion at dosages ranging from 50-100 U/kg daily. 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 hemolytic anemia and methemoglobinemia. Some authorities recommend screening for G-6- PD deficiency prior to administration of the drug.

In addition, because humans do not express urate oxidase, Rasburicase can potentially elicit an immune response.

Studies are underway to establish the safety and efficacy of Rasburicase in those populations at highest risk for developing tumor lysis syndrome. It is approved by the US 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 the treatment of adults in various parts of the world, including Australia, Canada, and parts of Europe.

Hydration

Volume depletion is a major risk factor for tumor lysis syndrome and must be corrected vigorously. Aggressive IV hydration not only helps to correct electrolyte disturbances by diluting extracellular fluid, 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, IV 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 therapy.

Continuous infusion rates as high as 4-5 L daily (or 3 L/m2 daily), yielding urine volumes of at least 3L daily, should be given unless the patient's cardiovascular status indicates impending volume overload.

Diuresis

The 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 nonmonomeric patient with hyperkalemia or for the patient with evidence of fluid overload.

Urinary Alkalinization

The use of isotonic sodium bicarbonate solutions intravenously to promote alkaline diuresis has the potential benefit 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. An 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 guide therapy and avoid overzealous alkalinization. Consider withdrawing sodium bicarbonate from IV 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, IV acetazolamide at doses of 250-500 mg daily (5 mg/kg daily) may be added to decrease proximal tubule bicarbonate reabsorption, thereby increasing urinary ph.

Treatment of Hyperkalemia

Aggressively treat and monitor hyperkalemia. Immediately restrict dietary potassium and remove potassium from IV fluids. Acute treatment modalities include IV infusion of glucose plus insulin to promote redistribution of potassium from the extracellular to the intracellular space, and IV calcium gluconate as cardio protection for potassium levels greater than 6.5 mmol/L or for patients with electrocardiographic alterations.

IV hydration with alkaline fluid 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.

Treatment of Hyperphosphatemia and Hypocalcemia

Hyperphosphatemia is managed with oral phosphate binders and the same solution of glucose plus insulin used for the 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 described therapies for the complications of tumor lysis syndrome 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.

• Medications
• Uricosuric Agents
• Electrolytes
• Diuretics, Loop
• Alkalinizing Agents
• Electrolyte Supplements, Parenteral
• Antidotes, Other

Medication Summary

The management of tumor lysis syndrome, other than hydration and alkalinization, necessitates the administration of drugs to correct metabolic disturbances. Use of these medications should be instituted before the start of chemotherapy; the goal is to achieve optimal metabolic stability. Medications can be adjusted after the start of chemotherapy in response to the level of tumor lysis and/or metabolic disturbances. Allopurinol, a xanthine oxidase inhibitor, reduces the conversion of nucleic acid byproducts to uric acid, in this way preventing urate nephropathy and subsequent oliguric renal failure.[26]

An alternative to allopurinol for decreasing uric acid load is Rasburicase (urate oxidase), which controls hyperuricemia by converting uric acid to water-soluble allantoin.

• Uricosuric Agents
• Allopurinol (Zyloprim, Aloprim)
• Rasburicase (Elitek)

Allopurinol (Zyloprim, Aloprim)

• Be sure to look up dosing, interactions, etc.

Clinical Context: Allopurinol inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine and xanthine, thus decreasing production and excretion of uric acid and increasing the levels of more soluble xanthine and hypoxanthine. The drug reduces the synthesis of uric acid without disrupting the biosynthesis of vital purines. Patient response is measured by serum uric acid levels assessed at 48 hours after the initiation of therapy. Dosage adjustments are made as needed.

Rasburicase (Elitek)

• Be sure to look up dosing, interactions, etc.

Clinical Context: Rasburicase is a recombinant form of the enzyme urate oxidase, which oxidizes uric acid to allantoin. It is indicated for the treatment and prophylaxis of severe hyperuricemia associated with the treatment of malignancy. Hyperuricemia causes a precipitant in the kidneys, which leads to acute renal failure. Unlike uric acid, allantoin is soluble and easily excreted by the kidneys. Elimination half-life for rasburicase is 18 hours.

Class Summary

These agents control hyperuricemia and are used to attempt to prevent urate nephropathy and subsequent oliguric renal failure.

Allopurinol inhibits xanthine oxidase, thereby reducing uric acid. The IV form (Aloprim) may be used for patients unable to tolerate oral administration. Caution is necessary because of the high uric acid concentration in the urine. Andreoli and associates explained some cases of renal failure on the basis of effects of allopurinol in altering purine excretion.

In the presence of allopurinol, the excretion of uric acid, xanthine, and hypoxanthine increases severa  hundred fold, enough to exceed their solubility limit in the renal tubules even at a urinary pH level of 7. Also, at a urinary pH level higher than 7.5, crystallization of hypoxanthine may occur, which necessitates withdrawal of bicarbonate from IV fluids.

Dextrose (D-glucose) plus insulin

• Be sure to look up dosing, interactions, etc.

Clinical Context: Insulin promotes the redistribution of potassium from extracellular to intracellular space. It stimulates the cellular uptake of potassium within 20-30 minutes. Glucose should be administered along with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.

Class Summary

These agents are used to prevent and treat hyperkalemia and restore electrolyte balance.

Furosemide (Lasix)

• Be sure to look up dosing, interactions, etc.

Clinical Context

Furosemide increases the excretion of water by interfering with the chloride-binding cotransport system. This, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. Furosemide has not proven to be beneficial as front-line therapy in tumor lysis syndrome. It may contribute to uric acid or calcium phosphate precipitation in renal tubules in volume- contracted patients.

Class Summary

These agents should be reserved for well-hydrated patients with insufficient diuresis.

• Alkalinizing Agents
• Acetazolamide (Diamox)
• Sodium bicarbonate (Neut)

Acetazolamide (Diamox)

• Be sure to look up dosing, interactions, etc.

Clinical Context: Acetazolamide is a carbonic anhydrase inhibitor. It may be added to decrease proximal tubule bicarbonate reabsorption, thereby increasing urinary pH.

Sodium bicarbonate (Neut)

• Be sure to look up dosing, interactions, etc.

Clinical Context: Sodium bicarbonate is used intravenously to alkalinize urine. It promotes alkaline diuresis, with the potential benefits of solubilizing, and thus minimizing, intratubular precipitation of uric acid. The 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, it must include close monitoring of urinary pH, serum bicarbonate, and uric acid levels. Consider withdrawing sodium bicarbonate from IV solutions once serum bicarbonate levels reach 30 mEq/L, urinary pH is greater than 7.5, or serum uric acid levels have normalized.

Intracellularly, sodium bicarbonate shifts potassium. It may be considered in the treatment of hyperkalemia, even in the absence of metabolic acidosis.

Class Summary

These agents may prevent the crystallization of uric acid.

• Electrolyte Supplements, Parenteral
• Calcium gluconate
• Calcium chloride

Calcium gluconate

• Be sure to look up dosing, interactions, etc

Clinical Context: Calcium gluconate is used for cardio protection when potassium levels are greater than 6.5 mmol/L or for patients with electrocardiographic alterations. This agent is able to moderate nerve and muscle performance and facilitates normal cardiac function.

Calcium chloride

• Be sure to look up dosing, interactions, etc.

Clinical Context: Administer IV calcium gluconate or calcium chloride to stabilize myocardial conduction in a patient with cardiac arrhythmias. Calcium also moderates nerve and muscle performance by regulating the action potential excitation threshold. IV calcium is indicated in all cases of severe hyperkalemia (ie, >6 mEq/L), especially when accompanied by electrocardiographic changes.

Calcium chloride contains about 3 times more elemental calcium than an equal volume of calcium gluconate. Therefore, when hyperkalemia is accompanied by hemodynamic compromise, calcium chloride is preferred over calcium gluconate.

The administration of calcium should be accompanied by the use of other therapies that actually help to lower the serum levels of potassium.

Other calcium salts (glubionate, gluceptate) have even less elemental calcium than calcium gluconate and are not generally recommended for the treatment of hyperkalemia.

Class Summary

Calcium is used to treat arrhythmias due to hyperkalemia or hypocalcemia. Frank or impending renal failure requires additional therapeutic measures. Hyperkalemia is the most common life-threatening emergency. Chemotherapy may have to be discontinued temporarily. The entire potassium intake should be immediately discontinued.

The use of calcium does not lower serum potassium levels. It is primarily used to protect the myocardium from the deleterious effects of hyperkalemia (ie, arrhythmias) by antagonizing the membrane actions of potassium.

• Antidotes, Other
• Sodium polystyrene sulfonate (Kayexalate, Kalexate, Kionex)
• Aluminum hydroxide (AlternaGEL)
• Sevelamer hydrochloride (Renagel, Renvela)

Sodium polystyrene sulfonate (Kayexalate, Kalexate, Kionex)

• Be sure to look up dosing, interactions, etc.

Clinical Context: Sodium polystyrene sulfonate is used in the second stage of therapy to reduce total-body potassium. This agent exchanges sodium for potassium and binds it in the gut, primarily in the large intestine. Its onset of action after oral administration is 2-12 hours and is longer when administered rectally.

Aluminum hydroxide (Alterna Gel)

• Be sure to look up dosing, interactions, etc.

Clinical Context: Aluminum hydroxide has been shown to be an effective phosphate binder. Because of their potential for toxicity, however, aluminum salts are not used as first-line therapy.

Sevelamer hydrochloride (Ranagel, Renvela)

• Be sure to look up dosing, interactions, etc.

Clinical Context: This is a polymeric phosphate binder for oral administration. It does not contain aluminum; thus, aluminum intoxication is not a concern.

Class Summary

Sodium polystyrene sulfonate is an exchange resin that can be used to treat mild to moderate hyperkalemia. Each milliequivalent of potassium is exchanged for 1 mEq of sodium. Agents to treat hyperphosphatemia are also used.