Pediatrics

Tumor lysis syndrome

OVERVIEW: What every practitioner needs to know

Tumor lysis syndrome (TLS) is defined as the combination of hyperuricemia, hyperphosphatemia, hyperkalemia, and acute kidney injury that results from lysis of cancer cells when treatment is initiated. The syndrome can lead to fatal cardiac dysrhythmias and acute kidney injury, so all patients potentially at risk for TLS should be closely monitored and provided with appropriate preventive measures, including intravenous fluids and rasburicase in intermediate- and high-risk cases. Patient at risk include those with bulky chemosensitive cancers, especially leukemias and lymphomas.

What is tumor lysis syndrome?

Tumor lysis syndrome (TLS) occurs when tumor cells break apart (lyse) and release their contents into the bloodstream so rapidly that normal homeostatic mechanisms cannot clear the cellular contents, which then accumulate in the bloodstream. Thus, the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. These electrolyte and metabolic disturbances can progress to clinical toxicities, including renal insufficiency, cardiac arrhythmias, seizures, and death due to multiorgan failure.

Although TLS can occur in patients with any type of cancer, it is most common with hematologic cancers, especially high-grade B-cell lymphomas such as Burkitt lymphoma.

Tumor lysis syndrome is defined by laboratory abnormalities (laboratory tumor lysis syndrome [ Table I]) and associated clinical findings (clinical tumor lysis syndrome [Table II]).

Table I.

Laboratory tumor lysis syndrome
Criteria Description
Timing From 3 days before starting anti-cancer therapy until 7 days afterwards
Metabolic abnormalities 2 or more of the abnormalities listed must be present during the same 24-hour period
Hyperuricemia Uric acid > 8.0 mg/dL in adults or > the upper limit of normal for age in children
Hyper-phosphatemia Phosphorus > 4.5 mg/dL in adults or > 6.5 mg/dL in children
Hyperkalemia Potassium > 6.0 mmol/L
Hypocalcemia Corrected calcium < 7.0 mg/dL or ionized calcium < 1.12 mmol/L. Corrected calcium in mg/dL is calculated by adding 0.8 x (4 – serum albumin level [measured in g/dL]) to the measured calcium concentration.
No other explanation for the metabolic abnormalities If a patient has an obvious alternative explanation for a particular abnormality, it cannot be used to define tumor lysis syndrome (e.g., pre-existing hyperparathyroidism with known abnormalities of calcium and phosphorus).

Table II.

Cinical tumor lysis syndrome
Criteria Description
Meets criteria for laboratory tumor lysis syndrome See Table I
Symptoms, signs, or laboratory evidence of organ damage Most common clinical findings
Hyperuricemia Acute kidney injury is defined in this context as an increase in serum creatinine of 0.3 mg/dL (or a single value > 1.5 times the upper limit of the age-appropriate normal if no baseline creatinine is available) or the presence of oliguria (average urine output less than 0.5 mL/kg body weight per hour over a 6-hour period)
Hyperphosphatemia Acute kidney injury
Hyperkalemia Cardiac dysrhythmia, sudden death probably or definitely caused by hyperkalemia
Hypocalcemia Cardiac dysrhythmia, sudden death, seizure, neuromuscular irritability (tetany, paresthesias, muscle twitching, carpopedal spasm, Trousseau’s sign, Chvostek’s sign, laryngospasm or bronchospasm), hypotension, or heart failure probably or definitely caused by hypocalcemia

Are you sure your patient has tumor lysis syndrome? What are the typical findings for this disease?

A medical history typical for TLS may include a large tumor burden or a history of decreased oral intake, vomiting, and decreased urine output, but most patients with TLS or at risk to develop TLS are in fact asymptomatic.

Key symptoms and signs include:

  1. Asymptomatic laboratory abnormalities are the most common presentation of TLS.

  2. Oliguria

  3. Nausea and vomiting

  4. Symptoms of hypocalcemia – paresthesias (especially perioral), seizure

What other disease/condition shares some of these symptoms?

Because tumor lysis syndrome is a syndrome, it is defined as the presence of specific laboratory and clinical abnormalities (see Table I and Table II), and as such, there is no differential diagnosis per se.

However, individual components of the syndrome can have many potential causes. For example, hyperuricemia can result from gout, Lesch-Nyhan syndrome, acute kidney injury, major surgery, and many other causes. Hyperphosphatemia and hypokalemia can be caused by hyperparathyroidism and other endocrine disorders. Hyperkalemia can result from excessive potassium replacement in intravenous fluids, end-stage renal disease, and other conditions. Acute kidney injury occurs in many different clinical situations and is covered in another chapter.

Fortunately, the history, physical examination, and laboratory findings provide the context sufficient to diagnosis tumor lysis syndrome with confidence.

What caused this disease to develop at this time?

  • Tumor lysis syndrome is the most common disease-related emergency encountered in children with newly diagnosed leukemia and lymphoma, and has been reported occasionally in children with bulky chemosensitive solid cancers (e.g., germ cell tumor, neuroblastoma). The incidence of the syndrome depends on cancer-related factors (cancer mass, cell lysis potential); patient characteristics; and the supportive care provided.

    Cancer-related factors

    The greater the cancer mass, the greater the quantity of cellular contents released with treatment. Cancers with high cell lysis potential (e.g., those that are very sensitive to chemotherapy, radiation therapy, and the increasingly large number of biologic therapies) include most pediatric lymphomas, acute leukemias, and other cancers that respond rapidly to chemotherapy, such as germ cell tumors.

    Patient factors at presentation

    High-risk patient characteristics include pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension, and acidic urine at the time of presentation (which worsens uric acid precipitation in the kidney).

    Supportive care provided at presentation

    Supportive care dramatically affects the development of tumor lysis syndrome. Patients promptly treated with intravenous fluids and monitored carefully for electrolyte abnormalities and oliguria have a much lower incidence of clinical tumor lysis syndrome than those who remain dehydrated with hyperuricemia for a period of time, such that uric acid crystals precipitate in the kidneys and cause acute kidney injury, which then leads to poor phosphorus excretion and hyperphosphatemia that precipitates in soft tissues as calcium phosphate crystals, and further worsens acute kidney injury.

    Similarly, patients at high risk for tumor lysis syndrome who are treated with rasburicase to rapidly lower uric acid have a much lower incidence of renal failure than those treated with allopurinol alone. In the 1990’s, when rasburicase was available in France but not in the United States, patients with advanced stage Burkitt lymphoma who were enrolled in a 2-country study had a 15% incidence of dialysis in the United States, but only 3% in France, thus emphasizing the importance of proper supportive care to prevent clinical tumor lysis and severe acute kidney injury.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Diagnosis of tumor lysis syndrome depends on levels of serum potassium, phosphorus, calcium, uric acid, and creatinine.

  • If two or more of these values are abnormal (above the upper limits of normal for potassium, phosphorus, or uric acid; below the lower limit of normal for calcium; 1.5 times the age- and sex-adjusted upper limit of normal for creatinine or an increase in creatinine of at least 0.3 mg/dL above baseline if a baseline value is available).

Would imaging studies be helpful? If so, which ones?

  • Imaging studies are not generally useful for diagnosis of TLS, but in patients with newly-diagnosed cancer, imaging studies facilitate assessment of the extent and bulk of the cancer mass, and thus provide important information on the risk for TLS.

  • Renal ultrasound can identify masses compressing the kidneys, ureters, or bladder and is useful in the differential diagnosis of patients with cancer and low urine output, which could result from TLS or from external compression.

Confirming the diagnosis

  • Patients with newly diagnosed leukemia or lymphoma (or bulky chemosensitive solid tumors) should have immediate measurement of serum electrolytes, creatinine, uric acid, and lactate dehydrogenase (LDH). Patients are then risk-stratified based on clinical and laboratory criteria to guide treatment.

Risk stratification:

  • Patients who present with clinical tumor lysis syndrome and are managed most aggressively (see “Established clinical tumor lysis syndrome” in the next section).

  • Those who present with laboratory tumor lysis syndrome and are managed as “ High risk” patients

  • Those who present without tumor lysis syndrome are risk-stratified based on the cancer cell mass (small, medium, large), cell lysis potential (low, medium, high), and patient presenting features (no at-risk features versus presence of one or more at-risk features). These characteristics are used to assign a risk category for clinical tumor lysis syndrome, as shown in Table III.

Table III.

Risk stratification for patients at risk for clinical tumor lysis syndrome
Tumor lysis syndrome status at presentation Cancer mass Cell lysis potential Patient presentation Risk category
Clinical tumor lysis syndrome present Very high
Laboratory tumor lysis syndrome present High
No tumor lysis syndrome present Large High High
Large Medium Intermediate
Large Low Low
Medium High High
Medium Medium At-risk features (dehydration, acidosis, hypotension, other nephrotoxins) Intermediate
Medium Medium No at-risk features Low
Medium Low Low
Small Negligible

If you are able to confirm that the patient has tumor lysis syndrome, what treatment should be initiated?

What prevention, treatment, and monitoring should be initiated for patients at risk for tumor lysis syndrome?

  • Established clinical tumor lysis syndrome – intravenous fluids, rasburicase, cardiac monitoring, intensive care unit, laboratory testing every 4 to 6 hours (more often if warranted)

  • High risk for clinical tumor lysis syndrome – intravenous fluids, rasburicase, cardiac monitoring, inpatient, laboratory testing every 6 to 8 hours (more often if warranted)

  • Intermediate risk for clinical tumor lysis syndrome – intravenous fluids, rasburicase or allopurinol, inpatient, laboratory testing every 8 to 12 hours

  • Low risk for clinical tumor lysis syndrome – intravenous fluids, allopurinol, inpatient, laboratory testing daily

  • Negligible risk for clinical tumor lysis syndrome – no prevention, treatment, or monitoring

Details of Tumor Lysis Syndrome Management

Intravenous fluids – in children with newly diagnosed leukemia or lymphoma, the goal is to rapidly achieve euvolemia using normal saline boluses (20 mL/kg over 30 minutes), then continue fluids (1/2 NS) at approximately twice the maintenance rate (2500 to 3000 mL/m2 of body surface area) to achieve and maintain high urine output (at least 2 mL/kg/hour) to prevent uric acid and calcium phosphate precipitation in the renal tubules. Serum sodium should be monitored because some patients require more or less sodium than that in ½ NS solutions.

NO Urine alkalinization – addition of bicarbonate to intravenous fluids is not necessary in countries in which rasburicase is available, and in fact can be harmful because alkaline urine promotes calcium phosphate precipitation in renal tubules and consequent acute kidney injury.

NO exogenous potassium – potassium should never be included in intravenous fluids of patients at risk for tumor lysis syndrome unless they have severe hypokalemia. Potassium can rise quickly once anti-cancer therapy is started, so asymptomatic hypokalemia should be managed with watchful waiting.

Reduction of potassium – despite avoiding exogenous potassium, patients with tumor lysis syndrome can have a rapid rise in potassium, which can be managed with sodium polystyrene sulfonate (Kayexalate) 1 to 2 g/kg/day given orally every 6 hr or as a retention enema in 20% sorbitol. If electrocardiographic changes are present, treat immediately with bicarbonate 0.5 mEq/kg by intravenous push, 10% calcium gluconate 0.5 mL/kg IV over 10 min, and 10% glucose 0.5 g/kg IV with 0.3 units of regular insulin per gram of glucose. Furosemide should be added only if the patient is well hydrated. Arrange for urgent hemodialysis if hyperkalemia with electrocardiographic changes does not respond to these measures or if life-threatening hyperkalemia recurs after a transient response.

Allopurinol – 100 to 500 mg/m2/day (maximum, 800 mg/day) is given in three divided doses. The dose of allopurinol should be reduced in the presence of renal insufficiency. Once the uric acid is normal for several days and the cancer cell mass has decreased, allopurinol can be discontinued. Usually treatment is needed for a week or less.

Rasburicase – 0.15 mg/kg to 0.2 mg/kg (rounded to the nearest 1.5 mg vial size) administered intravenously over 30 minutes. After rasburicase administration, all subsequent uric acid levels must be measured from blood samples placed immediately in ice to prevent ex vivo breakdown of uric acid on the way to the lab, which would give results of artificially low uric acid levels. For example, when a blood sample is taken from a patient with rasburicase in the bloodstream and a uric acid of 5 mg/dL, the rasburicase will metabolize the uric acid in the tube and within an hour the uric acid in the tube will often be <0.5 mg/dL. Placing the sample immediately on ice neutralizes the enzymatic activity of rasburicase and allows a more accurate uric acid measurement.

Phosphate binders – Aluminum hydroxide (50-150 mg/kg/d) or calcium carbonate (for patients with low serum calcium concentrations) in divided doses orally every 6 hours can be given to treat or prevent hyperphosphatemia. Patients with symptomatic hypocalcemia should receive 10% calcium gluconate at a dosage of 0.5 mL/kg IV over 10 min, but only if symptomatic, since increasing the serum calcium level in a patient with hyperphosphatemia increases the calcium x phosphate product and the risk of ectopic precipitation of calcium phosphate crystals and acute kidney injury.

What are the adverse effects associated with each treatment option?

Intravenous fluids – In children with newly diagnosed leukemia or lymphoma, it is almost impossible to overhydrate unless there are extenuating circumstances (a history of cardiac problems, presenting with a symptomatic pleural effusion). The goal is to rapidly achieve euvolemia using normal saline boluses, then achieve and maintain high urine output (at least 2 mL/kg/hour) to prevent uric acid and calcium phosphate precipitation in the renal tubules. Patients at risk for TLS should have frequent monitoring of electrolytes, including sodium, since administration of high-volume 1/2 NS can sometimes cause hyponatremia.

Allopurinol – Allergic reactions (particularly skin rash) are fairly common with allopurinol, but rarely occur during the 4-5 day course needed to manage patients at risk for tumor lysis syndrome. More worrisome is that allopurinol blocks conversion of xanthine to uric acid, and in patients with a high cancer cell mass can lead to xanthine accumulation and xanthine nephropathy.

Rasburicase – Allergic reaction occurs in 0.6% of patients treated with rasburicase, so diphenhydramine, epinephrine, and hydrocortisone should be readily available. Patients who react usually do so during the 30-minute infusion, so a dose of rasburicase can safely be given prior to transfer to another facility.

Hemolysis occurs in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and known deficiency of this enzyme is an absolute contraindication to rasburicase use. Male patients of African, African American, and some of Mediterranean origin have a 10% prevalence of G6PD deficiency, and female patients from these ethnic groups a 1% prevalence. Therefore, screening for G6PD deficiency is warranted in patients (particularly boys) of high-risk ethnic groups.

Since rasburicase is most effective when administered early in the patient’s course, G6PD screening should be run STAT and rasburicase administered as soon as negative results are documented. In situations where screening cannot be performed in time, the clinician must weigh the risks of acute kidney injury from hyperuricemia against the risks of hemolysis should the patient prove G6PD deficient. A small “test dose” of rasburicase (1.5 mg) may allow for some reduction in uric acid without inducing major hemolysis; if no evidence of hemolysis is present 4 hours later, a larger dose may be administered.

Note that this strategy has not been investigated in clinical trials, but seems preferable to administration of a full dose of rasburicase to a patient with a 10% risk for G6PD deficiency, since major hemolysis is inevitable in such a situation.

What are the possible outcomes of tumor lysis syndrome?

The prognosis of patients at risk for clinical tumor lysis syndrome is excellent. If patients are risk-stratified and treated according to risk group, then most clinical tumor lysis can be prevented altogether; in the rare cases in which it occurs, patients rarely require dialysis. In countries where rasburicase is available and widely used, the need for dialysis to manage tumor lysis syndrome is rare in pediatric leukemia and lymphoma patients.

Risks of therapy for tumor lysis syndrome are very low, with the exception of rasburicase use in males from ethnic groups with a high prevalence of G6PD deficiency.

What causes this disease and how frequent is it?

  • The incidence depends on cancer factors (cancer cell mass and cell lysis potential), patient factors, and supportive care provided. Any association with sex, age, race, or other epidemiologic factors occurs only because the types of cancers that occur in children differ in these subgroups.

  • Tumor lysis syndrome has no known genetic basis.

How do these pathogens/genes/exposures cause tumor lysis syndrome?

When cancer cells lyse, they release potassium, phosphorus, and nucleic acids, which are metabolized into hypoxanthine, then xanthine and finally uric acid, which must be excreted in the urine. TLS occurs when the amount of potassium, phosphorus, nucleic acids, and cytokines released from cell lysis exceeds the body’s homeostatic mechanisms to deal with them. Renal excretion is the primary means of clearing urate, xanthine, and phosphate, which can precipitate in any part of the renal collecting system and cause inflammation and obstruction.

Uric acid can induce acute kidney injury by intra-renal crystallization and by crystal-independent mechanisms, including renal vasoconstriction, impaired autoregulation, decreased renal blood flow, oxidation, and inflammation. Cancer cell lysis also releases cytokines that can cause a systemic inflammatory response syndrome. Calcium phosphate can precipitate in the renal tubules with worsening of acute kidney injury. The risk is particularly high when patients have very high serum phosphorus levels and require intravenous calcium to treat symptomatic hypocalcemia.

High solute concentration, low solubility, and slow urine flow make crystallization more likely and therefore increase the risk for tumor lysis syndrome. Higher urine pH (alkaline urine) increases the solubility of uric acid but decreases that of calcium phosphate, so use of bicarbonate is rarely helpful in patients at risk for tumor lysis syndrome. In patients treated with allopurinol, the accumulation of xanthine, a precursor of uric acid, which has low solubility, can cause xanthine nephropathy.

In addition to the renal damage caused by the above mechanisms, in patients with clinical tumor lysis syndrome, hyperphosphatemia can cause secondary hypocalcemia leading to neuromuscular irritability, cardiac dysrhythmia, and seizure; and hyperkalemia can cause serious and occasionally fatal cardiac dysrhythmias.

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

When properly managed, long-term complications of tumor lysis syndrome are rare. If acute kidney injury occurs, sequelae can include permanent loss of renal function with higher risk for recurrent acute kidney injury later. It is not known whether patients with clinical tumor lysis syndrome have other late sequelae, such as hypertension.

Are additional laboratory studies available; even some that are not widely available?

N/A

How can tumor lysis syndrome be prevented?

Early recognition of patients with cancer who may be at risk for tumor lysis syndrome and prompt referral for diagnosis and supportive care are the keys to preventing tumor lysis syndrome. Prevention of dehydration, acidosis, and accumulation of high levels of uric acid, and avoiding nephrotoxins (e.g., vancomycin) can protect renal function and prevent acute kidney injury.

What is the evidence?

These references provide detailed reviews of all aspects of tumor lysis syndrome, including useful figures and tables that elucidate tumor lysis syndrome pathophysiology, risk stratification, and management.

Howard, SC, Jones, DP, Pui, CH. "The tumor lysis syndrome". N Engl J Med. vol. 364. 2011. pp. 1844-54.

Coiffier, B, Altman, A, Pui, CH. "Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review". J Clin Oncol. vol. 26. 2008. pp. 2767-78.

Risk stratification in patients at risk for tumor lysis syndrome

Montesinos, P, Lorenzo, I, Martin, G. "Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model". Haematologica. vol. 93. 2008. pp. 67-74.

Gemici, C. "Tumor lysis syndrome in solid tumors". J Clin Oncol. vol. 27. 2009. pp. 2738-9.

Cairo, MS, Gerrard, M, Sposto, R. "Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents". Blood. vol. 109. 2007. pp. 2736-43.

Truong, TH, Beyene, J, Hitzler, J. "Features at presentation predict children with acute lymphoblastic leukemia at low risk for tumor lysis syndrome". Cancer. vol. 110. 2007. pp. 1832-9.

The role of uric acid

Shimada, M, Johnson, RJ, May, WS. "A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome". Nephrol Dial Transplant. vol. 24. 2009. pp. 2960-4.

The role of xanthine

LaRosa, C, McMullen, L, Bakdash, S. "Acute renal failure from xanthine nephropathy during management of acute leukemia". Pediatr Nephrol. vol. 22. 2007. pp. 132-5.

The potential role of cytokines

Hijiya, N, Metzger, ML, Pounds, S. "Severe cardiopulmonary complications consistent with systemic inflammatory response syndrome caused by leukemia cell lysis in childhood acute myelomonocytic or monocytic leukemia". Pediatr Blood Cancer. vol. 44. 2005. pp. 63-9.

The role of rasburicase

Goldman, SC, Holcenberg, JS, Finklestein, JZ. "A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis". Blood. vol. 97. 2001. pp. 2998-3003.

Jeha, S, Kantarjian, H, Irwin, D. "Efficacy and safety of rasburicase, a recombinant urate oxidase (Elitek), in the management of malignancy-associated hyperuricemia in pediatric and adult patients: final results of a multicenter compassionate use trial". Leukemia. vol. 19. 2005. pp. 34-8.

Cortes, J, Moore, JO, Maziarz, RT. "Control of plasma uric acid in adults at risk for tumor lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study". J Clin Oncol. vol. 28. 2010. pp. 4207-13.

Ongoing controversies regarding etiology, diagnosis, treatment

Although the etiology and diagnosis of TLS are well established, one controversy in treatment is how to identify patients as having low, intermediate, or high risk for clinical TLS. Another controversy is how to manage hyperuricemia in patients at intermediate risk, who have been treated with allopurinol, low-dose rasburicase, and full-dose rasburicase and for whom published guidelines offer conflicting recommendations. I usually use a single dose of rasburicase 0.15 mg/kg in intermediate-risk patients, then monitor for recurrent hyperuricemia.

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