Tumor lysis syndrome (TLS) is a potentially serious complication of treating certain cancers.1,2 When exposed to chemotherapy, malignant cells die and burst (lyse) releasing the contents of these cells into the bloodstream.3 Rapid release of these intracellular contents shifts electrolyte concentrations outside of normal physiologic ranges. These alterations in electrolytes can impair organ function and cause temporary or permanent organ damage.

Tumor lysis syndrome is characterized by a combination of hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia. Complications of TLS can range from mild (nausea and muscle cramps) to serious (cardiac arrhythmia, seizure, and death). Different studies report wide variations in the rates of TLS occurrence. Among the highest was 42%, reported in a study of adults with acute, high-grade non-Hodgkin lymphoma.4 A study of pediatric patients with non-Hodgkin lymphoma observed only a 4.4% total incidence of TLS.5 Mortality rates due to TLS have been reported as high as 2.5% of patients.6


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PATHOPHYSIOLOGY

Certain types of malignancies are very sensitive to chemotherapy; when exposed to these cytotoxic agents, tumor cells lyse and release their contents including DNA, proteins, and electrolytes. The DNA released from lysed cells is broken down to uric acid. This breakdown is a multistep process. First, DNAase breaks the DNA down into smaller molecules called nucleotides. The purine nucleotides are converted to hypoxanthine. Then, the enzyme xanthine oxidase converts hypoxanthine to xanthine, then to uric acid. Uric acid is not very soluble in the acidic environment of the kidney. If uric acid accumulates, it may form urate crystals in the renal tubules or collecting ducts leading to obstruction. This obstruction can reduce urine output and lead to renal failure.7 In addition to crystal formation, high levels of uric acid can reduce renal blood flow, increase inflammation, and disrupt the usual regulation of renal function.7 High urine output helps keep crystals from forming and damaging the kidneys.

One important function of the kidneys is to maintain the balance of potassium, phosphorus, and other electrolytes. Cancer cells release large amounts of potassium and phosphorus when they die. If the kidneys cannot remove these electrolytes fast enough, they can build up to dangerously high levels. Hyperkalemia can lead to cardiac abnormalities, including potentially fatal arrhythmias. When phosphorus is high, it binds to calcium to form crystals. This lowers serum calcium levels, which can lead to confusion, muscle spasms, tetany, or seizures.1 These calcium phosphate crystals also have the potential to damage the kidney.8

DEFINITION OF TUMOR LYSIS SYNDROME

TLS is subdivided into laboratory TLS or clinical TLS. A diagnosis of laboratory TLS is based solely on laboratory findings. The commonly used Cairo-Bishop system defines laboratory TLS as the presence of at least two electrolyte disturbances (Table 1). In addition, these abnormalities must occur between 3 days prior to and 7 days after starting chemotherapy.3

The Cairo-Bishop system defines clinical TLS as laboratory TLS plus one of the following complications: acute kidney injury (serum creatinine 1.5x upper limit of normal or greater), cardiac arrhythmia, seizure, or sudden death.3 Approximately 5% to 6% of patients at high risk for TLS will develop acute kidney injury during treatment. Nearly half of those will require hemodialysis.9 Other possible symptoms of TLS include lethargy, nausea, edema, syncope, fluid overload, and heart failure. While these symptoms do not meet the definition of clinical TLS, they should be monitored and managed according to institutional practice.

RISK FACTORS FOR TLS

Tumor lysis syndrome prevention is key to averting organ damage and other complications. The challenge comes with accurately identifying which patients are at highest risk for TLS so appropriate prophylaxis can be prescribed. Researchers and clinicians have worked to develop a standardized method for categorizing a patient’s risk of developing TLS. The current evidence suggests that the most important factors are type of cancer, extent of disease, presenting laboratory test values, age, and renal function.1,2,8

Different malignancies are associated with different risks of TLS. In general, acute leukemias and lymphomas (particularly Burkitt lymphoma) are associated with the highest risk of TLS.2,10 Patients with acute leukemia often present with elevated white blood cell count (WBC); these cells are usually very sensitive to chemotherapy. TLS risk is high when a large number of malignant cells are present, and when they rapidly lyse when exposed to chemotherapy.11 Cases have been reported in which patients with acute leukemia developed TLS even before chemo-therapy is started, a condition known as acute spontaneous TLS. Although this condition is very rare, a patient may have laboratory or clinical symptoms of TLS at presentation.

Chronic leukemias, indolent lymphomas, and myeloma are usually associated with lower risk of TLS. Solid tumors pose the lowest risk for TLS. The reason may be that solid tumors are generally less sensitive to chemotherapy, and therefore less likely to lyse, than most hematologic malignancies. Even so, cases of patients with small cell lung cancer, neuroblastoma, and metastatic breast cancer developing TLS have been reported.12

An extensive disease burden has been shown to increase the risk of developing TLS.10 Extensive disease is often defined as a solid tumor larger than 10 cm, lactate dehydrogenase (LDH) more than two times the upper limit of normal, or leukemia with elevated WBC (more than 50,000 cells/µL for acute myelogenous leukemia [AML], or more than 100,000 cells/µL for acute lymphoblastic leukemia [ALL]). Table 2 describes the risk stratification for TLS by disease.8

Adequate renal function helps maintain electrolytes in their usual physiologic ranges; therefore, patients with poor renal function are at higher risk for developing TLS.1 Whether patients have impaired renal function prior to beginning cancer treatment or develop kidney injury during treatment, the inability to excrete the contents of lysed cells as quickly as they are released into the bloodstream can lead to TLS.

PROPHYLAXIS AND TREATMENT

An improved understanding of TLS development led to therapies designed to prevent and treat the condition. These treatments focus on maintaining a normal balance of electrolytes in the blood and are designed to maximize kidney function, prevent uric acid formation, and break down existing uric acid.

Hydration Intravenous hydration is the cornerstone of TLS prophylaxis.13 Increased fluid intake leads to greater urine output, which improves excretion of excess electrolytes. Recommended treatment is to administer 2.5 to 3 L/m2 of IV fluids every 24 hours to patients at the highest risk of TLS.1-3 Patients should maintain a urine output of at least 2 mL/kg/hour. Loop diuretics (eg, furosemide [Lasix, generics]) may be considered if hydration alone is not enough to maintain adequate urine output, although this is somewhat controversial and no randomized clinical data support their use.1,3