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 Introduction

Tumor lysis syndrome (TLS) is an oncological emergency where in spontaneous or treatment-induced cell death leads to a constellation of metabolic abnormalities that can result in potentially life threatening complications. It is characterized by hyperkalemia, hyperuricemia, hyperphosphatemia and hypocalcemia. Etiopathogenesis is related to spontaneous cell death of rapidly growing tumor or more commonly to administration of cytotoxic chemotherapy in patients with hematologic malignancies and less so with solid malignancies. The precise incidence of TLS is not known, and neither racial nor gender predilection exists. Approximately 18% of the patients who develop TLS die of its complications [1]. The cornerstone of the management of TLS includes knowledge of its causes, recognition of high-risk patients, vigilant monitoring and prompt initiation of appropriate preventive and therapeutic measures when indicated.

Risk factors [2, 3]

1) The presence of high leukocyte count, bulky adenopathy, hepatosplenomegaly or both (i.e. B-cell lymphomas/ leukemias, T-cell lymphomas/ leukemias) often evidenced by elevated pretreatment lactate dehydrogenase (LDH); 2) Tumor highly sensitive to chemotherapy or radiation therapy; 3) Elevated pretreatment uric acid levels; 4) Compromised renal function; 5) Use of potentially nephrotoxic drugs.

Pathophysiology

TLS occurs a few hours or a few days after the initiation of therapy. Cell death leads to release of potassium, phosphate, uric acid, and other purine metabolites (Figure 1) [4-7] jeopardizing the kidney's capacity for clearance with resultant hyperkalemia, hyperphosphatemia, hyperuricemia, and secondary hypocalcemia [8]. Significant increase in serum LDH occurs frequently.

Figure 1: Purine catabolism pathway.

Hyperkalemia poses the greatest immediate threat to the patient with TLS. Release of intracellular potassium from dying cells is the main cause of hyperkalemia. Lowering of adenosine triphosphate (ATP) levels before cell lysis can also lead to leakage of potassium, accounting for the fact that a rise in serum potassium is often the first sign of TLS.

Hyperuricemia is the most common finding of TLS. The real culprit is not the hyperuricemia but the increased renal uric acid excretion, occurring as a result of hyperuricemia, causes the symptoms. When present in high concentrations uric acid crystallizes in the renal parenchyma, distal tubules and collecting ducts where luminal pH is 5.0, leads to intraluminal tubular obstruction and oliguria.

Hyperphosphatemia follows cell lysis, resulting in hyperphosphaturia and hypocalcemia. Hyperphosphaturia enhances the risk of nephrocalcinosis and tubular obstruction. Severe hypocalcemia can complicate hyperkalemia and its associated electrocardiography (ECG) changes as well as hypotension.

Acute renal failure occurring in the setting of TLS is usually multifactorial. Contributing factors include intravascular volume depletion, precipitation of nucleic acid metabolites most notably uric acid and calcium phosphate crystals in the renal tubules (acute nephrocalcinosis).

Diagnosis

The standard definition of TLS comprises of clinical and laboratory definitions. This was originally proposed by Hande & Garrow in 1993, standardized by Cairo & Bishop in 2004, which was later modified by Howard et al in 2011 [9-11] (Table 1).

Table 1: Definition of tumor lysis syndrome (TLS) by Howard et al. 2011.

Risk stratification of patients

Prior to initiation of chemotherapy and/ or steroids patients must be classified into low, intermediate or high risk groups depending on the disease type, WBC count and any additional risk factors as shown in the table 2 [11, 12].

Table 2: Risk stratification of patients with TLS (pre-chemotherapy).

Management

Management of TLS includes preemptive measures and therapeutic measures (Table 3) [10-13].

Preemptive measures

Preemptive measures for the TLS are administered based on the risk-stratification of the patients as shown in tables 2 and 3. These measures should be initiated at least 24 hours prior to chemotherapy.

1) Institution of adequate hydration; 2) Administration of allpurinol; 3) Consideration of Rasburicase in intermediate/ high risk patients; 4) Monitoring of urine output, renal function tests and other labs periodically depending on the risk stratification. 

Table 3: Management of TLS based on risk stratification of the patients.

Therapeutic Measures (for established TLS) [6, 11-13]

1) Aggresive hydration is the single most important intervention. Approximately 3000ml/m²/day is recommended; 2) Alkalinization of urine remains controversial. Although alkalinization is recommended to avoid crystallinization of uric acid, it favors precipitation of calcium/ phosphate complexes in renal tubules, a concern in patients with concomitant hyperphosphatemia. Administration of bicarbonate to achieve alkalinization can worsen the neurologic manifestations of hypocalcemia. Thus alkalinization of urine is not uniformly recommended and in the majority of cases should be avoided; 3) Hyperkalemia should be treated aggressively: Calcium gluconate (10-30 ml of 10% solution intravenously over 5 minutes) antagonizes the cardiac effects of hyperkalemia, Hypertonic dextrose and insulin can shift potassium back into the cells, Loop diuretics can be used to eliminate excess potassium in patients without renal failure, Hemodialysis is indicated in severe cases with renal impairment (K >7.0mmol/L); 4) Hyperphosphatemia and its resultant hypocalcemia: restrict oral intake / iv phosphorus, oral phosphate binders, a) Sevelamer 800 mg-1600 mg PO three times a day with meals - Drug of choice in patients with hypercalcemia, b) Lanthanum carbonate 500-1000 mg PO three times a day with meals, c) Calcium acetate 1334 mg-2668 mg PO three times a day with meals - Avoid in hypercalcemic patients, d) Calcium carbonate1000 mg-2000 mg (elemental calcium) PO three times a day with meals - Avoid in hypercalcemic patients, e) Aluminum hydroxide 300 mg -600 mg PO three times a day with meals - Avoid in patients with renal dysfunction; 5) Hyperuricemia: Allopurinol lowers serum uric acid by inhibiting enzyme xanthine oxidase (Figure 1) but has no effect on preexisting uric acid. Allopurinol should be initiated 24-48 hours prior to chemotherapy. Recommended dose of Allopurinol is 400mg/m²/day orally or 200 - 400 mg/m²/day intravenously. Rasburicase (Recombinant urate oxidase) catalyzes enzymatic oxidation of uric acid into allantoin, which has high urinary excretion. US FDA approved this drug in 2009 based on clinical trial EFC 4978 [14]. Recommended dose is 0.15 - 0.2 mg/kg over 30 minutes once daily for 5 days. It must be administered 4 hours prior to chemotherapy. Uric acid levels are reduced by 86% within 4 hours of rasburicase treatment compared to only 12% in allopurinol treated patients leading to more rapid control [4]. Rasburicase is contraindicated in glucose-6 phosphate dehydrogenase deficient patients, known hypersensitivity reactions, hemolytic anemia or methemoglobinemia. Allopurinol blocks the conversion of xanthines to uric acid reducing the effectiveness of Rasburicase and therefore should not be given together. 6) Uremia (Renal failure): Fluid, electrolyte & blood pressure management, dose adjustment of nephrotoxic drugs, hemodialysis if conservative management fails.

Conclusion

Tumor lysis syndrome is an oncological emergency which can be prevented by early identification of risk factors, clinical, laboratory parameters and prompt initiation of prophylactic measures. Prevention of TLS is the most important step in its management, since it avoids life-threatening complications, unwarranted reduced dosing and/ or delays in chemotherapy. In addition it reduces length of hospital stay and need for dialysis in these patients, thus reducing morbidity, mortality and total treatment.

Acknowledgement

We thank Dr. Bhaskar Rao MD & CEO, KIMS Hospital for his encouragement and support. We would also like to express our gratitude to our fellow & senior radiation oncologists and medical physicists for their constant inspiration and backing.

Conflict of Interest

The authors wish to express that they have no conflict of interest.