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Tumour lysis syndrome

1.GENERAL INFORMATION

1.1 Incidence, risk factors and pathophysiology

Tumour lysis syndrome (TLS) is characterized by several metabolic life-threatening disturbances. It is defined as a metabolic triad of hyperuricaemia (increase by > 25% from baseline or > 8 mg/dL), hyperkalaemia (increase by > 25% from baseline or > 6 meq/L), and hyperphosphataemia (increase by > 25% from baseline or > 4.5 mg/dL) and can be associated with hypocalcaemia (decrease by > 25% from baseline or < 7 mg/dL).
A clinical TLS is the combination of laboratory disturbances and renal failure (glomerular filtration rate < 60 ml/min), cardiac arrythmias or seizures.

It is observed in patients treated for haematological malignancies such as acute lymphoid leukaemia (ALL), acute myeloid leukaemia (AML), high-grade lymphoma (e.g. Burkitt lymphoma), or after initial treatment for bulky solid tumours. It may also occur spontaneously.TLS is caused by massive release of intracellular contents after tumour cell death
• The catabolism of nucleic acids to hypoxanthine and xanthine by xanthine oxidase results in hyperuricaemia. The high concentration of uric acid can lead to crystallization within the renal tubules, resulting in obstruction of tubular flow and acute renal failure. Renal failure is further exacerbated by hypovolaemia.

• The release of intracellular potassium, present in the cytoplasm of tumour cells at concentrations substantially higher than in the extracellular space together with a decreased renal function leads to hyperkalaemia.
• Increasing levels of phosphorus due to immediate cellular release result in secondary hypocalcaemia due to the down-regulation of calcium by the hyperphosphataemia. Hypocalcaemia may also be the result of the precipitation of calcium phosphate in soft tissues secondary to the acute development of hyperphosphatemia.

Patients have a high risk of developing TLS if at least 1 of the following factors is present
• Host-related factors (co-morbidities): dehydration; hyponatraemia in patients with solid tumours; pre-existing renal impairment; obstructive uropathy; hyperuricaemia (uric acid >10 mg/dL).

• Disease-related factors (e.g. cancers with a high and rapid response to anticancer therapy): bulky disease; metastatic germ cell tumours; high-grade lymphomas (e.g. Burkitt’s lymphoma, T-cell lymphoblastic non-Hogdkin lymphoma); acute lymphoblastic leukaemia; elevated serum lactate dehydrogenase (LDH)(>2 upper normal limit).
• Therapy-related factors: intensive polychemotherapy including cisplatin, cytosine arabinoside, etoposide, methotrexate.

2. DIAGNOSIS

2.1 Clinical symptoms and signs

The symptoms and signs of TLS are usually non-specific.
• Hyperurecaemia and hyperphophatemia can result in an renal failure and patients may manifest symptoms of uraemia or volume overload.
• Hyperkalaemia can result in lethal cardiac arrhythmias and seizures.
• Hypocalcaemia can cause muscle cramps, cardiac arrhythmias and tetany.

2.2 Diagnosis

Laboratory studies usually show elevated uric acid, phosphorus, potassium, and LDH levels and a low calcium level.
An ECG should be performed in all patients with electrolyte abnormalities to detect serious arrhythmias and conduction abnormalities.

3. PROGNOSIS

The prognosis of TLS depends on early recognition and treatment. In case of early intervention, most complications might be reversible. Although renal dysfunction might require dialysis, it is usually reversible with prompt supportive measures.

4. TREATMENT

4.1 Prevention

TLS should be anticipated and prevented in high-risk patients. During anticancer treatment, these high-risk patients should be monitored by the determination of LDH, uric acid, sodium, potassium, creatinine, BUN, phosphorus and calcium every 12 hours for the first three days, and every 24 hours subsequently for the first 48-72 hours after starting anticancer treatment. This is a standard option, on a type C basis.

Preventive measures consist of
• Administration of allopurinol (300-600 mg/d) for 2 to 3 days before planned treatment. This xanthine oxidase inhibitor reduces the conversion of nucleic acid metabolites to uric acid and prevents urate nephropathy and renal failure. Dose reduction is necessary in patients with renal insufficiency and if given concomitantly with mercaptopurine, 6-thioguanine or azathioprine. This is a standard option, on a type C basis
• Adequate hydration with IV fluids in high-risk patients should start 24-48 hours before initiation of anticancer therapy and continue for 48-72 hours after completion of treatment. This is a standard option, on a type C basis. If the cardiovascular status allows, continuous infusion of 4-5 L saline 0.9%/d yielding urine volumes of at least 3 L/d should be given, as a standard option, on a type C basis.
• Recombinant urate oxidase (rasburicase (0.15-0.2 mg/kg/d IV infused over 30 min for 5 d; dilute in 50 mL 0.9% NaCl)) can be used, as a standard option, on a type 2 level of evidence when the uric acid levels cannot be lowered sufficiently by standard approaches. Rasburicase catalyses the conversion of poorly soluble uric acid to soluble allantoin. This effectively decreases plasma and urinary uric acid levels. It does not increase the excretion of xanthine and other purine metabolites and does not increase tubule crystallization. It is contraindicated in pregnancy and glucose-6-phosphate dehydrogenase deficiency, in which it accelerates catabolism of xanthine and hypoxanthine, inducing an accumulation of excess hydrogen peroxide causing haemolytic anaemia and met-hemoglobinaemia. In order to avoid xanthine accumulation and lack of substrate for rasburicase, concomitant allopurinol should not be administered.

This is a standard option, on a type R basis.
• Urinary alkalinization with intravenous isotonic sodium bicarbonate solutions remains controversial. Hypothetically it promotes alkaline diuresis and might minimize intratubular precipitation of uric acid when urinary pH is above 7.0. However, it may worsen hypocalcaemia by shifting ionized calcium to its non-ionized form and increase the likelihood of calcium phosphate precipitation in renal tubules. It is not recommended as standard practice, but it can be considered as suitable for individual clinical use, on a type R basis.

• Diuretics should be used with caution; they are considered as suitable for individual clinical use,on a type C basis.

Low-risk patients should receive oral allopurinol and hydration, as suitable for individual clinical use, on a type C basis. High-risk patients should receive rasburicase and hydration in an inpatient setting (standard option; type 2 evidence). At the end of the treatment with rasburicase, patients should start receiving oral allopurinol.

4.2 Treatment

Patients with an acute TLS before anticancer therapy should start immediately with TLS-directed treatment, and if possible, anticancer therapy should be postponed until all parameters are corrected, as a standard option, on a type C basis.
Patients with established TLS need to be hospitalized and monitored every 6 hours for the first 24 hours and daily subsequently for vital parameters (heart rate, blood pressure, urine output, respiratory rate), serum uric acid level, serum electrolytes (phosphate, calcium, potassium), renal function (serum creatinine, BUN, urine pH and osmolality, urine specific gravity). Blood cell count, serum LDH, albumin, serum osmolality, blood gases and acid-base equilibrium, electrocardiogram, and body weight should be assessed every 24 hours, as a standard option, on a type C basis .

Treatment is by

• Administration of intravenous fluids via a central venous access should be given to maintain a urine output of 100 mL/m² per hour or greater (standard option; type C basis). An infusion rate of 3 L/m² per day is appropriate if cardiovascular status allows. This is a standard option, on a type C basis.
• Administration of allopurinol (600-900 mg/d up to a maximum of 500 mg/m²/d) orally or IV isstandard option, on a type C basis. Dose reduction is necessary in patients with renal insufficiency and it is suitable for individual clinical use, on a type C basis.

• Administration of recombinant urate oxidase rasburicase is standard option, on a type 3 level of evidence.

• Aggressive treatment of hyperkalaemia

o Restriction of potassium intake and discontinuation of potassium sparing medication is a standard option, on a type C basis .

o Sodium polystyrene sulfonate (Kayexalate®) 15-30 g every 6 h orally (can be used rectally) in combination with sorbitol is a standard option, on a type C basis.

o Insulin (regular) 10 units IV in dextrose (50%) 50-100 mL IV is a standard option, on a type 2 level of evidence.
o Calcium gluconate (10%) 10-20 mL (100-200 mg) IV is suitable for individual clinical use, on a type C basis.
o Sodium bicarbonate 45 mEq IV (1 ampule of 7.5% NaHCO3) in case of acidosis; can be repeated after 30 minutes, as suitable for individual clinical use, on a type C basis.
o Albuterol inhalations (2.5 mg) is a standard o ption, on a type 2 level of evidence.
o Dialysis is indicated in severe hyperkalaemia not responsive to other measures; renal failure; volume overload is a standard option, on a type 2 level of evidence.
• Treatment of hyperphosphataemia. This can be by restricting phosphate intake, as a standard option, on a type C basis, phosphate binders such as aluminium hydroxide or glucose in combination with insulin are suitable for individual clinical use, on a type C basis. It may lead to hypocalcaemia, which usually resolves after phosphate levels are corrected.
• Correction of hypocalcaemia is if there is suitable for individual clinical use, on a type C basis , if there is evidence of neuromuscular irritability (e.g. Chvostek or Trousseau sign).
• Dialysis. This is a standard option, on a type C basis in patients with oliguric renal failure, congestive heart failure, pericarditis, severe encephalopathy, or severe hyperkalaemia or patients who do not respond to medical therapy.

INDEX

Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26: 2767-78 [Medline]

Tosi P, Barosi G, Lazzaro C, Liso V, Marchetti M, Morra E, et al. Consensus conference on the management of tumor lysis syndrome. Haematologica 2008; 93: 1877-85 [Medline]

Goldman SC, Holcenberg JS, Finklestein JZ, Hutchinson R, Kreissman S, Johnson FL, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood. 2001; 97: 2998-3003 [Medline]

Mahoney BA, Smith WA, Lo DS, Tsoi K, Tonelli M, Clase CM. Emergency interventions for hyperkalaemia.Cochrane Database Syst Rev 2005; (2):CD003235 [ Medline]