Introduction

Tumour Lysis Syndrome (TLS) is a life-threatening oncological emergency that can occur spontaneously, or after chemotherapy or radiotherapy. It is caused by the death, or lysis, of large numbers of tumour cells, which in turn results in the rapid release of intracellular ions, nucleic acids, proteins and their metabolites into the systemic circulation. The sudden rise in plasma levels of these compounds can overwhelm the body’s homeostatic mechanisms and produce metabolic abnormalities such as hyperuricaemia, hyperkalaemia, hyperphosphataemia, secondary hypocalcaemia, and uraemia. These metabolic disturbances can, in turn, lead to renal failure, cardiac arrhythmias, seizures, neurological complications and potentially, sudden death. TLS is more common on the first cycle of treatment. Early recognition of at-risk patients, initiation of prophylaxis prior to chemotherapy and prompt management of TLS, if it occurs, is essential.

According to the current classification system of Cairo and Bishop, TLS can be classified as either:

  • Laboratory TLS (LTLS) – laboratory evidence of the metabolic changes associated with TLS, without symptoms; or
  • Clinical TLS (CTLS) – LTLS plus one or more specific abnormal laboratory parameters or the development of a life-threatening symptom such as cardiac arrhythmia.

Clinical Manifestations

Symptoms of TLS are observed more commonly within 12 to 72 hours after the initiation of cytotoxic treatment and are manifestations of:

  1. Hyperuricaemia (nausea and vomiting, oliguria, haematuria, acute kidney injury due to precipitation of uric acid crystals in renal tubules, and scarring of tubules which may lead to long-term renal impairment);
  2. Hyperkalaemia (lethargy, muscle cramps, paraesthesia, cardiac dysrhythmia);
  3. Hyperphosphataemia (oliguria, anuria, acute kidney injury due to precipitation of calcium phosphate crystals in renal tubules); and
  4. Hypocalcaemia (neuromuscular irritability or tetany, seizures, cardiac dysrhythmia).

Risk Factors

Some risk factors that may predispose patients to developing TLS include:

  • Pre-existing renal insufficiency or renal failure;
  • Chemosensitive malignancies (e.g. Burkitt Lymphoma, acute lymphoblastic leukaemia);
  • Solid tumours with a high cell proliferation rate, and expected rapid response to high intensity/highly potent chemotherapy (e.g. neuroblastomas, germ-cell tumours and small-cell lung cancer);
  • Large tumour burden (greater than 10cm);
  • Elevated white cell count (WCC) (greater than 25 x 109/L);
  • Elevated lactate dehydrogenase (LDH) (greater than 2 x ULN);
  • Dehydration and decreased urinary flow; and
  • Pre-existing uraemia, hyperuricaemia, or hyperphosphataemia.

The risk of developing TLS can be stratified as high (greater than 5%), intermediate (1 to 5%) or low (less than 1%) based on tumour type and other markers.

Prophylaxis

Early risk assessment and institution of appropriate prophylaxis to prevent TLS is essential. Adequate hydration and maintenance of urine output is the mainstay of prevention, and pre-emptive administration of hypouricaemic agents should be considered.

  1. Hydration
    Increased hydration and enhanced urinary flow promote urinary excretion of uric acid and phosphate. Vigorous hydration (3L/m2/day of IV fluid) is recommended for patients at intermediate or high risk of TLS and those presenting with LTLS or CTLS prior to treatment. This should be continued for several days to maintain a urine output of at least 100mL/m2/hour and a urine specific gravity of less than or equal to 1.010g/mL.
  1. Hypouricaemic agents
    1. Allopurinol is a xanthine oxidase inhibitor that blocks the conversion of hypoxanthine and xanthine to uric acid. This effectively reduces the formation of new uric acid, however it does not reduce existing levels of uric acid. The recommended dose is 100mg/m2 orally every eight hours (maximum 800mg/day) which should be initiated 24-48 hours prior to cytotoxic therapy and continued until 3-7 days after completion, or until uric acid levels and other laboratory evidence of tumour lysis have normalised.
    2. Rasburicase is a recombinant form of urate oxidase, which converts uric acid to the more soluble allantoin, making it readily excreted in the urine. It is the preferred first-line treatment for patients with a high risk of developing CTLS as it is well tolerated, rapidly lowers serum uric acid (within four hours of dose), and is effective in the prevention and treatment of hyperuricemia in TLS. The recommended dose is 0.20mg/kg intravenously once daily for 5-7 days, or a fixed 3mg or 6mg single IV dose for intermediate or high-risk patients respectively initiated 24-48 hours prior to cytotoxic therapy.
  1. Urinary Alkalinisation
    Urinary alkalinisation with sodium bicarbonate is not currently recommended as there is a lack of clear evidence demonstrating benefit. In fact, alkalinisation has the potential disadvantage of promoting calcium phosphate deposition in patients who develop marked hyperphosphataemia, and hence it should be avoided, especially when rasburicase is available.

Management of TLS

If clinical TLS develops in spite of prophylactic measures, institutional guidelines for the management of clinical manifestations must be initiated immediately.

  1. Hyperkalaemia (remains the most dangerous component of TLS as it can cause sudden death due to cardiac dysrhythmia). Management options include:
    1. Using calcium gluconate for cardiac stabilisation while awaiting haemodialysis
    2. Glucose plus insulin, or beta agonists such as salbutamol to encourage intracellular shift of potassium
    3. Administration of exchange resins (sodium polystyrene sulfonate) to assist gastrointestinal removal of potassium
    4. Haemodialysis and haemofiltration for effective removal of potassium and correction of renal failure
  1. Hyperphosphataemia:
    1. Administration of phosphate-binding agents (oral calcium, aluminium, magnesium)
    2. Restricting dietary intake of phosphat
  1. Hypocalcaemia (compensatory action due to hyperphosphataemia) can lead to life-threatening dysrhythmias and neuromuscular irritability. Symptomatic hypocalcaemia should be treated with calcium replacement (by either IV or oral route) depending on blood level and patient status, at the lowest dose required to relieve symptoms. IV calcium is reserved for patients with cardiac symptoms while oral calcium is also used for phosphate binding. Non-symptomatic hypocalcaemia does not require treatment since the administration of excessive calcium increases the risk of calcium phosphate crystallisation.

References:

  1. Cancer Institute of NSW. Supporting document – Prevention and management of tumour lysis syndrome. Sydney: EviQ; 2016.
  2. 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 Jun 1; 26(16): 2767-2778.
  3. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011 May 12; 364(19): 1844–1854.

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