Prevention and management of tumour lysis syndrome

• Tumour lysis syndrome (TLS) is a life-threatening oncological emergency. It can occur spontaneously or after chemotherapy or radiation therapy. It is caused by the death, or lysis, of large numbers of cancer cells.
• Cell lysis results in the release of intracellular ions, nucleic acids, proteins and their metabolites into the systemic circulation.
• The resulting metabolic abnormalities such as hyperuricaemia, hyperkalaemia, hyperphosphataemia, secondary hypocalcaemia and uraemia, can in turn lead to renal failure, cardiac arrhythmias, seizures, neurological complications and potentially, sudden death.
• TLS is more common In the first cycle of treatment. Early recognition of at risk patients, initiation of prophylaxis prior to anticancer therapy and prompt management of TLS, if it occurs, is essential.

TLS can be classified as either:^r

• 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.

Cairo and Bishop definition of laboratory tumour lysis syndrome (LTLS)^rr

• The presence of 2 or more of the metabolic abnormalities below at presentation, OR
• Change of 25% from baseline within 3 days prior to or 7 days after commencement of therapy.

Cairo and Bishop definition of clinical tumour lysis syndrome (CTLS)^rr

• The presence of LTLS PLUS
• One or more of the following clinical complications (not directly or probably attributable to a therapeutic agent):
  • renal insufficiency defined by increase in serum creatinine greater than or equal to 1.5 x ULN (institution, age and gender defined),
  • cardiac arrhythmia/sudden death, and/or
  • seizure.

Cairo and Bishop tumour lysis syndrome grading^rr

Cairo and Bishop developed a grading system to assist in assessing the severity of TLS based on degree of elevation of serum creatinine, presence and type of cardiac arrhythmia and presence and severity of seizures.

*No laboratory tumour lysis syndrome (LTLS). 
**Elevated creatinine is defined as 1.5 times greater than ULN (institution, age and gender defined). 
Note: Elevated creatinine, arrhythmia and seizures not directly attributable to a therapeutic agent.

Adapted from © Cairo et al 2004^r

Clinical manifestations

Although symptoms may occur before the commencement of anticancer therapy, they are observed more commonly within 12 to 72 hours after the initiation of anticancer treatment.^r Symptoms include:

• nausea and vomiting
• diarrhoea
• anorexia
• lethargy
• oedema
• fluid overload
• congestive heart failure
• haematuria
• cardiac dysrhythmia
• seizures
• muscle cramps
• tetany
• syncope.

Risk factors for developing tumour lysis syndrome include:

• high tumour cell proliferation rate
• bulky disease (greater than 10 cm)
• increased WCC (greater than 25 x 10⁹/L)
• increased LDH (greater than 2 x ULN)
• chemosensitive malignancies
• high intensity or highly potent therapy
• novel or targeted therapy, used alone or in conjunction with conventional anticancer agents, even in patients with low-grade disease.^rr

Malignancies associated with a higher risk of TLS include:

• Burkitt lymphoma/leukaemia
• acute lymphoblastic leukaemia
• lymphoblastic lymphoma
• diffuse large-cell lymphoma
• solid tumours with high proliferative rate and rapid response to therapy.

Additional conditions that may predispose patients to developing TLS:

• renal insufficiency or renal failure
• dehydration
• decreased urinary flow
• pre-existing uraemia or hyperuricaemia
• pre-existing hyperphosphataemia.

Risk stratification

Evidence and expert consensus based guidelines^r stratify the risk of developing TLS as High (greater than 5%), Intermediate (1 to 5%) or Low (less than 1%) and provide algorithms that can be used to assess the risk based on tumour type and other markers.

Patient stratification by tumour lysis risk

*e.g. neuroblastomas, germ-cell tumours and small-cell lung cancer
Note: The presence of other TLS risk factors such as renal dysfunction or elevated uric acid, phosphate or potassium levels can increase the level of risk associated with any given tumour; e.g. Patients stratified to the low risk category, with renal dysfunction and/or renal involvement, are moved to the intermediate risk category.

Adapted from © Coiffier et al 2008^r and © Cairo et al 2010.^r

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. 
Consideration should be given to delaying treatment in high risk patients until prophylactic measures can be commenced. If a delay is not appropriate, then ensure patient is managed in an ICU or haematology/oncology unit with staff with the appropriate expertise and skills as deemed by the local institution. 
If prophylactic measures fail and clinical TLS develops, institutional guidelines for the management of hyperkalaemia, hyperphosphataemia and hypocalcaemia, as well as other clinical manifestations, need to be initiated immediately. 

The following tumour lysis prophylaxis algorithm, dealing with hyperuricaemia, is adapted from Coiffier et al.^r incorporating their tumour lysis risk stratification. It is intended as a guide only. The decision as to which prophylaxis to use should always be based on individual patient risk factors, the treatment they are receiving, and local institutional policies.

Image © J Clin Oncol 2008 ^r

Hydration

Increased hydration and enhanced urinary flow promotes urinary excretion of uric acid and phosphate. A 2008 International Expert Panel on TLS^r recommended vigorous hydration in patients at intermediate or high risk of TLS and those presenting with LTLS or CTLS prior to treatment.^r

• Unless contraindicated aim to hydrate with 3 L/m²/day of IV fluid.
• Continue for several days to maintain a urine output of at least 100 mL/m²/hour and a urine specific gravity of less than or equal to 1.010 g/mL.^rr
• Weigh twice daily and maintain strict fluid balance chart.
• Diuretics may be used to maintain urine output if necessary, but should not be required in patients with relatively normal renal and cardiac function and are contraindicated in patients who are hypovolaemic or have obstructive uropathy.
• Potassium, calcium and phosphate should not initially be added to hydration fluids to avoid exacerbation of the hyperkalaemia, hyperphosphataemia and calcium phosphate precipitation that may occur once tumour break down begins.

Urinary alkalinisation^r

• Urinary alkalinisation with sodium bicarbonate is NOT currently recommended as there is a lack of clear evidence demonstrating benefit. The only available experimental study suggested that hydration with saline alone is as effective as alkalinisation in minimising uric acid precipitation.^r
• Urinary alkalinisation should be avoided in patients with tumour lysis syndrome, especially when rasburicase is available, as alkalinisation has the potential disadvantage of promoting calcium phosphate deposition, in patients who develop marked hyperphosphataemia once tumour breakdown begins.
• If alkalinisation is used, it should be initiated when the serum uric acid level is high and discontinued when hyperphosphataemia develops.
• IV sodium bicarbonate should only be administered to patients with metabolic acidosis.

Hypouricaemic agents

Allopurinol

Allopurinol competitively inhibits xanthine oxidase, blocking the conversion of hypoxanthine and xanthine to uric acid. Allopurinol effectively reduces formation of new uric acid, however it does not reduce existing levels of uric acid. Therefore, in patients with pre-existing hyperuricaemia (serum uric acid > 0.45 mmol/L) rasburicase is the preferred hypouricaemic agent^r. There is a risk of acute obstructive renal failure, due to xanthine crystal deposition in the renal tubules, with allopurinol. Allopurinol also can cause skin rashes and increased liver function tests. There are also a number of clinically significant drug interactions with allopurinol including cyclophosphamide, high dose methotrexate, mercaptopurine and azathioprine (mercaptopurine and azathioprine require a 60 to 75% dose reduction if used concurrently with allopurinol).

Dosage and administration:

• 100 mg/m² orally every 8 hours (maximum 800 mg/day)^rr
• 300 mg/day used in practice by majority of haematologists, however increasing allopurinol dose or switching to rasburicase may be necessary in the presence of deteriorating biochemical or clinical markers.^r
• Initiate 24 to 48 hours prior to cytotoxic therapy if possible, and continue until three to seven days after completion, or until uric acid level and other laboratory evidence of tumour lysis (e.g. elevated serum LDH levels) have normalised.
• Reduce dose by 50% or more in the presence of renal failure.
• Prophylactic hydration with careful monitoring is generally safe to use in patients with an allergy to allopurinol.^r
• Adjust dose of co-administered interacting drug(s) or allopurinol.

Rasburicase

A recombinant form of urate oxidase, rasburicase converts uric acid to allantoin which is readily excreted in the urine. It is well tolerated, rapidly lowers serum uric acid, and is effective in prevention and treatment of hyperuricemia in TLS.^r Normalisation of uric acid level occurs in about four hours. There is no rationale for the use of allopurinol and rasburicase together.

Rasburicase should be considered in patients:

• at intermediate or high risk of developing TLS; especially those with renal impairment and/or unable to tolerate high fluid input,
• with pre-existing LTLS and/or CTLS (prior to cytotoxic therapy),
• unable to tolerate or allergic to allopurinol, or
• who do not adequately respond to standard TLS preventive measures of hydration and allopurinol.

Dosage:

• 0.20 mg/kg once daily IV for 5 to 7 days^r or fixed 3 mg or 6 mg single IV dose (intermediate or high risk patients respectively).^rr
• Initiate 24 to 48 hours prior to cytotoxic therapy.

Administration:^r

• Dilute in 50 mL sodium chloride 0.9% and infuse IV over 30 minutes (do not use any IV glucose solution for dilution due to potential incompatibility).
• Infuse via a different line/lumen than that used for chemotherapy; if a separate line is not available, flush well with saline between rasburicase and chemotherapy.
• If weight based dosing is used, it is recommended to round the dose to the nearest 1.5 mg (available vial size) to avoid wastage (rasburicase costs ~$400 per mg).

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