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 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
Increased hydration and enhanced urinary flow promotes urinary excretion of uric acid and phosphate. A 2008 International Expert Panel on TLSr 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 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.
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 agentr. 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.
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.
- 0.20 mg/kg once daily IV for 5 to 7 daysr 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.
- 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).