Tumour Lysis Syndrome (2015)

3-6% of patients with high grade tumours. 1/3 need dialysis. 15% mortality

 

Definition

-       Laboratory TLS - ≥2 of the following occurring 3 days prior or 7 days post initiation of treatment for cancer:

o   Uric acid ≥476 umol/l or 25% increase from baseline

o   Potassium ≥6.0 mmol/l or 25% increase from baseline

o   Phosphate ≥1.45 mmol/l (adults) or ≥2.1 mmol/l (children) or 25% increase

o   Calcium ≤1.75 mmol/l or 25% decrease from baseline

-       Clinical TLS – Laboratory TLS plus at least one of:

o   Creatinine ≥1.5 x the ULN

o   Cardiac arrhythmia

o   Seizure

o   Sudden death

 

Biology

-       Most likely to occur just prior to, or at start of, chemotherapy when disease most active

-       Metabolic syndrome caused by breakdown of malignant cells

-       Excessive release of nucleic acids, proteins and intracellular metabolites from the tumour cells overwhelm the normal homostatic control mechanisms.

-       Hyperkalaemia occurs first and can be life threatening within 6 hours of onset of TLS

-       Uric acid crystals precipitate into the renal tubules, preventing the excretion of the other TLS metabolites. This creates a downward spiral of acute kidney failure.

 

Risk Factors

-       High tumour burden

-       High grade tumour with rapid turnover (e.g. Burkitts, ALL)

-       Pre-existing renal impairment

-       Increased age

-       Use of highly active, cell-cycle specific chemotherapy

-       Concomitant use of drugs that increase uric acid levels – alcohol, vit C, aspirin, caffeine, cisplatin, thiazides, levodopa, phenothiazines, theophylline.

 

Drugs

 

Allopurinol (Xanthine Oxidase Inhibitor)

-       Reduces production of uric acid by decreasing the rate of conversion of hypoxanthine to xanthine, and of xanthine to allopurinol.

-       Both hypoxanthine and xanthine are more soluble than uric acid and so less precipitation occurs in the renal tubules.

-       Does not increase rate of breakdown of uric acid that is already present so its therapeutic effect is delayed by 24-72 hours.

 

Rasburicase (Exogenous recombinant urate oxidase)

-       Recombinant form of mammalian urate oxidase. Not found in humans.

-       Metabolises urate to allantoin, a substance 10x more soluble than uric acid.

-       Acts immediately, and on any uric acid that is already formed.

-       CI in G6PD deficiency

-       Allopurinol should not be given together as its M.O.A may delay the effect of rasburicase.

 

Risk Stratification

-       Low Risk

o   Clinical decision based on lack of risk factors and low tumour burden

-       Intermediate Risk

o   Not high or low risk

-       High Risk

o   AML or ALL with WBC >100

o   Burkitts leukaemia / lymphoma or ALL

o   High grade lymphoma with bulky disease (LDH 2x ULN or >10cm on CT)

o   Prior renal impairment or allopurinol allergy

 

Prophylaxis

-       Low Risk

o   Monitoring + 3L/24 hrs Hydration + consider omitting Allopurinol

-       Intermediate Risk

o   Monitoring + 3L/24 hrs Hydration + 7 days 300mg Allopurinol

-       High Risk

o   Monitoring + 3L/24 hrs Hydration + single dose 3mg Rasburicase

o   Monitoring bloods must be taken to lab on ice (rasburicase will continue to lower urate level in vitro at room temperature à falsely reassuring result)

 

Treatment

 

-       MDT approach with haematology, renal and intensive care

-       Cardiac monitoring (calcium / potassium)

-       3L/m2 IV fluids to maintain high urine output >100ml/m2/hour

-       Rasburicase 0.2mg/kg/day, duration determine by clinical response

-       Dialysis if fluid overload / electrolytes uncontrolled (furosemide é uric acid deposition)

-       Hyperphosphataemia – nil specific

-       Hypocalcaemia – only treat if symptomatic

-       Hyperkalaemia – usually treatments but short-lived effect, likely need dialysis

 

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