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Tumour Lysis Syndrome

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What is Tumour Lysis Syndrome?

Tumour Lysis Syndrome (TLS) is a life threatening oncological emergency characterised by metabolic abnormalities including hyperuricaemia, hyperphosphataemia and hyperkalaemia. This is caused by tumour cell death resulting in a sudden release into the blood stream of intracellular products (nucleic acids, potassium and phosphate). This can result in clinical toxicities including renal insufficiency, arrhythmias, seizures, neurological complications and potentially sudden death. Hypocalcemia is an indirect consequence of TLS and is mostly associated with hyperphosphatemia because the excess phosphate binds available serum calcium.

TLS may occur spontaneously before therapy (chemotherapy or radiation), but more often after the start of therapy including steroids. Severe TLS is most commonly associated with malignancies with high rate of cell turn over and or high tumour burden, particularly Burkitt lymphoma, lymphoblastic lymphoma and acute lymphoblastic leukaemias with high presentation white cell counts.

Risk for TLS is divided into Low Risk (<1%), Intermediate Risk (1-5%) and High Risk (>5%).

Signs and symptoms

Hyperkalemia       Nausea 
Slow, weak or irregular pulse 
Muscle weakness 
Cardiac arrhythmias 
Hyperphosphatemia  No obvious signs 
Often associated with hypocalcemia  
Hypocalcemia         Muscles cramps  
Facial twitch (Chvostek sign)  Very late signs
Carpopedal spasm (Trouseau sign) Very late signs
Paresthesias Very late signs
Tetany Very late signs
Seizures Very late signs
Laryngeal stridor  Very late signs
ECG abnormalities (shortened QT, bradycardia , widened T waves) Very late signs
Hyperuricemia and renal insufficiency   Oliguria or anuria 
Crystals forming in urine 
Hypertension 

Risk stratification

High Risk (HR) 
1. Lymphoma  a) Stage III/IV Burkitts and lymphoblastic lymphoma
  b) Stage I/II Burkitts and lymphoblastic lymphoma + LDH ≥ 500 IU/L 
2. Acute lymphoblastic leukaemia  a) WCC ≥ 100 x 109/L 
  b) WCC < 100 x 109/L + LDH ≥ 500 IU/L 
3. Acute myeloid leukaemia  a) WCC ≥ 100 
4. Any Intermediate risk disease  a) with renal dysfunction or renal impairment 
  b) wth electrolyte abnormalities
    i. urate > 0.42 mmol/L
    ii. potassium > 5.0 mmol/L
    iii. phosphate > 2.00 mmol/L 
Intermediate Risk (IR)  
1. Lymphoma  a) Stage I/II Burkitts and Lymphoblastic Lymphoma
2. Acute lymphoblastic leukaemia  a) WCC < 100 x 109/L 
3. Acute myeloid leukaemia   a) WCC 25 - 100 x 109/L 
b) WCC < 25 x 109/L + LDH ≥ 500 IU/L 
4. Chemosensitive solid tumours    a) Neuroblastoma 
b) Germ cell tumours 
c) Non-Hodgkin's Lymphoma 
5. Any low risk disease with renal dysfunction or renal involvement  
Low Risk (LR)  
1. Acute myeloid leukaemia  a) WCC < 25 
2. Other solid tumours   

Observations

  • Q4 hourly pulse, blood pressure (stipulate 95th percentile systolic and diastolic limits for age, and sex), respiratory rate. If concerned, increase frequency of monitoring.
  • High risk patients or those who start to develop tumour lysis need intensive nursing management or PICU bed.
  • Dip stick every urine looking for leukocytes and hematuria
  • Accurate fluid balance
  • Twice daily weights if clinically stable
  • Patient's height and weight so you can calculate the surface area (m2) of the patient
    mathsformula 

Additional investigations to consider

  • Renal ultrasound if B-cell Non-Hodgkins lymphoma and B-cell acute lymphoblastic lymphoma to assess for renal infiltrations/obstruction
  • CXR for mediastinal mass (if not done initially)

Treatment

tumour lysis syndrome

See Rasburicase drug protocol

Tumour Lysis symptom management

Steps for Management of Hyperkalemia
Get an urgent ECG - look for broad QRS, peaked T waves.
For patients who are intravascularly depleted, give fluids. 
For acute reduction of hyperkalaemia the following measures can be taken:
- IV calcium gluconate 10% solution 0.5 ml/kg
- 0.5 g/kg 10% glucose IV with 0.3 U actrapid insulin/gram glucose
- NaHCO3 IV 0.5mmol/kg
- Nebulised salbutamol
- Calcium resonium 0.5-2 g/kg can be given orally. This causes a less immediate but more sustained drop in the potassium level.
Begin dialysis urgently if patient is oliguric/anuric.
Steps for Management of Hyperphosphataemia
Phosphate may rise above normal despite treatment:
Increase fluids to 4 L/m2/day (5 L/m2/day has been needed for some patients)
Monitor biochemistry Q6 hourly.
A PO4 > 3 mmol/l will inevitably result in some renal dysfunction; a level > 4 mmol/l is an indication for haemodialysis
Steps for Management of Hypocalcemia
Hypocalcaemia can usually be managed without IV calcium:
If the phosphate is level is high, consult the renal physician after discussing first with the paediatric oncologist on call.
Also, try to avoid frusemide as this can cause a precipitous drop in calcium levels.
Never give calcium IM, SC or as an IV bolus. A CVL is preferred for administration. If using peripherally, monitor site closely.
In symptomatic patients, calcium can be added when the phosphate level starts to drop:
Infuse 10% Calcium gluconate diluted to 2% solution (10 ml of 10% Ca-gluconate in 40 ml 0.9% NaCl = 0.04 mmol/ml) with ECG monitoring for severe hypocalcaemia with seizures or arrythmias at 0.1 mmol/kg/hr of 2% Ca-gluconate solution IV with ECG monitoring (approximately 0.5 ml/kg/dose) 
Calcium replacement within PICU will be decided by PICU Consultant 
For less severe cases, start infusion at 0.05 mmol/kg/hr (1.3 ml/kg/hr)
Check magnesium concentration as well 
Avoid CaCl2 as it may cause local vein toxicity and late ulceration. 
Avoid adding calcium to fluids (if at all possible) whilst the phosphate level is rising because calcium phosphate will complex out in the kidneys and renal damage will worsen.

Fluid overload and hypertension

In TLS, a degree of fluid overload is inevitable and may have to be accepted if the phosphate is increasing.

  • The use of frusemide will worsen hypocalcaemia but may be necessary if the patient becomes hypertensive.
  • Patients with TLS are particularly prone to hypertensive encephalopathy.

Renal failure

If this is present prior to starting treatment then USS or CT should be performed to assess the degree of obstruction as ureteric stenting or nephrostomy tubes may be required.

Renal failure with decreased urine output that does not respond to physical stenting or diuretics may require dialysis. Indications for dialysis include:

  • uncontrollable potassium increases > 6 mmol/l
  • phosphate increase > 4 mmol/l
  • severe oliguria/anuria
  • fluid overload, particularly if ongoing blood product support is required
  • worsening creatinine (level for dialysis is dependent on age and weight so discuss this with the renal team), urea >50 mmol/l (8.0 umol/L)

This is a guideline only; management should be based on individual consideration upon Consultants discretion.

References

  1. Coiffier at all. Guidelines for the management of pediatric and adult tumour lysis syndrome: an evidence based review. JCO. 2008;26 (16): 2767-2778.
  2. Truong et al. Features at presentation predict children with acute lymphoblastic leukaemia at low risk for tumour lysis syndrome. Cancer. 2007; 110(8): 1832-1839.
  3. Cairo M.S. et al. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus; British Journal of Haematology (2010); 149: 578-586
  4. Howard S.C. et al. The tumor lysis syndrome: The New England Journal of Medicine (2011): 364:1844-54
  5. Stanton et al. A randomised comparison between Rasburicase and Allopurinol in children with lymphoma or leukaemia at high risk for tumour lysis. Blood;2001(10);97:2998-3003.
  6. Handbook of supportive care in pediatric oncology. Sick Kids hospital Toronto. Editor Oussama Alba. Jones and Bartlett 2010.

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Document Control

  • Date last published: 06 May 2016
  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network
  • Owner: Ruellyn Cockcroft
  • Review frequency: 2 years