Tumour lysis syndrome

• Overview:

  • Tumour lysis syndrome (TLS) is an oncological emergency that occurs when malignant cells rapidly break down
  • Cells release their contents into the blood stream causing significant electrolyte level changes
  • Most common in patients with lymphoproliferative malignancies after initiation of treatment e.g. lymphoma, leukaemia and myeloma
• Aetiology:

  • Most commonly occurs after the initiation of chemotherapy - particularly in regimens that include cell cycle phase-specific drugs
  • Typically occurs between 12-72 hours after treatment is given
  • Also known to occur with other treatments - steroids, hormones and radiotherapy (less common)
  • Cancer cells have a high turnover rate, producing large amount of nucleic acids (broken down into uric acid) and phosphate
  • When chemotherapy is started, these cells can break down rapidly, releasing their intracellular content
  • Quickly overwhelms the body's normal homeostatic response
• Metabolic and electrolyte abnormalities:

  • Hyperuricaemia (high uric acid - product of nucleic acid)
  • Hyperphosphataemia
  • Hypocalcaemia (secondary to raised phosphate)
  • Hyperkalaemia
• Spontaneous TLS can also occur, particularly in high-grade haematological malignancies, which naturally have a very high cell turnover rate, but this is rare.
• Patients with certain malignancies are more at risk of TLS:

  • Poorly differentiated lymphomas (e.g. Burkitt lymphoma, high-grade non-Hodgkin lymphomas)
  • Leukaemia: particularly acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and transformed chronic myeloid leukaemia (CML)
  • Fast-growing solid tumours (e.g. hepatocellular carcinoma, small cell lung cancer, breast cancer)
• General risk factors:

  • Large tumour burden
  • LDH >1500
  • Extensive bone marrow involvement
  • High tumour sensitivity to chemotherapy
  • Specific chemotherapy agents e.g. cisplatin
  • Pre-existing renal impairment
  • Dehydration
  • Concurrent use of nephrotoxic agents
• Symptoms:

  • Nausea and vomiting
  • Confusion
  • Muscle cramps and tetany
  • Diarrhoea
  • Lethargy
  • Reduced urine output
  • Syncope
  • Chest pain
  • Palpitations
• Clinical examination:

  • No specific examination findings but may correlate with underlying malignancy or electrolyte disturbances
  • Lymphadenopathy
  • Splenomegaly
  • Peripheral oedema - renal failure
  • Trousseau's sign - hypocalcaemia
  • Chovstek's sign - hypocalcaemia
  • Tachycardia - cardiac arrhythmias
• Bedside investigations:

  • ECG - check for arrhythmias - hyperkalaemia, hyperphosphatemia or hypocalcaemia
  • Urine pH - in the presence of hyperuricaemia, if urine pH <5 there is increased risk of uric acid crystals
• Lab investigations:

  • FBC - patients with leukocytosis are at increased risk of TLS as it correlates with tumour burden
  • U&Es - identify renal impairment and electrolyte abnormalities
  • Bone profile - phosphate and calcium
  • Uric acid
  • LDH
• There are two sets of diagnostic criteria for TLS: laboratory TLS and clinical TLS.
• Laboratory TLS is defined as two or more of the following, occurring between 3 days before and 7 days after initiation of cancer treatment:

  • Uric acid ≥476 micromol/L (≥8 mg/dL) or 25% increase from baseline
  • Potassium ≥6 mmol/L or 25% increase from baseline
  • Phosphate ≥1.45 mmol/L or 25% increase from baseline
  • Calcium ≤1.75 mmol/L or 25% decrease from baseline
• Clinical TLS is diagnosed in patients who meet the criteria for laboratory TLS and at least one of the following:

  • Increase in serum creatinine ≥1.5 times the upper limit of normal
  • Cardiac arrhythmia
  • Seizure
  • Sudden death
• Risk stratification:

  • Identify patients at an increased risk of TLS so preventative measures can be implemented
• Low risk:

  • Regular monitoring of blood tests (U&Es, bone profile, uric acid, LDH)
  • Monitor fluid balance
  • Consider allopurinol if hyperuricaemia is present before starting chemotherapy treatment (300mg for 7 days, to start 2 days before chemotherapy treatment)
• Intermediate risk:

  • Regular monitoring of blood tests (U&Es, bone profile, uric acid, LDH), including 1-2 times daily for the first three days of treatment and daily after that
  • Intravenous hydration with normal saline for two days before treatment (aim to maintain urine output 100 mL/m²/hour)
  • Allopurinol should be given to patients with hyperuricemia; if allopurinol does not reduce serum uric acid, consider rasburicase
• Rasburicase:

  • Recombinant form of urate-oxidase enzyme
  • Catalyses the oxidation of uric acid to a soluble metabolite
  • Allopurinol decreases uric acid production but has no significant effect on the current uric acid levels
  • Rasburicase does decrease current uric acid levels
• High risk:

  • Regular monitoring of blood tests (U&Es, bone profile, uric acid, LDH), including 3-4 times daily after starting treatment
  • Intravenous hydration with normal saline for two days before treatment (aim to maintain urine output 100 mL/m²/hour)
  • Rasburicase should be given to patients with hyperuricaemia
• If TLS develops, then early recognition and escalation of management are essential. Early liaison with intensive care is required, as patients may require renal replacement therapy. 
• General management of TLS includes:

  • Intravenous fluids: aiming to maintain urine output >100 mL/m²/hour (monitor urine output hourly)
  • Observations should be monitored at least 4-6 hourly, including fluid balance assessment
  • Daily weights
  • Blood tests every 6 hours after diagnosis of TLS
  • ECG at baseline, consider cardiac monitor if hyperkalaemia/hypocalcaemia
• Management of electrolyte abnormalities:

  • Hyperuricaemia: intravenous rasburicase for 3-7 days (use maximum dose allopurinol if rasburicase contraindicated)
  • Hyperkalaemia: calcium gluconate for cardiac protection, followed by a glucose/insulin infusion
  • Hyperphosphataemia: phosphate-binding agents can be considered but are rarely used
  • Hypocalcaemia: symptomatic hypocalcaemia should be treated with IV calcium gluconate; seizures can be managed with anticonvulsant medication
• Complications:

  • AKI - calcium phosphate deposition and uric acid
  • Cardiac arrhythmias
  • Seizures - hypocalcaemia and/or hyperphosphataemia
  • Lactic acidosis - due to chemotherapy induced cell death and AKI