Tumour Lysis Syndrome

Introduction

Tumour lysis syndrome (TLS) is an oncological emergency that occurs when malignant cells rapidly break down, releasing their contents into the bloodstream. This causes significant changes to the levels of electrolytes within the blood and can be life-threatening if not recognised and treated. 

It most commonly occurs in patients with lymphoproliferative malignancies after initiation of treatment.

Aetiology

TLS most commonly occurs after the initiation of chemotherapy, particularly in regimes that include cell cycle phase-specific drugs.¹

It typically occurs between 12-72 hours after treatment is given. TLS has also been known to occur with other treatments such as corticosteroids, hormonal therapy and radiotherapy, but this is less common.

Cancer cells typically have a high turnover rate, producing large amounts of nucleic acids (broken down to uric acid) and phosphate. When chemotherapy is started, these cells can break down rapidly, releasing the intracellular contents, which quickly overwhelm the body’s normal homeostatic response. 

This release results in several metabolic and electrolyte abnormalities:

• Hyperuricaemia
• Hyperphosphataemia
• Hypocalcaemia (secondary to hyperphosphataemia)
• 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.

Risk factors

Patients with certain malignancies are more at risk of TLS:²

• 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)

Other risk factors include:²

• Age
• Large tumour burden
• LDH >1,500 IU
• Extensive bone marrow involvement
• High tumour sensitivity to chemotherapy
• Specific chemotherapy agents (cisplatin, etoposide, fludarabine, intrathecal methotrexate, paclitaxel, rituximab, radiation, interferon, corticosteroids, tamoxifen)
• Pre-existing renal impairment
• Dehydration
• Concurrent use of nephrotoxic agents

Clinical features

History

Symptoms of TLS are vague and non-specific. Patients will present generally unwell with symptoms related to the electrolyte disturbances found in TLS:

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

The history may identify risk factors for TLS.

Clinical examination

There are no specific examination findings for TLS. However, findings may correlate with the underlying malignancy or electrolyte disturbances:

• Lymphadenopathy: due to the underlying malignancy
• Splenomegaly: due to the underlying malignancy
• Peripheral oedema: due to renal failure
• Trousseau’s sign: due to hypocalcaemia
• Chovstek’s sign: due to hypocalcaemia
• Tachycardia: due to cardiac arrhythmias

Investigations

Investigations are used to diagnose TLS and assess for complications. Investigations are also used to monitor patients at risk of TLS, especially before or during treatment. 

Bedside investigations

Relevant bedside investigations include:

• ECG: performed if hyperkalaemia, hyperphosphataemia or hypocalcaemia develop to check for arrhythmias
• Urine pH: performed in the presence of hyperuricaemia; if urine pH < 5, there is an increased risk of precipitation of uric acid crystals, which may cause obstruction

Laboratory investigations

Relevant laboratory investigations include:

• Full blood count: patients with leukocytosis are at increased risk of TLS as it correlates with tumour burden
• Urea & electrolytes: to identify renal impairment and electrolyte abnormalities (e.g. hyperkalaemia)
• Bone profile: to identify hyperphosphataemia and hypocalcaemia.
• Uric acid: raised uric acid is a risk factor for developing TLS and a feature of TLS (hyperuricemia)
• LDH: raised LDH is a risk factor for TLS. 

Diagnosis

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

Management

Risk stratification and prevention

Risk stratification involves identifying patients at an increased risk of developing TLS so that appropriate preventative measures can be implemented. 

The aim is to prevent TLS from developing and identify patients with TLS early so appropriate management can be started. 

Table 1. Risk stratification for TLS

After a patient’s level of risk has been established, 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

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

Management of TLS³

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 includes:

• 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 according to local guidelines

Complications

Complications of TLS include:

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

Key points

• TLS occurs when there is massive cell breakdown and release of intracellular contents, causing electrolyte and metabolic abnormalities
• It generally occurs after initiating chemotherapy and is most common in haematological malignancies and cancers with a high tumour burden
• Diagnosis is based on laboratory findings of hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia
• Patients at risk of TLS can be given preventative measures in the form of IV hydration, allopurinol and rasburicase
• Once TLS is established, the focus should be on aggressive hydration and managing the associated electrolyte imbalances

Editor

Dr Chris Jefferies

References

1. BMJ Best Practice. Tumour Lysis Syndrome. Published 2023. Available from: [LINK] 
2. Life in The Fast Lane. Tumour Lysis Syndrome. Published 2020. Available from: [LINK]
3. British Journal of Haematology. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology. Published 2015. Available from: [LINK]