Tumour Lysis Syndrome

Introduction

Tumour lysis syndrome (TLS) is what happens when a very large number of tumour cells die at once and spill their contents into the circulation faster than the kidneys can clear them. It is the one oncological emergency that is essentially iatrogenic and predictable, which is why the examinable content is heavily weighted towards prevention rather than rescue.³

It occurs most often 12 to 72 hours after the first dose of effective treatment for a bulky, rapidly dividing, chemosensitive malignancy. It can also occur spontaneously before any treatment in very high-turnover disease such as Burkitt lymphoma, and increasingly with highly effective targeted agents - venetoclax in chronic lymphocytic leukaemia is the modern example, and its dose is escalated over weeks specifically to avoid it.

Once established it carries significant mortality, requires renal replacement therapy in a substantial proportion of patients, and delays the cancer treatment that the patient needs. Prevented, it costs a bag of saline and a tablet.

Pathophysiology

Every abnormality in TLS follows from a single event - the rupture of a very large number of cells - and can be derived from what is inside a cell.

The renal injury is what makes the syndrome self-amplifying. Crystal deposition and the volume depletion that often accompanies the illness reduce glomerular filtration; potassium, phosphate and urate can then no longer be excreted, so their levels climb further, causing more crystal deposition. Interrupting that loop with fluid, before treatment begins, is the whole basis of prophylaxis.

Lactate dehydrogenase, released from the same cells, is a useful surrogate for tumour burden and cell turnover, and a high LDH is one of the strongest risk markers.

Definitions and risk stratification

The Cairo-Bishop classification distinguishes laboratory from clinical TLS, and is worth knowing because it explains why patients are monitored biochemically before they have any symptoms.¹

Who is at risk

• Tumour factors - large bulk, high proliferation rate, high sensitivity to the planned treatment, high LDH, high white cell count, extensive marrow involvement
• Patient factors - pre-existing chronic kidney disease, dehydration or hypovolaemia, oliguria, a raised baseline uric acid, and nephrotoxic drugs
• Treatment factors - the first cycle of an intensive regimen, rituximab in bulky disease, and rapid-onset targeted agents

Clinical features

The biochemistry deranges before the patient feels unwell, which is precisely why monitoring is scheduled rather than symptom-triggered. When symptoms do occur they are non-specific and easily attributed to the chemotherapy itself.

• General - nausea, vomiting, anorexia, lethargy and malaise, typically 24 to 48 hours after treatment
• Renal - oliguria, haematuria, flank pain, fluid overload with oedema and breathlessness, and the confusion of uraemia
• Hyperkalaemia - muscle weakness, cramps, palpitations, and cardiac arrest. It may be entirely asymptomatic until the arrhythmia.
• Hypocalcaemia - perioral and peripheral paraesthesiae, muscle cramps, carpopedal spasm, tetany, Chvostek's and Trousseau's signs, prolonged QT and seizures
• Cardiac - arrhythmias of any kind, and sudden death, which may be the first manifestation
• Neurological - confusion, seizures, and rarely coma

Investigations

• U&Es, creatinine and eGFR - baseline and then 4 to 6 hourly in high-risk patients for the first 24 to 48 hours
• Potassium, phosphate, corrected calcium and magnesium on the same schedule
• Uric acid - and note that if rasburicase is being used, samples must be taken into a pre-chilled tube and transported on ice, because the enzyme continues to degrade urate in the sample and gives a falsely low result
• LDH - a marker of tumour burden and cell turnover, useful for risk assessment and monitoring
• FBC, coagulation screen and LFTs
• ECG and continuous cardiac monitoring in high-risk patients or established TLS - peaked T waves, a prolonged PR interval, broadening of the QRS, and a prolonged QT from hypocalcaemia
• Strict fluid balance with hourly urine output, catheterising if necessary
• Venous blood gas for a rapid potassium and for acidosis
• Renal tract ultrasound if there is oliguria, to exclude obstruction - a bulky retroperitoneal lymphoma can obstruct the ureters and mimic or compound TLS
• G6PD status before rasburicase in patients of African, Mediterranean, Middle Eastern or South-East Asian ancestry

Prevention

Prophylaxis is chosen by risk category and started before the first dose of anti-cancer treatment.^2,3

Hydration

Vigorous intravenous fluid, usually 0.9% sodium chloride at around 2 to 3 litres per square metre per day, is the foundation of prevention in every risk group. The aim is a urine output above 100 mL per hour in an adult, which maintains tubular flow and keeps urate and phosphate in solution. Fluids are started 24 to 48 hours before treatment where possible and continued for several days afterwards.

• Do not add potassium to maintenance fluids in a patient at risk
• Use loop diuretics only for established fluid overload in an adequately filled patient, not to force a diuresis
• Monitor for overload in the elderly and in anyone with cardiac or renal impairment
• Stop nephrotoxic drugs - NSAIDs, aminoglycosides, ACE inhibitors, and contrast where avoidable

Allopurinol

Allopurinol inhibits xanthine oxidase, preventing the conversion of hypoxanthine and xanthine to uric acid. It is given to low and intermediate risk patients, ideally starting 24 to 48 hours before treatment, at 300 mg daily with dose reduction in renal impairment.⁶

Rasburicase

Rasburicase is recombinant urate oxidase, an enzyme humans lack. It converts uric acid to allantoin, which is five to ten times more soluble and readily excreted. It therefore removes existing urate rather than merely preventing more, and lowers the level within hours. It is used for high-risk patients as prophylaxis, and for established TLS with significant hyperuricaemia.

What is no longer done

Urinary alkalinisation with sodium bicarbonate is no longer recommended. The rationale was that uric acid is more soluble at alkaline pH, but raising the urinary pH simultaneously reduces the solubility of calcium phosphate, promoting its deposition in the tubules - and phosphate nephropathy is at least as damaging as urate nephropathy. With adequate hydration and rasburicase available, alkalinisation offers no advantage. It still appears as a distractor in questions.

Management of established tumour lysis syndrome

Treat the potassium first, support the kidneys, and involve nephrology and critical care early. Anti-cancer treatment is usually continued or resumed once the metabolic disturbance is controlled, since the tumour is the source of the problem.

1. Hyperkalaemia - continuous cardiac monitoring; intravenous calcium gluconate if there are ECG changes, to stabilise the myocardium; insulin with dextrose and nebulised salbutamol to shift potassium intracellularly; a potassium binder such as sodium zirconium cyclosilicate or patiromer to remove it; and dialysis if refractory
2. Hyperphosphataemia - oral phosphate binders, continued hydration, and dialysis if severe
3. Hypocalcaemia - treat only if symptomatic. Giving calcium in the presence of a high phosphate promotes calcium phosphate precipitation in the kidneys and soft tissues, so asymptomatic hypocalcaemia is left alone and corrects as the phosphate falls.
4. Hyperuricaemia - rasburicase, having checked G6PD status where indicated
5. Acute kidney injury - maintain filling, stop nephrotoxins, and refer early for renal replacement therapy
6. Escalate to critical care for arrhythmia, refractory hyperkalaemia, seizures or the need for urgent dialysis

Complications

The main complications are acute kidney injury requiring dialysis, which occurs in a substantial minority of high-risk patients; cardiac arrhythmia and sudden cardiac death from hyperkalaemia; and seizures from hypocalcaemia. Multi-organ failure follows in the most severe cases.

There are also consequences for the cancer treatment. TLS delays subsequent cycles, may require dose reduction, and in patients who need renal replacement therapy the choice of agents and their dosing become considerably more complicated. Some patients are left with chronic kidney disease from nephrocalcinosis, which then restricts the drugs available for the rest of their treatment.

A rarer but important complication is that fluid loading in a patient with bulky mediastinal lymphoma and superior vena cava obstruction, or with pre-existing cardiac disease, causes pulmonary oedema. Prophylaxis is not risk-free, and fluid balance in these patients needs the same attention as the biochemistry.

Red flags

Prognosis

With appropriate prophylaxis, clinical TLS is now uncommon even in the highest-risk patients, and most episodes of laboratory TLS resolve with fluids and rasburicase without lasting harm. Where clinical TLS does develop, mortality is significant - reported at around 15% in some series - and is driven by arrhythmia and multi-organ failure.^4,5

The paradox worth appreciating is that TLS is a marker of a treatment that is working. The tumours that cause it are the chemosensitive ones - Burkitt lymphoma and acute lymphoblastic leukaemia are potentially curable even when they present with enormous disease burden. The task is therefore to get the patient safely through the first few days so that curative treatment can continue, rather than to moderate the treatment.

For finals, the reliable answer to "how would you manage this patient's risk of tumour lysis syndrome?" is: risk stratify before treatment, give intravenous fluids aiming for a high urine output, give allopurinol for intermediate risk or rasburicase for high risk, check G6PD before rasburicase, monitor bloods 4 to 6 hourly for the first 48 hours, and do not alkalinise the urine.