Tumor lysis syndrome and how to avoid

Definition

• • Combination of metabolic and electrolyte abnormalities that occurs in patients with cancer, usually after the initiation of cytotoxic treatment but also spontaneously

  • Characterised by excessive cell lysis resulting in hyperuricaemia, hyperphosphataemia, hyperkalaemia, and hypocalcaemia

  • TLS is most common with lymphomas and leukaemias, in particular Burkitt's lymphoma and acute lymphoblastic leukaemia

  • It is also associated with other haematological malignancies and solid tumours.

Risk Factors

• • haematological malignancy

  • large tumour burden

  • chemosensitive tumours

  • recent chemotherapy

  • renal impairment

  • dehydration

Differential diagnosis

• • Isolated hyperuricaemia

    • Also associated with malignancy, particularly haematological tumours

    • May be asymptomatic or present with nephrolithiasis or gout

• Isolated hyperkalaemia

  • • Can present with fatigue, weakness, paraesthesia, palpitations, or life-threatening arrhythmias

    • Patient may be taking potassium-sparing medication, systemic heparin, or NSAIDs

    • Renal failure and frequent blood transfusions can contribute

• • Isolated hyperphosphataemia

    • History of dehydration and volume depletion, pulmonary embolism, bone metastases, or advanced renal failure

    • Use of bisphosphonates, laxatives, and antacids may contribute

    • Symptoms such as tetany and cramping relate to hypocalcaemia caused by hyperphosphataemia.

• Isolated hypocalcaemia

  • • Perioral numbness or tingling, paraesthesia of hands and feet, positive Trousseau or Chvostek sign.

Epidemiology

• • Approximate incidence:

    • 6.1% in non-Hodgkin's lymphoma (NHL)

    • 5.2% in acute lymphocytic leukaemia

    • 3.4% in acute myeloid leukaemia

Aetiology

• • TLS appears in haematological malignancies characterised by a high proliferating rate

    • In particular non-Hodgkin's lymphoma, acute lymphocytic leukaemia, and acute myeloid leukaemia

  • Less frequently, TLS appears in other haematological malignancies such as chronic lymphocytic leukaemia and multiple myeloma

  • It is rarely associated with solid tumours, but to date it has been described in a number of primary cancers, including breast cancer, small cell lung cancer, and testicular cancer

  • The risk of developing TLS is increased if the tumour consists of rapidly dividing cells, if the bulk of the disease is high, and if response to treatment is good

  • Pre-existing renal impairment and/or dehydration are predisposing factors that may be modifiable and should be identified prior to treatment initiation

  • High serum lactate dehydrogenase and white blood cell count correlate with high tumour volume and are associated with a high likelihood of TLS

  • Although there is a correlation between advanced age and TLS, age is not an independent risk factor

    • The increased likelihood of developing TLS is most likely related to a reduction in glomerular filtration rate

Clinical features

• • History of haematological malignancy

  • Pre-existing renal compromise

  • Syncope/chest pain/dyspnoea

  • Seizures

  • Nausea and vomiting

  • Anorexia

  • Diarrhoea

  • Muscle weakness

  • Muscle cramps

  • Lethargy

  • Paraesthesia

  • Lymphadenopathy

  • Splenomegaly

  • Hypertension/hypotension

  • Oliguria/anuria/haematuria

Pathophysiology

• • Malignant cells have a high turnover rate

    • => Produce a greater amount of nucleic acid products (which transform to uric acid) and phosphate (approximately 4 times the amount carried by a normal lymphocyte)

  • TLS is caused by the rapid destruction of tumour cells, usually in response to chemotherapy

    • The release of intracellular contents into the bloodstream results in an elevation in serum levels of uric acid, potassium, and phosphate, and a reduction in the level of calcium

  • The ability of the kidney to eliminate these large amounts of byproducts becomes saturated.

  • Hyperuricaemia, in combination with acidic urine and reduced urinary flow, may result in precipitation of uric acid crystals, renal tubular obstruction, and a decline in renal function

    • This is the most common mechanism of acute renal failure in TLS.

  • Hyperphosphataemia may lead to the formation of calcium phosphate crystals and precipitation, resulting in nephrocalcinosis and urinary obstruction.

  • Secondary hypocalcaemia has been reported as a consequence of hyperphosphataemia, which may be symptomatic if severe.

  • Hyperkalaemia is related to the massive cell degradation but may be exacerbated by the development of acute renal failure or lactic acidosis

  • The clinical manifestations of TLS are directly related to these pathophysiological abnormalities

    • Hyperkalaemia, hyperphosphataemia, and hypocalcaemia may result in cardiac arrhythmias and sudden death

    • Hypocalcaemia can lead to muscle cramps, tetany, and seizures

    • Acute renal failure may lead to fluid overload and pulmonary oedema

Investigations

• • Serum uric acid

  • Serum phosphate

  • Serum potassium

  • Serum calcium

  • Full blood count

    • High levels of pretreatment WBC increase the likelihood of developing laboratory and clinical TLS

  • Lactate dehydrogenase

    • High pretreatment levels increase the likelihood of developing laboratory and clinical TLS

  • Serum creatinine

    • A sign of clinical TLS

  • Serum urea

    • Consistent with renal impairment and acute renal failure, or may be raised with dehydration

  • Urine pH

    • Uric acid is poorly soluble in water and becomes less soluble in an acidic environment (urine pH <5)

    • Uric acid crystals can precipitate in renal tubules and cause tubular obstruction and nephropathy

  • ECG

    • Abnormalities with hyperkalaemia include peaked T waves, prolongation of PR and QRS intervals, and flattening of P waves

    • This might be followed by atrioventricular conduction blocks and ventricular fibrillation or asystole

    • In hypocalcaemia, QT prolongation may be seen, which predisposes to ventricular arrhythmias. arrhythmia with hyperkalaemia, hyperphosphataemia, or hypocalcaemia

Management

a) conservative

• • Patients with indolent non-Hodgkin's lymphoma or low proliferating malignancies are at low risk

    • These patients can be observed with regular monitoring of blood biochemistry and regular assessment of fluid balance and vital signs

  • Nephrotoxic agents such as NSAIDs, aminoglycoside antibiotics, and intravenous contrast should be avoided in patients with haematological malignancy undergoing chemotherapy

b) medical

• • Prechemotherapy intravenous hydration

    • Two days before the initiation of systemic cytotoxic therapy, patients should receive intravenous hydration with isotonic sodium chloride

    • Maintain a high urinary output of 100 mL/hour (3 mL/kg/hour in children <10 kg body weight).

  • Phosphate binder

    • Phosphate-binding agents such as aluminium antacids are given to reduce bowel absorption of phosphate

    • Aluminium may cause constipation, whereas magnesium is more likely to cause diarrhoea

    • A combination antacid may reduce colonic adverse effects

  • Allopurinol

    • Can prevent formation of uric acid but cannot destroy the uric acid already present

    • It has been shown to reduce the incidence of urate nephropathy related to uric acid crystal precipitation

    • When used with purine-based chemotherapeutic agents such as mercaptopurine or azathioprine, dose reductions of these agents are required

  • Rasburicase

    • Initial management with a single dose of rasburicase (recombinant urate-oxidase enzyme) may be considered in paediatric patients

    • Rasburicase may be initiated in adults if treatment with allopurinol fails to treat hyperuricaemia

  • Loop diuretic

    • A high glomerular filtration rate results in a reduction of uric acid, phosphate, and potassium in the bloodstream by improving the elimination of uric acid and phosphate

    • Aggressive hydration improves intravascular volume and enhances renal blood flow

    • If urine output is not satisfactory despite volume repletion, then loop diuretics may be used

    • Loop diuretics may cause precipitation of uric acid and calcium phosphate in the tubules and should therefore be avoided in patients with renal obstruction or volume depletion

c) surgical

• • n/a

Prognosis

• • There are no data on prognosis of TLS following successful treatment or prevention

  • Since the introduction of rasburicase, acute renal failure requiring dialysis has been significantly reduced

  • Increased understanding of the pathophysiology and awareness of TLS among physicians has led to better management and better outcomes

    • Official management guidelines have yet to be formulated, but efforts are in progress

  • The outcome and duration of inpatient stay may vary if complications such as cardiac arrhythmias, seizures, or acute renal failure develop

    • Most of these complications can be managed successfully in large specialist centres.