Tumour lysis syndrome is the most common disease-related emergency in patients with haematologic cancers. This article summarises current strategies for risk assessment, prophylaxis and management
Geoff Saunders FRPharmS BPharm MPhil FCPP BCOP
Consultant Oncology Pharmacist
The Christie NHS Foundation Trust
Tumour lysis syndrome (TLS) is classed as an oncological emergency; without appropriate management it can have serious consequences for the patient. Practitioners involved in the treatment of patients with cancer should have a thorough understanding of the underlying causes of TLS and have the knowledge to prevent its occurrence or to treat appropriately. This article reviews the definition of TLS, looks at its causes, identifies patients most at risk of developing TLS and describes the complications that patients may develop if treated inappropriately. The management of patients will be described from a preventative as well as a therapeutic viewpoint with a look at the drugs commonly used in this setting. Finally, developments in this area of therapy are described.
Tumour lysis syndrome is a metabolic disorder characterised by disturbances in renal function and biochemistry including uric acid, phosphate, potassium, calcium, urea, creatinine and lactate dehydrogenase. TLS can occur spontaneously in patients with tumours of a high proliferative rate; however, TLS is encountered more commonly after initiation of treatment with either chemotherapy or radiotherapy.
A classification of laboratory TLS and clinical TLS has been proposed in an attempt to differentiate between patients with biochemical abnormalities that require no therapeutic intervention and those with life-threatening abnormalities. This concept is being further defined to take into account pre-existing abnormal values and patients developing TLS, either before initiation of therapy or more than four days afterwards.(1)
Rapid cellular destruction and release of their contents, particularly nucleic acids, proteins and phosphorus, can overwhelm normal body systems resulting in hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia and uraemia.
Catabolism of nucleic acids results in the production of hypoxanthine and xanthine, which are further converted by the enzyme xanthine oxidase to uric acid. Uric acid has poor solubility and has limited clearance by the kidneys. As the concentration of uric acid increases, the probability of crystal formation and precipitation in the renal tubles increases, leading to renal impairment and failure.
Patients at risk are those with a high tumour burden that is sensitive to treatment; typically this includes non-Hodgkins lymphoma and other haematological malignancies, such as Burkitts lymphoma, acute lymphoblastic leukaemia, acute myeloid leukaemia and certain solid tumours, for example, testicular cancer presenting with a large mediastinal mass.
If untreated, TLS can result in impaired renal function owing to the crystallisation of uric acid or calcium phosphate in the renal tubules. In some cases, this can result in acute renal failure and even death.
Hyperphosphataemia can lead to nausea, vomiting, diarrhoea, lethargy or seizures. Severe hypocalcaemia can lead to cardiac arrhythmia, hypotension, tetany and muscular cramps.
Elevated potassium levels can produce cardiac irregularities including arrest or neuromuscular effects, for example, parasthesia.
Patients recognised to be at high risk of developing TLS, either because of type of malignancy or pre-existing biochemical abnormalities, should be given intravenous fluids to ensure adequate hydration and renal output and be treated with prophylactic doses of either allopurinol or rasburicase depending on level of risk and institutional guidelines.(2)
The management of TLS is reliant upon correcting any biochemical abnormalities, hydration, and prevention of further urate formation. Care should be taken not to exacerbate renal dysfunction by the precipitation of calcium phosphate crystals when administering calcium-containing drugs to patients with high phosphate levels. Adequate hydration is important as it maintains the intravascular volume, improves renal blood flow and glomerular filtration rate, increases xanthine solubility, and promotes urate excretion.
The use of sodium bicarbonate to produce alkaline urine is controversial, because, while uric acid solubility is improved, the solubility of hypoxanthine and xanthine is decreased. Phosphate binders, such as oral aluminium hydroxide, should be limited to one or two days in paediatric patients to avoid cumulative aluminium toxicity.
In addition to guidelines for the prevention and treatment of TLS published by bodies such as the American Society of Clinical Oncology or the British Medical Journal, many institutions have produced their own evidence-based guidelines.(3,4)
Allopurinol is a prodrug of a xanthine analogue that competively inhibits the enzyme xanthine oxidase, which is responsible for the conversion of hypoxanthine and xanthine to uric acid. Allopurinol will not reverse the production of urates already formed but it will prevent the formation of further uric acid, allowing levels to stabilise or fall. Used prophylactically, allopurinol will decrease the risk of renal dysfunction related to uric acid crystalisation.
The dose of purine-based agents such as mercaptopurine or azathioprine should be decreased when combined with allopurinol because their rate of metabolism will be reduced. The manufacturers of capecitabine advise that concomitant use with allopurinol should be avoided.
Rasburicase is a recombinant form of the enzyme urate oxidase, which converts uric acid to allantoin and which is five-to-ten-times more soluble in urine than uric acid, resulting in a rapid decrease in serum urate levels. Because of cost considerations, rasburicase is often used only in cases of established TLS or for prophylaxis in high-risk patients. Treatment is usually given at a dose of 200 micrograms per kg over five-to-seven days. Hypersensitivity reactions can occur in approximately 1% of patients.
The relatively high acquisition cost of rasburicase compared with other treatment strategies in TLS has prompted the consideration of alternative dosing approaches. In a small study, the use of a 3mg fixed dose of rasburicase repeated for patients receiving several days of chemotherapy or persistently elevated serum urate levels was shown to adequately control TLS with the majority of patients requiring just a single dose.(5)
TLS is an oncological emergency that should be anticipated in patients considered to be at high risk; prophylactic measures, hydration and anti-urate therapy should be employed before commencing treatment to prevent TLS in at-risk patients. Patients with established TLS should receive prompt treatment according to best practice or institutional guidelines.
- Tumour lysis syndrome (TLS) commonly arises in patients with certain haematological malignancies at the commencement of treatment.
- TLS should be anticipated in at-risk patients and prophylactic treatment with fluids and/or allopurinol should be administered before any active treatment.
- Any underlying biochemical abnormalities should be controlled before initiating therapy.
- Established TLS should be treated immediately following evidence-based guidelines.
- Cairo M, Bishop M. Tumour lysis syndrome: New therapeutic strategies and classification. Br J Haematol 2004;127:3–11.
- Lorigan P et al. Tumour lysis syndrome: case report and review of the literature. Ann Oncol 1996;7:631–6.
- Coffier B et al. Guidelines for the management of pediatric and adult tumour lysis syndrome: An evidence based review. J Clin Oncol 2008;26:2767–78.
- BMJ Group. Tumour Lysis Syndrome –Treatment –Step by step – Best Practice. http://n3.bestpractice.bmj.com/best-practice/monograph/936/treatment/step-bystep.html (accessed 9 August 2013).
- Coutsouvelis J, Wiseman M, Hui L. Effectiveness of a single fixed dose of rasburicase 3mg in the management of tumour lysis syndrome. Br J Clin Pharmacol 2012;75:550–3.