Tumor lysis syndrome (TLS) is a potentially life-threatening complication that has been described since the first use of modern cytotoxic chemotherapy.
Tumor lysis syndrome (TLS) is a potentially life-threatening complication that has been described since the first use of modern cytotoxic chemotherapy.[1-3] As discussed in the accompanying review by Muslimani and colleagues, the identification of high-risk patients and the provision of early intervention are the cornerstones of managing patients in danger of developing TLS. Yet despite the fact that cases of TLS have been encountered for nearly 40 years, it has been extremely challenging to construct a clinically meaningful definition of the condition and a method for estimating its severity.
Identifying potential risk factors was a logical first step. In 2004, Cairo and Bishop, building on initial work by Hande and Garrow, devised a comprehensive grading system for TLS with the goals of early identification and prevention of complications. Risk factors included tumor type, tumor characteristics (eg, bulky tumor, high cellular proliferation rate, sensitivity to cytoreductive therapy), and other host-related factors. This classification system also included a grading system for describing the severity of TLS; the five grades were based on the degree of serum creatinine elevation, the presence of and type of cardiac arrhythmia, and finally, the presence and severity of seizures. As was the intent of the authors, the Cairo-Bishop grading system has been used extensively in clinical practice and experimental studies to further define and answer important questions regarding TLS.
However, Cairo and Bishop were well aware that their classification system was just a starting point, and, as it was utilized in various settings, that it would require modification and modernization. In 2008, Coiffier et al provided an updated, evidence-based review of guidelines for the management of TLS. In general, the authors recommended that patients with a low risk of TLS be monitored for the development of TLS and complications but receive only normal hydration and no prophylaxis for hyperuricemia, except in the presence of metabolic changes, bulky and/or advanced disease, and/or highly proliferative disease, in which case allopurinol should be added. Patients with an intermediate risk of TLS were to be monitored for TLS and complications, and given increased hydration (3 L/m2 per day) and allopurinol (100 to 300 mg, po, q8h, daily); however, such patients would not need alkalinization. In patients with a high risk of TLS, the authors recommended frequent monitoring, aggressive hydration (3 L/m2 per day) unless there was evidence of renal insufficiency and oliguria, and one dose of rasburicase (0.15 to 0.2 mg/kg), to be repeated only if clinically necessary. In addition, they noted that in patients with a history of glucose-6-phosphate dehydrogenase, rasburicase was contraindicated and allopurinol should be used instead. Patients who ultimately develop TLS and who were originally classified as having either low or intermediate risk should receive rasburicase unless clinically contraindicated.
In 2010, an international panel of clinical oncologists with expertise in pediatric and adult hematologic malignancies and TLS management published updated disease-specific, evidence-based guidelines for the management of pediatric and adult patients who had or who were at risk for TLS. These guidelines again focused on prevention as the best approach to TLS management and provided further guidance for the treatment of patients in whom TLS has developed. The 2010 consensus panel on TLS proposed a medical decision tree that incorporates histological diagnosis, extent and bulk of disease (stage, lactate dehydrogenase [LDH] level, bulk), use of specific cytotoxic agents, age at diagnosis and pre-existing renal dysfunction or renal involvement as major risk factors.  In contrast to the guidelines presented by Coiffier et al in 2008, which did not address all malignancies or uniformly assess risk based on renal function, the 2010 guidelines were designed to be uniformly applicable to all patients at risk for TLS.
TLS risk evaluation was based on three sequential phases that, taken together, provided a final determination of TLS risk. First, patients were assessed for laboratory TLS.[4,5] Next, risk assessment based on malignant disease type as well as age and stage, response to and type of chemotherapy, bulk of disease, WBC count and LDH levels was used to classify hematologic malignancies and solid tumors as low, intermediate, or high risk. The third step required an adjustment to be made based on renal function and renal involvement; patients with lymphomas or leukemias were upgraded by one risk category if there was renal dysfunction or renal involvement or if their uric acid, potassium, or phosphate level was higher than the upper limit of normal. Patients were then classified as having high risk, intermediate risk, or low risk of developing TLS.
This is the first TLS risk classification system to combine multiple factors into a final assessment of a patient's risk of TLS rather than restricting analysis to individual parameters. The resulting risk of TLS developing in patients with low-risk disease was estimated to be <1%, with a level of evidence ranging from 2+ to 4. The risk of TLS developing in patients with intermediate-risk disease was estimated to be 1% to 5%, with a level of evidence of 1+ to 2+. The risk of TLS developing in patients with high-risk disease was estimated to be >5%, with a level of evidence of 1++ to 1+. The prophylaxis recommendations were a modified version of those contained in the 2008 review by Coiffier et al.
The 2010 TLS consensus panel's risk classification system integrates diverse criteria into a user-friendly, simple model. The new guidelines also have important clinical implications for the prevention and management of TLS-associated hyperuricemia because they are the first to define specific roles for allopurinol and rasburicase. Although the Cairo-Bishop classification may still be useful for identifying patients who are at high risk for TLS, the new guidelines take the next step by providing the level of evidence and the grade of each recommendation. It is pleasing to both authors that this has occurred, as the identification, prevention, and treatment of TLS continue to evolve and improve.
Financial Disclosure:This work was supported in part by the Center for Cancer Research, National Cancer Institute, Intramural Research Program.
1. Zusman J, Brown DM, Nesbit ME. Hyperphosphatemia, hyperphosphaturia and hypocalcemia in acute lymphoblastic leukemia. N Engl J Med. 1973;289:1335-40.
2. O'Regan S, Carson S, Chesney RW, Drummond KN. Electrolyte and acid-base disturbances in the management of leukemia. Blood. 1977;49:345-53.
3. Cohen LF, Balow JE, Magrath IT, et al. Acute tumor lysis syndrome. A review of 37 patients with Burkitt's lymphoma. Am J Med. 1980;68:486-91.
4. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin's lymphoma. Am J Med. 1993;94:133-9.
5. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3-11.
6. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767-78.
7. Cairo MS, Coiffier B, Reiter A, Younes A. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149:578-86.
8. Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ. 2001;323:334-6.