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Originally published as JCO Early Release 10.1200/JCO.2008.19.6030 on November 3 2008 © 2008 American Society of Clinical Oncology.
Management of Tumor Lysis Syndrome: Need for Evidence-Based Guidelines
Department of Hematology/Oncology, Children's Hospital & Research Center Oakland, Oakland, CA
Pediatric Hematology/Oncology, Children's Hospital of Pittsburgh, Pittsburgh, PA
Department of Pediatrics, The University of Chicago, Chicago, IL
Division of Hematology/Oncology, Children's Hospital and Department of Pediatrics, Dana-Farber Cancer Institute, Boston, MA To the Editor: We read with interest the recent review article by Coiffier et al,1 which outlines guidelines for the management of tumor lysis syndrome (TLS). The article provides a good overall review of the pathogenesis and clinical consequences of this condition in pediatric and adult patients. However, we are concerned that little to no data exist to support many of the authors' recommendations for managing TLS in pediatric patients. In fact, the authors have indicated that eight of the 11 recommendations outlined in their article are based on case reports and clinical examples with little or no systematic empirical evidence (Table 6; Level V, Grade D). Additional details are needed to clarify the proposed risk-group stratification presented in Table 5. For example, are all patients with Burkitt's lymphoma considered high risk regardless of stage? The authors recommend admission to an intensive care unit and administration of rasburicase for high-risk patients. Do the authors recommend this type of care for patients with stages I and II Burkitt's lymphoma? Unless there is clear-cut evidence of TLS, what is the evidence that this intensive treatment plan is needed? Furthermore, the administration of rasburicase to children at risk for tumor lysis in the setting of normal renal function when uric acid levels are normal or slightly elevated has not been proven to decrease the metabolic complications and morbidity of TLS compared with allopurinol.2 Several additional comments and recommendations also deserve discussion. First, the recommendation to no longer alkalinize urine to prevent and/or treat TLS is concerning. The authors are correct in stating that the role of alkalinization alone has never been properly studied in patients. However, the study they cite in the article (Conger et al,3 reference 29 in the original article) to support their claim that alkalinization is not required was based on animal studies, in which endogenous urate oxidase activity was inhibited by oxonic acid in rats that were deficient in vasopressin. Hyperuricemia was induced in these animals with a one-time bolus infusion of lithium urate (300 mg/kg). Conger et al recognized there may be important "species differences" between rats and humans that were not overcome by simply blocking the activity of endogenous urate oxidase in the model. In addition, the transient hyperuricemic state induced in this rat model differs considerably from human TLS, and the authors state in their article that "it would be inappropriate to suggest that urine alkalinization be abandoned as a therapeutic modality in hyperuricemic renal failure." To our knowledge, there are no other publications that corroborate the rat studies. Sodium bicarbonate has been used to alkalinize the urine of thousands of patients at risk for TLS, with only a handful of reports of xanthine or calcium phosphate nephropathy (both often cited as potential complications of overly vigorous urinary alkalinization in a hyperuricemic setting). Clearly, decisions regarding whether urinary alkalinization should be abandoned in patients at risk for TLS should not be based on a single animal study. Rather, prospective randomized clinical trials are needed to define the true risk versus benefit of urinary alkalinization in TLS. Second, the recommendation of no diuresis for patients at "low risk" for TLS (Fig 2) is not supported by any evidence. "Low risk" is not equivalent to "no risk." However, this is a group in which nonalkaline diuresis might well be appropriate, and this management concept should be tested in a clinical trial. Third, the recommendation to use one fourth normal saline in large volumes up to twice the normal maintenance amount may be hazardous. Do the authors have evidence regarding the safety of such an approach? In addition, any syndrome of inappropriate secretion of antidiuretic hormone that might occur because of vincristine or cyclophosphamide given during initial treatment could be exacerbated by use of such hypotonic fluid. Fourth, we are curious as to the magnitude of the effect of rasburicase on serum uric acid levels. If blood samples obtained for this measurement are not placed on ice throughout processing and measurement in the clinical laboratory, the levels may be falsely low because of ongoing enzymatic destruction of uric acid by the drug in the blood samples obtained. We have never seen any primary data that address this issue, and are concerned that many samples are not being properly handled in busy oncology practices. Do the authors have these data? In summary, little to no data exist to support most of the guidelines for managing TLS outlined in this article. Furthermore, some of the recommendations, such as using large volumes of hypotonic saline, have potential risks. Additional studies are needed to define risks and determine the optimal management of TLS in children. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on November 3, 2008 REFERENCES
1. Coiffier B, Altman A, Pui Ching-Hon, et al: Guidelines for the management of pediatric and adult tumor lysis syndrome: An evidence-based review. J Clin Oncol 26:2767-2778, 2008 2. Goldman SC, Holcenberg JS, Finklestein JZ, et al: A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 97:2998-3003, 2001 3. Conger JD, Falk SA: Intrarenal dynamics in the pathogenesis and prevention of acute urate nephropathy. J Clin Invest 59:786-793, 1977[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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