Manuscript received September 9, 2010; accepted April 8, 2011.
* Current affiliation: Incyte Corporation, Wilmington, DE.
Correspondence to: Karen P. Seiter, MD, New York Medical College, Munger Pavilion, Room 250, Valhalla, NY 10595; telephone: 914-493-7514; fax: 914-594-4420; e-mail: karen_seiter@nymc.edu.
Tumor lysis syndrome (TLS) is a relatively common, potentially life-threatening complication of aggressive cytotoxic therapy characterized by metabolite and electrolyte abnormalities (eg, hyperuricemia). To increase the awareness of the risk of hyperuricemia and TLS in adult patients with cancer, who are likely to have age- or lifestyle-related comorbidities, the authors examine the pathophysiology and risk of TLS in adult patients with a broad spectrum of cancer diagnoses. Current recommendations for effective prophylaxis and management of TLS are summarized briefly. Particular emphasis is given to the appropriate role of antihyperuricemic therapy with rasburicase in adults, based on the recent results of a phase III clinical study.
Tumor lysis syndrome (TLS) is a serious, potentially life-threatening condition of metabolic derangement and impaired electrolyte homeostasis. TLS can occur in patients with cancer as a result of spontaneous or, more commonly, treatment-induced tumor cell death and typically is seen in patients with hematologic, rather than solid organ, malignancies who are undergoing chemotherapy. It is particularly an issue for patients with rapidly growing tumors and a high tumor burden (as evidenced by a high white blood cell [WBC] count in leukemia and elevated serum lactate dehydrogenase [LDH] levels and/or advanced clinical stage in lymphoma) at the beginning of chemotherapy. TLS is caused by a sudden, massive release of cell content from lysed tumor cells into the bloodstream, which overwhelms the body’s capacity for homeostatic regulation. Because persistent or progressive metabolic derangement is associated with a high risk of organ failure, TLS is a clinical emergency.
To facilitate the diagnosis, prevention, and treatment of TLS, Cairo and Bishop established precise criteria for the categorization of TLS on the basis of metabolic abnormalities and the associated significant clinical toxicities that require clinical intervention.1 According to Cairo and Bishop, laboratory TLS (LTLS) is defined by the presence of two or more of the following metabolic abnormalities: hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia. Clinical TLS (CTLS) is defined as LTLS accompanied by at least one clinical complication, such as renal impairment (defined as a serum creatinine concentration greater than 1.5 times the upper limit of normal), cardiac arrhythmia, or seizure. The aforementioned clinical manifestations should not be directly or likely attributable to a therapeutic agent (eg, a rise in creatinine levels after administration of a nephrotoxic drug).1
Estimates from clinical studies of the incidence of TLS vary widely.2 In a review of case records of 102 patients with high-grade non-Hodgkin’s lymphoma (NHL), 42% of patients had signs of LTLS and 6% had CTLS.3 In contrast, analysis of data from a sample of 755 European children and adults with newly diagnosed or recurrent acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or NHL indicated a 19% incidence of hyperuricemia and a 5% incidence of LTLS per episode of administration of an induction therapy ¬regimen.4
Pathophysiology of TLS in adults
The pathophysiology and clinical consequences of TLS have been discussed infrequently in the context of adult patient populations. Yet adult ¬patients are more likely than pediatric patients to experience potentially serious metabolic, cardiac, renal, or multisystemic comorbidities. Such comorbidities, whether chronic illnesses present at the initiation of anticancer therapy or acute conditions that develop during administration of aggressive cytoreductive regimens, require special consideration because they may amplify the metabolic and electrolyte imbalances caused by tumor cell lysis and may have secondary pathophysiologic consequences. In adults, these effects may further weaken an already strained homeostatic regulation and thereby significantly increase the risk of serious clinical complications of TLS.5 Elderly patients (age > 65 years) with cancer are particularly likely to have comorbidities, which may worsen their prognosis in the event of TLS, including baseline chronic renal insufficiency and/or heart disease.6
Hyperuricemia is one of the hallmarks of LTLS. If not reversed quickly, severe hyperuricemia may have serious clinical consequences, particularly acute kidney injury (AKI), which is an independent risk factor for mortality (even mild AKI).2 Additionally, hyperuricemia can lead to a variety of distressing symptoms, such as gastrointestinal complaints (nausea, vomiting, diarrhea, and anorexia), lethargy, hematuria, flank or back pain, fluid overload, edema, arthralgias, hypertension, and signs of obstructive uropathy.7
The risk of renal complications is particularly high in elderly patients with baseline renal disease, which may have been caused by diabetes, hypertension, renal artery stenosis, chronic pyelonephritis, amyloidosis, glomerular disease, or treated malignancies.6 Furthermore, congestive heart failure, use of thiazide or loop diuretics, obesity, type II diabetes, renal impairment, hypertriglyceridemia, and peripheral vascular disease are major cardiovascular risk factors associated with hyperuricemia.6