Serious clinical consequences may arise not only from hyperuricemia but also from TLS-related electrolyte abnormalities (ie, hyperphosphatemia, hyperkalemia, or hypocalcemia). AKI, cardiac arrhythmia, and neurologic impairment, such as seizures or higher CNS dysfunction, may result from severe hyperphosphatemia and secondary hypocalcemia caused by calcium phosphate precipitation in renal tubules. These two metabolic disturbances also may present with muscle cramps, tetany, or perioral numbness or tingling; rare symptoms include fatigue, bone and joint pain, pruritus, and rash.7 Hyperphosphatemia can be exacerbated by excessive use of phosphate-containing laxatives or enemas, which is especially common in the elderly. Hyperkalemia also can lead to neuromuscular symptoms, but principally, it may cause potentially life-threatening cardiac dysfunction.2
Because of the decrease in physiologic reserves with age, the aforementioned electrolyte abnormalities are associated with increased morbidity and mortality in the elderly.8 For example, renal function generally declines with age, and age-related reduction in renin and aldosterone levels increases the risk of hyperkalemia.6 Particularly among the elderly, the risk of hyperkalemia is increased in those with renal tubular reabsorption/secretion defects, those with type II diabetes who develop type IV renal tubular acidosis as the result of hyporeninemic hypoaldosteronism, and those who take nonsteroidal anti-inflammatory drugs on a long-term, scheduled basis.9,10 Although antihypertensive medications generally have cardioprotective and renoprotective properties, many antihypertensives actually may increase the risk of hyperkalemia in elderly patients with renal tubular acidosis.11,12 Also in adults, hypocalcemia may result from vitamin D deficiency, impaired vitamin D metabolism, low intestinal Ca2+ absorption, phosphate retention, chronic hypomagnesemia, serum protein abnormalities, and parathyroid hormone resistance; it may also occur as a medication adverse effect (specifically relevant for patients with cancer treated with bisphosphonates, anticonvulsants, cis¬platin, and the combination of 5-fluor¬¬ouracil and ¬leucovorin).6,13
Risk of TLS in adults with cancer
The risk of TLS in adults with cancer depends on multiple components, including disease-related factors, the type and aggressiveness of anticancer treatment, other medications concomitantly administered, and patient (host)-related factors. TLS has been observed primarily in patients with hematologic malignancies, with particularly high incidences reported for those with Burkitt (and Burkitt-like) lymphoma, precursor B-lymphoblastic leukemia/lymphoma, high-stage T-cell anaplastic large cell lymphoma, and ALL.2
Demographic data from compassionate-use studies of the uricolytic agent rasburicase (Elitek) in patients with or at high risk of acute cancer-associated hyperuricemia and TLS seem to suggest that AML with high WBC counts and select types of NHL (mostly high-grade and some intermediate-grade lymphomas) are associated with a high risk of TLS in adults.14,15 Based on the findings of two European studies, between 3% and 17% of adult patients with AML may experience LTLS or CTLS in response to induction therapy.4,16 In one of the two studies, approximately 20% of adults with AML, ALL, or NHL experienced hyperuricemia after induction therapy.4 Data from the second study, which included 772 adults with AML (including some cases of chronic myelogenous leukemia [CML] in blast crisis) who had received induction chemotherapy, were used to develop a risk-prediction model for CTLS in adult patients with AML.16 According to the model, high WBC count, pretreatment hyperuricemia, and high baseline serum creatinine and LDH concentrations were significant independent prognostic factors for the development of LTLS and CTLS.16
An independent international panel of experts in pediatric and adult hematologic malignancies and TLS recently developed guidelines for the management of TLS based on a comprehensive risk-stratification algorithm. These guidelines were published in 2008 by the American Society of Clinical Oncology.17 Patients were considered to be at high, intermediate, or low risk of TLS, depending on the specific type of malignancy, tumor burden, and type of cytoreductive therapy administered.
In addition to these basic risk categories, other risk factors such as renal function and plasma uric acid (PUA) level at baseline were incorporated into the recommendations for TLS prevention and treatment.17 For example, the presence of baseline hyperuricemia (defined as a serum uric acid level > 7.5 mg/dL) is a modifier of the recommendation of antihyperuricemic therapy for patients at intermediate risk of TLS; if there are high baseline PUA levels, the drug of choice should not be allopurinol but rather rasburicase.17 However, these guidelines do not address all malignancies or uniformly assess risk depending on renal involvement by the disease or kidney function.
Consequently, another consensus panel was convened to build upon the 2008 guidelines and produce a medical decision tree for ranking patients with cancer as low, intermediate, or high risk of TLS. For this project, risk factors included biologic evidence of LTLS, tumor proliferation, and bulk and stage of malignant tumor, as well as renal impairment and/or involvement by the disease at the time of TLS diagnosis; subsequently, an algorithmic model of low-, intermediate-, and high-risk TLS classification and associated TLS prophylaxis recommendations were finalized.18 TLS risk factors of particular relevance for elderly patients are age-related alterations in heart anatomy and function, obesity, generalized deconditioning, alterations of the cardiovascular and circulatory systems, use of multiple drugs with potential pharmacodynamic interactions, age-related decrease in glomerular filtration rate, tobacco use, excessive alcohol consumption, and unhealthy dietary ¬habits.6