Risk and prevention strategies can help avert tumor lysis syndrome

Abstract

Tumor lysis syndrome (TLS), a potential complication of cancer treatment, occurs when malignant cells quickly lyse, or break open, and the internal contents of the cell spill out into the bloodstream, causing metabolic abnormalities. Most often occurring 48–72 hours after the initiation of cancer treatment for hematologic malignancies, TLS may present before cancer therapy and occur with other tumor types, such as breast cancer, small cell lung cancer, and neuroblastoma.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar, 2Am J Med. 2004; 116: 546-554Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google ScholarPathophysiologyThrough different mechanisms, chemotherapy and targeted-cancer therapies lyse cancer cells. These lysed cancer cells release large amounts of potassium, phosphorus, proteins, and nucleic acids into the systemic circulation. As the kidneys struggle to keep up with the excretion of the lysed cell contents, hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia can quickly develop.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar, 2Am J Med. 2004; 116: 546-554Abstract Full Text Full Text PDF PubMed Scopus (245) Google ScholarHyperuricemia, the most common complication of TLS, is caused by the release of tumor cell proteins and nucleic acids. Followed by their enzymatic breakdown via xanthine oxidase to xanthine, lysed tumor cell proteins and nucleic acids are converted to their end product uric acid.3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google Scholar Table 1 lists electrolyte and metabolic disturbances that can quickly progress to toxic effects.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar, 5Pediatr Blood Cancer. 2005; 44: 63-69Crossref PubMed Scopus (25) Google Scholar, 6Transfus Apher Sci. 2009; 40: 41-47Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7Clinics (Sao Paulo). 2009; 64: 479-481Crossref PubMed Scopus (36) Google ScholarTable 1TLS complicationsSerum/tissue imbalanceResultHyperkalemiaArrhythmiasCalcium phosphateHypocalcemiaHyperuricemiaArrhythmias seizureXanthine precipitateXanthine precipitate; acute kidney injuryEvaluated cytokinesMultiorgan failureSource: Reference 8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar. Open table in a new tab Risk factors and diagnosisMalignancies most frequently associated with TLS have similar characteristics, including high sensitivity to cytotoxic therapy, large tumor burden, and high proliferation rate. Cancers with a higher risk for TLS include high-grade lymphomas, such as Burkitt lymphoma and non-Hodgkin lymphoma (NHL) along with acute lymphoblastic leukemia and acute myeloid leukemia.3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google ScholarOther features predisposing patients to TLS are advanced age, elevated serum lactate dehydrogenase levels, elevated white blood cell counts, poor baseline renal function, and preexisting comorbidities.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google ScholarBoth clinical features and laboratory findings define TLS. The Cairo-Bishop definition (Table 2) and grading system used to diagnose TLS defines laboratory TLS as two or more TLS-associated laboratory changes within 3 days before or 7 days after cytotoxic therapy administration.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar The diagnosis for clinical TLS is at least one clinical symptom plus laboratory TLS.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google ScholarTable 2Cairo-Bishop definitions of TLSLaboratory TLSaTwo or more of the following.Uric acid>8 mg/dL or 25% increase from baselinePotassium>6 mEq/L or 25% increase from baselinePhosphorous>2.1 mmol/L (children) or >1.45 mmol/L (adults) or 25% increase from baselineCalcium<1.75 mmol/L or 25% decrease from baselineClinical TLSbOne or more of the following plus laboratory TLS.Creatinine>1.5 upper limit of normal (age adjusted)Cardiac arrhythmia/sudden deathSeizureSource: References 4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar, 5Pediatr Blood Cancer. 2005; 44: 63-69Crossref PubMed Scopus (25) Google Scholar, 6Transfus Apher Sci. 2009; 40: 41-47Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7Clinics (Sao Paulo). 2009; 64: 479-481Crossref PubMed Scopus (36) Google Scholar.a Two or more of the following.b One or more of the following plus laboratory TLS. Open table in a new tab Although the true incidence of TLS is unknown, a retrospective review of 102 adult patients with high-grade NHL, most of whom received prophylaxis with allopurinol alone, reported a laboratory TLS incidence of 42%.9Am J Med. 1993; 94: 133-139Abstract Full Text PDF PubMed Scopus (251) Google Scholar Of those same patients, 6% developed clinical TLS.9Am J Med. 1993; 94: 133-139Abstract Full Text PDF PubMed Scopus (251) Google ScholarPatients are stratified into categories of low risk (<1%), intermediate risk (1%–5%), and high risk (>5%) for TLS to determine therapy for prophylaxis. Stratification criteria for this determination include type of malignancy, burden of disease, treatment, expected response to treatment, and renal function.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google ScholarWhile TLS is historically associated with traditional chemotherapy, treatment with novel targeted therapies is an identified risk for TLS.10Ann Hematol. 2016; 95: 563Crossref PubMed Scopus (73) Google Scholar See Table 3 for examples of targeted anticancer therapies associated with TLS.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar, 8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google ScholarTable 3Examples of targeted anticancer therapies associated with TLSGeneric nameTrade nameManufacturerAlemtuzumabLemtradaGenzyme, SanofiLenolidamideRevlimidCelgeneBlinatumomabBlincytoAmgenPomalinamidePomalystCelgeneBrentuximabAdcetrisSeattle GeneticsPonatinibIclusigAriad PharmaceuticalsRituximabRituxanGenentech, BiogenIbrutinibImbruvicaPharmacyclics, JanssenSunitinibSutentPfizerImatinibGleevecNovartisThalidomideThalomidCelgeneIxazomibNinlaroTakedaVenetoclaxVenclextaAbbVie, GenentechSource: Reference 11https://clinicalpharmacology.com/. Updated April 2016Google Scholar. Open table in a new tab PreventionAggressive I.V. hydration is the key prevention strategy for all patients at low, intermediate, or high risk for TLS. Hydration, and the subsequent increase in urinary output, minimizes the risk of uric acid or calcium phosphate precipitation in the renal tubules.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar, 8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar Adults and children at risk for TLS receive I.V. fluids at a rate of 2 L/m2 to 3 L/m2 per day.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar Hydration continues until the tumor burden is largely resolved, there is no evidence of TLS, and the patient has normal urinary output with adequate oral fluid intake. Patients with a low urinary output may require a diuretic.13J Clin Invest. 1977; 59: 786-793Crossref PubMed Scopus (111) Google ScholarKeeping serum uric acid in check with allopurinol or rasburicase (Elitek—Sanofi) preserves renal function and helps reduce serum phosphorus levels.14J Clin Oncol. 2001; 19: 697-704PubMed Google Scholar Although allopurinol prevents the formation of uric acid, it does not break down existing uric acid, nor does it help eliminate xanthine, which also forms precipitates. In addition, use of allopurinol requires 2 days to take effect; in the meantime, urate nephropathy may develop.MEDICAL DISCLAIMERThe information contained herein may not be construed as medical advice. It is for educational purposes only. Diplomat Pharmacy Inc. takes no responsibility for the accuracy or validity of the information contained herein, nor the claims or statements of any manufacturer.Rasburicase is more effective than allopurinol for prevention and treatment of TLS because it prevents xanthine accumulation and breaks down preexisting uric acid.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar, 15Blood. 2001; 97: 2998-3003Crossref PubMed Scopus (396) Google Scholar, 16www.cure4kids.org/private/lectures/ppt1468/C4K-1454-0MC-Tumor-Lysis.pdfGoogle Scholar, 17Blood. 2007; 109: 2736-2743PubMed Google Scholar Multiple studies have proven the effectiveness of rasburicase over allopurinol, placing rasburicase as first-line treatment for patients at high risk for clinical TLS and for patients with elevated baseline uric acid.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar, 15Blood. 2001; 97: 2998-3003Crossref PubMed Scopus (396) Google Scholar, 16www.cure4kids.org/private/lectures/ppt1468/C4K-1454-0MC-Tumor-Lysis.pdfGoogle Scholar, 17Blood. 2007; 109: 2736-2743PubMed Google ScholarRasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. In this group of patients, uric acid converts to hydrogen peroxide, causing methemoglobinemia and hemolytic anemia. Finally, although urinary alkalinization increases the solubility of uric acid, it is not recommended because it does not increase the solubility of calcium phosphate, which can lead to hyperphosphatemia.18Acute complications Pui C.-H. Childhood leukemias. Cambridge University Press, Cambridge, UK2006Google ScholarHyperkalemia is the most dangerous serum imbalance caused by TLS, as it can cause sudden death from cardiac dysrhythmia. Serum potassium is measured frequently, and patients are encouraged to limit potassium and phosphorus intake during their individual risk period for TLS.19Expert Opin Emerg Drugs. 2007; 12: 355-365Crossref PubMed Scopus (23) Google Scholar Patients who develop hyperkalemia are treated with oral sodium polystyrene sulfonate with the intent to avoid hemodialysis.Hypocalcemia can also lead to life-threatening dysrhythmias along with neuromuscular irritability. By controlling the serum phosphorus level, hypocalcemia may be prevented. Studies are lacking that show the benefit of phosphate binders such as sevelamer in TLS, yet they are typically used. Treatment for symptomatic hypocalcemia is the lowest dose of calcium to relieve symptoms, while asymptomatic hypocalcemia does not require treatment.To prevent calcium-phosphate precipitation, patients with hyperphosphatemia and hypocalcemia are not given calcium until serum phosphate is normalized with phosphate binders. If hypocalcemia persists or a patient is at risk for cardiac dysrhythmia, calcium gluconate is administered.3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google Scholar Table 4 describes TLS prevention strategies by risk category.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google ScholarTable 4Clinical TLS prevention strategies and monitoring by risk stratificationRisk levelHydrationAllopurinol or rasburicaseMonitoringaLaboratory monitoring includes serum electrolytes, creatinine, and uric acid.LowYesAllopurinolLaboratory tests dailyIntermediateYesAllopurinol or rasburicaseLaboratory tests every 8–12 hHighYesRasburicaseLaboratory tests every 6–8 h and continuous cardiac monitoringEstablished clinical TLSYesRasburicaseLaboratory tests every 4–6 h and continuous cardiac monitoringSource: Reference 8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar.a Laboratory monitoring includes serum electrolytes, creatinine, and uric acid. Open table in a new tab MonitoringFrequent monitoring of urine output is a key factor that allows for prompt treatment of TLS if prevention measures fail. Monitoring frequency depends on TLS risk category and continues over the entire period a patient is at risk for TLS.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar Duration of risk for TLS depends on the therapeutic regimen for the disease being treated.As an additional prevention measure, some patients at high risk for TLS receive low-intensity initial therapy, which is considered a treatment “prephase.”17Blood. 2007; 109: 2736-2743PubMed Google Scholar This prephase creates an environment of slower cancer cell lysis, allowing renal homeostatic mechanisms to keep up with clearing metabolites.17Blood. 2007; 109: 2736-2743PubMed Google ScholarConclusionA complication of cancer therapy, TLS is a potentially life-threatening syndrome presenting shortly after treatment begins. Usually developing in patients with hematologic malignancies, TLS remains a risk during cancer treatment with traditional chemotherapy as well as with novel, targeted therapies.Risk assessment, prevention strategies, and monitoring are of vital importance to averting TLS and its sequelae. As pharmacists, we can help patients understand TLS, its prevention strategies, and the importance of monitoring. We can also guide our patients to their prescribers, should the need arise. Tumor lysis syndrome (TLS), a potential complication of cancer treatment, occurs when malignant cells quickly lyse, or break open, and the internal contents of the cell spill out into the bloodstream, causing metabolic abnormalities. Most often occurring 48–72 hours after the initiation of cancer treatment for hematologic malignancies, TLS may present before cancer therapy and occur with other tumor types, such as breast cancer, small cell lung cancer, and neuroblastoma.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar, 2Am J Med. 2004; 116: 546-554Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google Scholar PathophysiologyThrough different mechanisms, chemotherapy and targeted-cancer therapies lyse cancer cells. These lysed cancer cells release large amounts of potassium, phosphorus, proteins, and nucleic acids into the systemic circulation. As the kidneys struggle to keep up with the excretion of the lysed cell contents, hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia can quickly develop.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar, 2Am J Med. 2004; 116: 546-554Abstract Full Text Full Text PDF PubMed Scopus (245) Google ScholarHyperuricemia, the most common complication of TLS, is caused by the release of tumor cell proteins and nucleic acids. Followed by their enzymatic breakdown via xanthine oxidase to xanthine, lysed tumor cell proteins and nucleic acids are converted to their end product uric acid.3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google Scholar Table 1 lists electrolyte and metabolic disturbances that can quickly progress to toxic effects.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar, 5Pediatr Blood Cancer. 2005; 44: 63-69Crossref PubMed Scopus (25) Google Scholar, 6Transfus Apher Sci. 2009; 40: 41-47Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7Clinics (Sao Paulo). 2009; 64: 479-481Crossref PubMed Scopus (36) Google ScholarTable 1TLS complicationsSerum/tissue imbalanceResultHyperkalemiaArrhythmiasCalcium phosphateHypocalcemiaHyperuricemiaArrhythmias seizureXanthine precipitateXanthine precipitate; acute kidney injuryEvaluated cytokinesMultiorgan failureSource: Reference 8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar. Open table in a new tab Through different mechanisms, chemotherapy and targeted-cancer therapies lyse cancer cells. These lysed cancer cells release large amounts of potassium, phosphorus, proteins, and nucleic acids into the systemic circulation. As the kidneys struggle to keep up with the excretion of the lysed cell contents, hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia can quickly develop.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar, 2Am J Med. 2004; 116: 546-554Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar Hyperuricemia, the most common complication of TLS, is caused by the release of tumor cell proteins and nucleic acids. Followed by their enzymatic breakdown via xanthine oxidase to xanthine, lysed tumor cell proteins and nucleic acids are converted to their end product uric acid.3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google Scholar Table 1 lists electrolyte and metabolic disturbances that can quickly progress to toxic effects.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar, 5Pediatr Blood Cancer. 2005; 44: 63-69Crossref PubMed Scopus (25) Google Scholar, 6Transfus Apher Sci. 2009; 40: 41-47Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7Clinics (Sao Paulo). 2009; 64: 479-481Crossref PubMed Scopus (36) Google Scholar Risk factors and diagnosisMalignancies most frequently associated with TLS have similar characteristics, including high sensitivity to cytotoxic therapy, large tumor burden, and high proliferation rate. Cancers with a higher risk for TLS include high-grade lymphomas, such as Burkitt lymphoma and non-Hodgkin lymphoma (NHL) along with acute lymphoblastic leukemia and acute myeloid leukemia.3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google ScholarOther features predisposing patients to TLS are advanced age, elevated serum lactate dehydrogenase levels, elevated white blood cell counts, poor baseline renal function, and preexisting comorbidities.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google ScholarBoth clinical features and laboratory findings define TLS. The Cairo-Bishop definition (Table 2) and grading system used to diagnose TLS defines laboratory TLS as two or more TLS-associated laboratory changes within 3 days before or 7 days after cytotoxic therapy administration.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar The diagnosis for clinical TLS is at least one clinical symptom plus laboratory TLS.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google ScholarTable 2Cairo-Bishop definitions of TLSLaboratory TLSaTwo or more of the following.Uric acid>8 mg/dL or 25% increase from baselinePotassium>6 mEq/L or 25% increase from baselinePhosphorous>2.1 mmol/L (children) or >1.45 mmol/L (adults) or 25% increase from baselineCalcium<1.75 mmol/L or 25% decrease from baselineClinical TLSbOne or more of the following plus laboratory TLS.Creatinine>1.5 upper limit of normal (age adjusted)Cardiac arrhythmia/sudden deathSeizureSource: References 4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar, 5Pediatr Blood Cancer. 2005; 44: 63-69Crossref PubMed Scopus (25) Google Scholar, 6Transfus Apher Sci. 2009; 40: 41-47Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7Clinics (Sao Paulo). 2009; 64: 479-481Crossref PubMed Scopus (36) Google Scholar.a Two or more of the following.b One or more of the following plus laboratory TLS. Open table in a new tab Although the true incidence of TLS is unknown, a retrospective review of 102 adult patients with high-grade NHL, most of whom received prophylaxis with allopurinol alone, reported a laboratory TLS incidence of 42%.9Am J Med. 1993; 94: 133-139Abstract Full Text PDF PubMed Scopus (251) Google Scholar Of those same patients, 6% developed clinical TLS.9Am J Med. 1993; 94: 133-139Abstract Full Text PDF PubMed Scopus (251) Google ScholarPatients are stratified into categories of low risk (<1%), intermediate risk (1%–5%), and high risk (>5%) for TLS to determine therapy for prophylaxis. Stratification criteria for this determination include type of malignancy, burden of disease, treatment, expected response to treatment, and renal function.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google ScholarWhile TLS is historically associated with traditional chemotherapy, treatment with novel targeted therapies is an identified risk for TLS.10Ann Hematol. 2016; 95: 563Crossref PubMed Scopus (73) Google Scholar See Table 3 for examples of targeted anticancer therapies associated with TLS.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar, 8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google ScholarTable 3Examples of targeted anticancer therapies associated with TLSGeneric nameTrade nameManufacturerAlemtuzumabLemtradaGenzyme, SanofiLenolidamideRevlimidCelgeneBlinatumomabBlincytoAmgenPomalinamidePomalystCelgeneBrentuximabAdcetrisSeattle GeneticsPonatinibIclusigAriad PharmaceuticalsRituximabRituxanGenentech, BiogenIbrutinibImbruvicaPharmacyclics, JanssenSunitinibSutentPfizerImatinibGleevecNovartisThalidomideThalomidCelgeneIxazomibNinlaroTakedaVenetoclaxVenclextaAbbVie, GenentechSource: Reference 11https://clinicalpharmacology.com/. Updated April 2016Google Scholar. Open table in a new tab Malignancies most frequently associated with TLS have similar characteristics, including high sensitivity to cytotoxic therapy, large tumor burden, and high proliferation rate. Cancers with a higher risk for TLS include high-grade lymphomas, such as Burkitt lymphoma and non-Hodgkin lymphoma (NHL) along with acute lymphoblastic leukemia and acute myeloid leukemia.3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google Scholar Other features predisposing patients to TLS are advanced age, elevated serum lactate dehydrogenase levels, elevated white blood cell counts, poor baseline renal function, and preexisting comorbidities.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar Both clinical features and laboratory findings define TLS. The Cairo-Bishop definition (Table 2) and grading system used to diagnose TLS defines laboratory TLS as two or more TLS-associated laboratory changes within 3 days before or 7 days after cytotoxic therapy administration.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar The diagnosis for clinical TLS is at least one clinical symptom plus laboratory TLS.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar Although the true incidence of TLS is unknown, a retrospective review of 102 adult patients with high-grade NHL, most of whom received prophylaxis with allopurinol alone, reported a laboratory TLS incidence of 42%.9Am J Med. 1993; 94: 133-139Abstract Full Text PDF PubMed Scopus (251) Google Scholar Of those same patients, 6% developed clinical TLS.9Am J Med. 1993; 94: 133-139Abstract Full Text PDF PubMed Scopus (251) Google Scholar Patients are stratified into categories of low risk (<1%), intermediate risk (1%–5%), and high risk (>5%) for TLS to determine therapy for prophylaxis. Stratification criteria for this determination include type of malignancy, burden of disease, treatment, expected response to treatment, and renal function.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar While TLS is historically associated with traditional chemotherapy, treatment with novel targeted therapies is an identified risk for TLS.10Ann Hematol. 2016; 95: 563Crossref PubMed Scopus (73) Google Scholar See Table 3 for examples of targeted anticancer therapies associated with TLS.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar, 8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar PreventionAggressive I.V. hydration is the key prevention strategy for all patients at low, intermediate, or high risk for TLS. Hydration, and the subsequent increase in urinary output, minimizes the risk of uric acid or calcium phosphate precipitation in the renal tubules.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar, 8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar Adults and children at risk for TLS receive I.V. fluids at a rate of 2 L/m2 to 3 L/m2 per day.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar Hydration continues until the tumor burden is largely resolved, there is no evidence of TLS, and the patient has normal urinary output with adequate oral fluid intake. Patients with a low urinary output may require a diuretic.13J Clin Invest. 1977; 59: 786-793Crossref PubMed Scopus (111) Google ScholarKeeping serum uric acid in check with allopurinol or rasburicase (Elitek—Sanofi) preserves renal function and helps reduce serum phosphorus levels.14J Clin Oncol. 2001; 19: 697-704PubMed Google Scholar Although allopurinol prevents the formation of uric acid, it does not break down existing uric acid, nor does it help eliminate xanthine, which also forms precipitates. In addition, use of allopurinol requires 2 days to take effect; in the meantime, urate nephropathy may develop.MEDICAL DISCLAIMERThe information contained herein may not be construed as medical advice. It is for educational purposes only. Diplomat Pharmacy Inc. takes no responsibility for the accuracy or validity of the information contained herein, nor the claims or statements of any manufacturer.Rasburicase is more effective than allopurinol for prevention and treatment of TLS because it prevents xanthine accumulation and breaks down preexisting uric acid.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar, 15Blood. 2001; 97: 2998-3003Crossref PubMed Scopus (396) Google Scholar, 16www.cure4kids.org/private/lectures/ppt1468/C4K-1454-0MC-Tumor-Lysis.pdfGoogle Scholar, 17Blood. 2007; 109: 2736-2743PubMed Google Scholar Multiple studies have proven the effectiveness of rasburicase over allopurinol, placing rasburicase as first-line treatment for patients at high risk for clinical TLS and for patients with elevated baseline uric acid.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar, 15Blood. 2001; 97: 2998-3003Crossref PubMed Scopus (396) Google Scholar, 16www.cure4kids.org/private/lectures/ppt1468/C4K-1454-0MC-Tumor-Lysis.pdfGoogle Scholar, 17Blood. 2007; 109: 2736-2743PubMed Google ScholarRasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. In this group of patients, uric acid converts to hydrogen peroxide, causing methemoglobinemia and hemolytic anemia. Finally, although urinary alkalinization increases the solubility of uric acid, it is not recommended because it does not increase the solubility of calcium phosphate, which can lead to hyperphosphatemia.18Acute complications Pui C.-H. Childhood leukemias. Cambridge University Press, Cambridge, UK2006Google ScholarHyperkalemia is the most dangerous serum imbalance caused by TLS, as it can cause sudden death from cardiac dysrhythmia. Serum potassium is measured frequently, and patients are encouraged to limit potassium and phosphorus intake during their individual risk period for TLS.19Expert Opin Emerg Drugs. 2007; 12: 355-365Crossref PubMed Scopus (23) Google Scholar Patients who develop hyperkalemia are treated with oral sodium polystyrene sulfonate with the intent to avoid hemodialysis.Hypocalcemia can also lead to life-threatening dysrhythmias along with neuromuscular irritability. By controlling the serum phosphorus level, hypocalcemia may be prevented. Studies are lacking that show the benefit of phosphate binders such as sevelamer in TLS, yet they are typically used. Treatment for symptomatic hypocalcemia is the lowest dose of calcium to relieve symptoms, while asymptomatic hypocalcemia does not require treatment.To prevent calcium-phosphate precipitation, patients with hyperphosphatemia and hypocalcemia are not given calcium until serum phosphate is normalized with phosphate binders. If hypocalcemia persists or a patient is at risk for cardiac dysrhythmia, calcium gluconate is administered.3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google Scholar Table 4 describes TLS prevention strategies by risk category.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google ScholarTable 4Clinical TLS prevention strategies and monitoring by risk stratificationRisk levelHydrationAllopurinol or rasburicaseMonitoringaLaboratory monitoring includes serum electrolytes, creatinine, and uric acid.LowYesAllopurinolLaboratory tests dailyIntermediateYesAllopurinol or rasburicaseLaboratory tests every 8–12 hHighYesRasburicaseLaboratory tests every 6–8 h and continuous cardiac monitoringEstablished clinical TLSYesRasburicaseLaboratory tests every 4–6 h and continuous cardiac monitoringSource: Reference 8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar.a Laboratory monitoring includes serum electrolytes, creatinine, and uric acid. Open table in a new tab Aggressive I.V. hydration is the key prevention strategy for all patients at low, intermediate, or high risk for TLS. Hydration, and the subsequent increase in urinary output, minimizes the risk of uric acid or calcium phosphate precipitation in the renal tubules.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar, 8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar Adults and children at risk for TLS receive I.V. fluids at a rate of 2 L/m2 to 3 L/m2 per day.1J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (486) Google Scholar Hydration continues until the tumor burden is largely resolved, there is no evidence of TLS, and the patient has normal urinary output with adequate oral fluid intake. Patients with a low urinary output may require a diuretic.13J Clin Invest. 1977; 59: 786-793Crossref PubMed Scopus (111) Google Scholar Keeping serum uric acid in check with allopurinol or rasburicase (Elitek—Sanofi) preserves renal function and helps reduce serum phosphorus levels.14J Clin Oncol. 2001; 19: 697-704PubMed Google Scholar Although allopurinol prevents the formation of uric acid, it does not break down existing uric acid, nor does it help eliminate xanthine, which also forms precipitates. In addition, use of allopurinol requires 2 days to take effect; in the meantime, urate nephropathy may develop. MEDICAL DISCLAIMERThe information contained herein may not be construed as medical advice. It is for educational purposes only. Diplomat Pharmacy Inc. takes no responsibility for the accuracy or validity of the information contained herein, nor the claims or statements of any manufacturer. MEDICAL DISCLAIMERThe information contained herein may not be construed as medical advice. It is for educational purposes only. Diplomat Pharmacy Inc. takes no responsibility for the accuracy or validity of the information contained herein, nor the claims or statements of any manufacturer. MEDICAL DISCLAIMERThe information contained herein may not be construed as medical advice. It is for educational purposes only. Diplomat Pharmacy Inc. takes no responsibility for the accuracy or validity of the information contained herein, nor the claims or statements of any manufacturer. The information contained herein may not be construed as medical advice. It is for educational purposes only. Diplomat Pharmacy Inc. takes no responsibility for the accuracy or validity of the information contained herein, nor the claims or statements of any manufacturer. Rasburicase is more effective than allopurinol for prevention and treatment of TLS because it prevents xanthine accumulation and breaks down preexisting uric acid.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar, 15Blood. 2001; 97: 2998-3003Crossref PubMed Scopus (396) Google Scholar, 16www.cure4kids.org/private/lectures/ppt1468/C4K-1454-0MC-Tumor-Lysis.pdfGoogle Scholar, 17Blood. 2007; 109: 2736-2743PubMed Google Scholar Multiple studies have proven the effectiveness of rasburicase over allopurinol, placing rasburicase as first-line treatment for patients at high risk for clinical TLS and for patients with elevated baseline uric acid.8Br J Haematol. 2010; 149: 578Crossref PubMed Scopus (330) Google Scholar, 15Blood. 2001; 97: 2998-3003Crossref PubMed Scopus (396) Google Scholar, 16www.cure4kids.org/private/lectures/ppt1468/C4K-1454-0MC-Tumor-Lysis.pdfGoogle Scholar, 17Blood. 2007; 109: 2736-2743PubMed Google Scholar Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. In this group of patients, uric acid converts to hydrogen peroxide, causing methemoglobinemia and hemolytic anemia. Finally, although urinary alkalinization increases the solubility of uric acid, it is not recommended because it does not increase the solubility of calcium phosphate, which can lead to hyperphosphatemia.18Acute complications Pui C.-H. Childhood leukemias. Cambridge University Press, Cambridge, UK2006Google Scholar Hyperkalemia is the most dangerous serum imbalance caused by TLS, as it can cause sudden death from cardiac dysrhythmia. Serum potassium is measured frequently, and patients are encouraged to limit potassium and phosphorus intake during their individual risk period for TLS.19Expert Opin Emerg Drugs. 2007; 12: 355-365Crossref PubMed Scopus (23) Google Scholar Patients who develop hyperkalemia are treated with oral sodium polystyrene sulfonate with the intent to avoid hemodialysis. Hypocalcemia can also lead to life-threatening dysrhythmias along with neuromuscular irritability. By controlling the serum phosphorus level, hypocalcemia may be prevented. Studies are lacking that show the benefit of phosphate binders such as sevelamer in TLS, yet they are typically used. Treatment for symptomatic hypocalcemia is the lowest dose of calcium to relieve symptoms, while asymptomatic hypocalcemia does not require treatment. To prevent calcium-phosphate precipitation, patients with hyperphosphatemia and hypocalcemia are not given calcium until serum phosphate is normalized with phosphate binders. If hypocalcemia persists or a patient is at risk for cardiac dysrhythmia, calcium gluconate is administered.3Haematologica. 2008; 93: 9-13Crossref PubMed Scopus (95) Google Scholar Table 4 describes TLS prevention strategies by risk category.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar MonitoringFrequent monitoring of urine output is a key factor that allows for prompt treatment of TLS if prevention measures fail. Monitoring frequency depends on TLS risk category and continues over the entire period a patient is at risk for TLS.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar Duration of risk for TLS depends on the therapeutic regimen for the disease being treated.As an additional prevention measure, some patients at high risk for TLS receive low-intensity initial therapy, which is considered a treatment “prephase.”17Blood. 2007; 109: 2736-2743PubMed Google Scholar This prephase creates an environment of slower cancer cell lysis, allowing renal homeostatic mechanisms to keep up with clearing metabolites.17Blood. 2007; 109: 2736-2743PubMed Google Scholar Frequent monitoring of urine output is a key factor that allows for prompt treatment of TLS if prevention measures fail. Monitoring frequency depends on TLS risk category and continues over the entire period a patient is at risk for TLS.4NEJM. 2011; 364: 1844-1854Crossref PubMed Scopus (527) Google Scholar Duration of risk for TLS depends on the therapeutic regimen for the disease being treated. As an additional prevention measure, some patients at high risk for TLS receive low-intensity initial therapy, which is considered a treatment “prephase.”17Blood. 2007; 109: 2736-2743PubMed Google Scholar This prephase creates an environment of slower cancer cell lysis, allowing renal homeostatic mechanisms to keep up with clearing metabolites.17Blood. 2007; 109: 2736-2743PubMed Google Scholar ConclusionA complication of cancer therapy, TLS is a potentially life-threatening syndrome presenting shortly after treatment begins. Usually developing in patients with hematologic malignancies, TLS remains a risk during cancer treatment with traditional chemotherapy as well as with novel, targeted therapies.Risk assessment, prevention strategies, and monitoring are of vital importance to averting TLS and its sequelae. As pharmacists, we can help patients understand TLS, its prevention strategies, and the importance of monitoring. We can also guide our patients to their prescribers, should the need arise. A complication of cancer therapy, TLS is a potentially life-threatening syndrome presenting shortly after treatment begins. Usually developing in patients with hematologic malignancies, TLS remains a risk during cancer treatment with traditional chemotherapy as well as with novel, targeted therapies.