Metabolic complications seen in patients with chemosensitive hematologic malignancies and high tumor burden.
The tumor lysis syndrome (TLS) occurs when the ability of the body to maintain electrolyte-uric acid homeostasis is overwhelmed as a result of the destruction of malignant cells and the massive release of cellular contents, including nucleic acids.
Caused by the abrupt release of cellular components into the blood stream after major lysis of cancer cells.
May be a life threatening process.
The increased risk of death from TLS is principally due to cardiac complications associated with severe acute hyperkalemia and hypocalcemia, particularly in patients with coexisting conditions.
The TLS is observed most commonly in patients with bulky, chemosensitive hematologic malignancies with high proliferative rates-lymphoma and acute leukemias predominating, In those who are undergoing intensive induction therapy.
Rapid destruction of malignant cells release potentially harmful chemicals including: nucleic acids, proteins, potassium, and phosphorus.
Release of chemicals overwhelms the mechanisms of homeostasis that can lead to arrhythmias, renal insufficiency, and seizures.
High tumor burden and or increased tumor turnover increases the risk of TLS.
Release of large amounts of potassium, phosphorus, and nucleic acids overwhelms homeostatic mechanism of the body, resulting in hyperkalemia, hyperphosphatemia, hyperuricemia and secondary hypocalcemia.
The acute kidney injury associated with TLS is principally a consequence of direct effects of hyperuricemia and hyperphosphatemia.
Uric acid is poorly soluble in plasma, and the degree of hyperuricemia can predict acute kidney injury in TLS in the context of cancer treatment.
Extracellular histone levels on markedly increased during tumor releases, and the increases associated with the severity of an acute kidney injury.
Acute kidney injury is associated with increased risk of complications, mortality, and complexity of care.
Uric acid can regulate pro inflammatory, cytokines, activating innate immunity toll-like receptors.
Malignancies most commonly associated with TLS are acute lymphocytic leukemia, lymphomas, Burkitt’s lymphoma, acute myelogenous leukemia and small cell carcinoma of the lung.
The reported incidence of the syndrome varies, depending upon the era of reports, ranging from 5 to 70%.
It rarely can occur spontaneously as a manifestation of an occult cancer, in association with glucocorticoids, and in patients with traditionally, non-chemosensitive cancers, and after radiation therapy.
Usually occurs most often during the first cycle of chemotherapy, but may occur later in the course of treatment.
The TLS syndrome may exist concurrently with hematophagocytosis or DIC.
Bishop and Cairo established criteria for TLS on the basis of metabolic abnormalities and associated clinical toxicities: Laboratory TLS defined by 2 or more of the following metabolic abnormalities-hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia, while clinical TLS is accompanied by at least one clinical complication such as renal impairment, cardiac arrhythmia, or seizure (Cairo MS, Bishop M).
Metabolic imbalances include hyperkalemia, hyperuricemia, hypocalcemia and hyperphosphatemia, which can lead to renal failure.
Hyperphosphatemia contributes to renal injury, directly, and indirectly by binding ionized, calcium, which is causes acute hypocalcemia, and calcium phosphate deposition in renal tubes.
Hypocalcemia can confer predisposition to technique, seizures, and arrhythmias.
Result of lysis of malignant cells with release of intracellular phosphate, potassium, and purines.
Characterized by massive release of tumor cell contents into the blood.
Can rarely occur in treatment of solid tumors such as breast cancer, sarcomas, ovarian cancer and small cell lung cancer.
May occur spontaneously prior to treatment in patients who have tumors with a high proliferative rate, such as diffuse large B-cell lymphoma, acute lymphoblastic leukemia or Burkitt lymphoma.
Hyperuricemia is the most frequent clinically recognized manifestation.
May lead to acute renal failure, cardiac arrhythmias, neurologic complications, and seizures.
Most commonly occurs during cytotoxic therapy, although biological agents such as CD20 monoclonal antibodies can induce TLS.
Observed in increased frequency with the advent of increasingly effective targeted therapies.
May be a laboratory or a clinical process.
Laboratory TLS is much more common of a phenomenon.
Laboratory TLS occurs within 24 hours with 2 or more electrolyte abnormalities in an asymptomatic patient from 3 days before to 7 days after treatment.
Clinical TLS refers to a rapid and extreme alteration in serum electrolytes consistent with laboratory changes with additional clinical complications and possible clinical sequelae, and represents a medical emergency requiring intervention.
Clinical complications include: nausea, vomiting, lethargy, renal failure, edema, congestive heart failure, and potentially sudden death.
Subacute TLS manifests by more gradual changes in laboratory tests.
Cairo-Bishop criteria for diagnosis requires 2 or more laboratory abnormalities with a 25% change from baseline occurring any time within 3 days before or 7 days after chemotherapy.
Howard criteria similar, but 25% change not essential, if abnormal labs present, and an additional laboratory change occurs within the same time limits as above.
The presence of laboratory TLS, elevated creatinine level, seizures arrhythmias or death defines clinical TLS.
In a review of 102 patients with high grade non-Hodgkin’s lymphoma 42% of patients had signs of laboratory TLS and 6% clinical TLS (Hande KR, Garrow GC).
In this study of 755 European children and adults with newly diagnosed or recurrent ALL, AML. or NHL experienced a 19% incidence of hyperuricemia and a 5% incidence of laboratory TLS per episode of administration of an induction treatment (Annemans L et al).
Preventing TLS includes laboratory monitoring, use of uric acid lowering agents, and adequate hydration.
Oral hydration is acceptable for patients at low risk and some patients with medium risk for TLS, but IV fluids are essential for high risk patients, and for some of intermediate risk.
In high risk patients aggressive hydration should be administered prior to therapy with a goal of at least 100 cc per hour production or urine.
In high risk patients adequate fluid volume should be maintained for 2 days prior to treatment, if possible, and 2-3 days following treatment.
Protocols to monitor intake and output, electrolytes, and uric acid should be employed in high risk patients, and correction of abnormalities instituted.
Elderly patients with cancer are particularly likely to have comorbidities that may worsen their prognosis in the presence of TLS, such as renal insufficiency and/or cardiac disease.
Hyperuricemia may lead to acute kidney injury which is an independent risk factor for mortality.
Hyperuricemia may lead to gastrointestinal complaints such as nausea, vomiting, diarrhea, and anorexia, lethargy, hematuria, flank or back pain, fluid overload, edema, arthralgias, hypertension, and signs of obstructive uropathy (Kennedy LD).
Hyperuricemia is a result of a breakdown of purine containing nucleic acids that are released from malignant cells.
Hydration and alkalinization of urine can decrease the risk of uric acid crystal deposition.
Alkalization is no longer recommended as it inhibits phosphorus excretion and may exacerbate hyperphosphatemia and increasing the risk of renal calcium phosphate precipitation, or enhance hypocalciumia with a risk of tetany, seizures, or arrhythmias.
Allopurinol is used to decrease uric acid formation.
Allopurinol has no effect on existing uric acid.
Allopurinol, a xanthine oxidase inhibitor,. requires 24-72 hours to effectively prevent de novo formation of uric acid.
Acute renal failure is one of the most immediate complications of this syndrome.
Rasburicase can reduce serum uric acid levels within 4 hours of administration, resulting in greater and faster reductions in uric acid than with allopurinol treatment.
In a randomized study of adults with hematological malignancies at risk for hyperuricemia rasburicase 0.2 mg/kilogram/day intravenously days one through five, rasburicase plus allopurinol 0.2 mg/kilogram/day intravenously, days one to three followed by oral allopurinol 300 mg/day, days 3-5, or allopurinol 300 mg/day, days one through five: plasma uric acid response was 87% with rasburicase, 78% with rasburicase plus allopurinol and 66% with allopurinol, and the time to uric acid control is four hours for rasburicase, four hours for rasburicase plus allopurinol and 27 hours for allopurinol (Cortes J et al).
Patients may need hemodialysis.
Prophylaxis and treatment:
The goals of prophylaxis and treatment for TLS to prevent a minimize serious or life-threatening electrolyte disturbances and acute kidney injury while maintaining extra cellular volume.
Pre-induction therapy requires requires baseline measurement of uric acid, potassium, and phosphate levels, renal function, and LDH.
Medications that cause or exacerbate acute renal injury should be avoided.
Cellular destruction releases purine nucleic acids, which are metabolized to hypoxanthine and xanthine and subsequently to uric acid.
Allopurinol and febuxostat are xanthine oxidase inhibitors that reduce plasma uric acid levels by inhibiting production.
These agents have equal efficacy.
The use of xanthene oxidation inhibitors can be associated with xanthine crystal nephropathy, rarely.
Rasburicase is a recombinant urate oxidase that decreases uric acid levels more relatively than xanthine oxidatase inhibiionis but without clear reduction in the risk of renal complications in the context of tumor lysis prophylaxis or treatment.
Rasburicase is associated with hypersensitivity or anaphylactic reactions in approximately one percent of patients, and neutralizing antibodies in up to 18% of persons previously exposed the rasburicase.
Rasburicase prophylaxis is considered for patients with high proliferative tumors plus a baseline uric acid that exceeds 8 mg/dL and a creatinine level higher than 1.5 times the baseline level of the upper limit of the normal range.
Rasburicase prophylaxis is also considered in patient in whom the administration of higher fluid volumes may be challenging.
Fluid management: patients with newly diagnosed or relapsed cancer have a predisposition to azotemia leukemia because of poor oral intake, increased insensible or G.I. fluid losses, and stress induced reduction of cardiac output or ineffective, circulating volume due to sepsis.
Azotemia in conjunction with nephrotoxic medications may lead to acute injury in susceptible patients.
Judicious fluid, and blood pressure management with replacement of insensible and G.I. fluid losses and maintenance of appropriate diuresis to minimalize the nephrotoxic effects of the products of tumor lysis syndrome.
Common recommendations include administering 1 to 3 L of fluids per square meter of body surface area per day to maintain a urineoutput of 2 mL per kilogram per hour, particularly during the first 24 to 72 hours after the initiation of systemic therapy, when the risk of tumor lysis is greatest.
Fluid overload should be avoided as it increases the probability of hypoxemia, pulmonary edema, and increased risk of death.
Hyperkalemia and hyperphosphatemia are managed by the redistribution or removal of potassium and phosphate.
Kanagement of acute hyper leukemia includes administration of intravenous calcium to antagonize the effects of potassium on cellular membranes, and therapies to redistribute potassium to cells – insulin with glucose or beta agonist such as albuterol.
Loop diuretics can increase renal potassium excretion.
Cation exchanges bind potassium in the G.I. tract facilitating removal.
Intermittent dialysis may be required.
Hyperphosphatemia may be the best predictor of acute kidney injury in patients with established tumor lysis syndrome,leading to an acute calcium phosphate nephropathy.
Management of hyperphosphatemia includes intravenous saline and diuresis to increase phosphorus excretion, oral phosphate, binders, and dialysis.
Progressive or recurrent hyperuricemia is presently uncommon with the use of rasburicase prophylaxis.