Hospital Medicine

Tumor lysis syndrome

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Tumor lysis syndrome

I. What every physician needs to know.

Tumor lysis syndrome is considered an oncologic metabolic emergency due to poor clinical outcome if it is unrecognized and untreated. Tumor lysis syndrome is comprised of a group of metabolic derangements. It can occur spontaneously, however, in most cases it is a result of initial treatment of underlying hematologic malignancy. There is a rapid release of intracellular potassium, phosphorus, nucleic acid following lysis of malignant cell. These abnormalities include hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and, frequently, acidosis, which may result in serious complications such as acute renal failure, cardiac arrhythmia, and/or neurologic complications such as seizures.

The release of intracellular potassium, phosphorus, and nucleic acids into the extracellular space due to rapid destruction of tumor cells can result in detrimental metabolic derangement in tumor lysis syndrome. Purines derived from cellular DNA are then further broken down into uric acid in the liver leading to hyperuricemia. The precipitation of this excess uric acid in the kidneys leads to nephropathy and renal insufficiency. Electrolyte imbalances are exacerbated by the decreased renal excretion of phosphorus and potassium. The elevated phosphorus levels may also lead to the precipitation of calcium phosphate crystals and cause a secondary hypocalcemia. Further renal injury results from the precipitation of calcium-phosphate in the renal tubules. Lastly, the metabolic acidosis that often develops with renal failure exacerbates the hyperkalemia.

The syndrome can occur spontaneously but primarily occurs in patients undergoing induction chemotherapy for hematologic malignancies and is often evident within 12-72 hours after the initiation of cytotoxic therapy due to rapid destruction of tumor cells. The factors that increase risk of tumor lysis syndrome include elevated LDH, extensive bone marrow involvement, pre-existing renal disease and reduced urinary output, advance age, and the use of drugs that increase serum uric acid such as alcohol, thiazide diuretics, levodopa. Rarely, tumor lysis syndrome may occur spontaneously prior to the initiation of therapy. In these spontaneous cases, hematologic malignancy especially the bulky, chemosensitive disease poses the highest risk. For example, patient with underlying Burkitt's lymphoma. There are also case reports of tumor lysis syndrome occurring in patients with solid malignancies, most commonly in breast cancer and small cell carcinoma, particularly of the lung. In addition, tumor lysis syndrome can be seen in children undergoing therapy for neuroblastoma.

Aggressive hydration and prophylaxis treatment prior to the induction chemotherapy for hematologic malignancy has been important in management of tumor lysis syndrome. In addition, it is important as clinician to understand and recognize the elevated risk of tumor lysis syndrome in some of the new chemotherapy agents such as the alkylating agent, benedamustine.

II. Diagnostic Confirmation: Are you sure your patient has Tumor Lysis Syndrome?

Tumor lysis syndrome can be subdivided into solely a laboratory diagnosis versus a clinical diagnosis. Laboratory diagnosis of tumor lysis syndrome is based on having two or more abnormal lab values including hyperuricemia, hyperkalemia, hyperphosphatemia, and/or secondary hypocalcemia occurring within 3 days prior to or up to 7 days after the initiation of cytotoxic therapy for malignancy. The diagnosis of clinical tumor lysis syndrome assumes a laboratory diagnosis plus one or more serious complications including renal insufficiency, cardiac arrhythmia or sudden cardiac death, and/or seizure not attributable to another underlying cause.

Although there is no universal standard for the diagnosis of tumor lysis syndrome, the most accepted definition is based on the 2004 Cairo-Bishop criteria which is subdivided into laboratory and clinical diagnosis.

  • Laboratory tumor lysis syndrome, patients must have two or more laboratory abnormalities, occurring within 3 days prior to or up to 7 days after the initiation of cyotoxic therapy.

    1. Hyperuricemia: greater than or equal to 8 mg/dL or a 25% increase from baseline.

    2. Hyperkalemia: greater than or equal to 6 mEq/L or a 25% increase from baseline.

    3. Hyperphosphatemia: greater than or equal to 4.5 mg/dL in adults or less than or equal to 6.5 mg/dL in children or a 25% increase from baseline.

    4. Secondary hypocalcemia: less than or equal to 7 mg/dL or a 25% decrease from baseline.

  • Clinical tumor lysis syndrome occurs when a patient meets two or more criteria for laboratory diagnosis and has an additional clinical complication attributed to the abnormalities such as renal insufficiency, cardiac arrhythmia, sudden cardiac death, and/or seizure not attributable to another underlying cause. Renal insufficiency evidenced by a serum creatinine greater than or equal to 1.5 times the upper limit or normal (not attributed to another underlying cause).

A. History Part I: Pattern Recognition:

Clinical symptoms of the disorder are rather non-specific. However, high clinical suspicion of tumor lysis syndrome is important in patient with hematologic malignancy. Symptoms arise based on the degree and severity of the electrolyte disturbances and may include nausea, vomiting, lethargy, muscle cramps, and tetany. Decreased urine output, fluid overload, edema, cardiac arrhythmia, and/or seizures may accompany later stages of clinical tumor lysis syndrome due to renal insufficiency, metabolic acidosis. Occasionally, patients may also report syncope. In patients who develop obstructive nephropathy and/or uropathy from the formation of uric acid stones or have bulky intraabdominal mass may manifest with symptoms of hematuria and flank pain.

B. History Part 2: Prevalence:

The incidence of clinical tumor lysis syndrome is estimated at 3-7% in leukemia and 4-11% in lymphomas overall; however, some subtypes have an incidence up to 25%. The overall incidence of tumor lysis syndrome in adults undergoing therapy for ALL, AML, NHL is 4.8% despite appropriate prophylaxis in 66% of these adult patients.

C. History Part 3: Competing diagnoses that can mimic Tumor Lysis Syndrome.

The diagnosis of tumor lysis syndrome should be considered in patients with known or suspected malignancy, particularly those undergoing cytotoxic therapy, after the exclusion of other underlying causes of renal failure and electrolyte imbalance.

Other causes of metabolic derangements must be considered. For example, renal failure arising from nephrotoxic drug therapy or acute tubular necrosis may lead to hyperkalemia, hyperphosphatemia, and metabolic acidosis. Hyperuricemia may be present at baseline in certain patient populations, particularly those with a history of gout or taking thiazide diuretics. Medications such as ACE inhibitors, angiotensin renin receptor blocker (ARBs) and potassium-sparing diuretics may lead to hyperkalemia.

D. Physical Examination Findings.

There are no pathognomonic physical examination findings in patients with tumor lysis syndrome. In patient with no known hematologic malignancy presented with metabolic derangements, the physical exam of lymph node enlargement, intra-abdominal mass, splenomegaly should increase clinical suspicion for new diagnosis of hematologic malignancy and tumor lysis syndrome. In patients with severe secondary hypocalcemia, Chvostek's sign and Trousseau sign may be present. Patients with oliguric renal failure may show signs of fluid overload including extremities edema, crackles on lung auscultations due to pleural effusions, and anasarca.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

High clinical suspicion of tumor lysis syndrome in setting of hematologic malignancy is important in recognizing tumor lysis syndrome. Lactate dehydrogenase (LDH), CMP (measurement of potassium, calcium, creatinine ), and/or ionized calcium, phosphorus, and a uric acid level should be obtained to establish the diagnosis of tumor lysis syndrome. In patients with hypoalbuminemia, a serum ionized calcium value may be preferred. These laboratory tests should be obtained every 6-8 hours initially then can transition to twice or daily blood draws once clinical and laboratory values improve.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

In patient without known malignancy, CT of abdomen/pelvis and chest may be warranted if there’s clinical examination of lymphadenopathy and intra-abdominal mass, however, there is no imaging modality that will diagnosis tumor lysis syndrome. Renal ultrasonography is useful to exclude obstructive uropathy, particularly in patients with bulky retroperitoneal adenopathy.

A telemetry monitor and standard 12-lead electrocardiogram should be performed to evaluate for complications of hyperkalemia and hypocalcemia. Peaked T waves, PR prolongation, widened QRS complex, and ventricular arrhythmias can happen in patients with hyperkalemia. Prolonged QT or QTc interval or ST changes may be noted with hypocalcemia.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

N/A

III. Default Management.

According to the British Committee for Standards in Hematology, risk assessment for tumor lysis syndrome in patients due to receive chemotherapy for any hematological malignancy (grade 1B evidence) is important in the management of tumor lysis syndrome.

  1. Low-risk: careful attention to monitoring and measurement of fluid status, labs results.

  2. Intermediate: 7 days of allopurinol prophylaxis with increase hydration post initiation of treatment until risk of tumor lysis syndrome resolved (grade 2C).

  3. High-risk: patients with acute lymphoblastic or myeloid leukemia with WBC >100 x 109/L, Burkitt lymphoma, lymphoblastic lymphoma, high grade lymphoma (diffuse large B cell lymphoma, T cell Non-Hodgkin lymphoma), and bulky disease which defined as LDH greater than twice of upper limited of normal, mass approximately >10 cm in diameter in adults are considered high-risk individuals. These patients should be aggressively treated with vigorous hydration and should also be offered prophylaxis with rasburicase (grade 1B).

A. Immediate management.

In patients at intermediate or high-risk for tumor lysis syndrome, steps aimed at prevention of the disorder should begin prior to the initiation of cytotoxic therapy. As in many clinical situations, initial steps are directed at urgent the clinical scenario. Hyperkalemia, renal failure and evidence of volume overload should be evaluated and treatment initiated promptly to prevent life-threatening complications such as cardiac arrhythmias and respiratory failure. Critical care physician and nephrologist should be considered in these clinical situations.

Following the prompt evaluation and treatment of the urgent clinical situation, the general treatment approach for tumor lysis syndrome is described below.

1. Aggressive hydration

There are no trials suggesting the best rate of IV fluid. Proposed suggestion is that these patients should receive aggressive hydration of isotonic or balanced IV fluids with an aim of 3 liters of fluid per 24 hours or maintain of high urine output 80–100 ml/m2/hr. The assurance that no additional potassium or phosphorus supplement is ordered in intravenous fluids is critical in this setting. The vigorous hydration is to prevent uric acid crystallization and calcium phosphate deposition in renal tubules which can result in renal failure. Patients should be monitored closely for the development of fluid overload and pulmonary edema. It is controversial to use loop diuretics and urinary alkalinization in the management of tumor lysis syndrome.

2. Electrolytes imbalances

Hyperkalemia: Intravenous calcium gluconate may be given to stabilize cardiac membranes for severe hyperkalemia or for electrocardiogram changes. For temporary serum reductions in potassium levels, intravenous insulin with dextrose or high dose of inhaled beta-agonists may be used. Oral sodium polystyrene resin, i.e. kayexalate, is recommended for definitive treatment of hyperkalemia. If these measures are insufficient or for severe metabolic derangements, renal replacement therapy should be considered with consultation of nephrology.

Hyperphosphatemia: Aggressive intravenous fluid resuscitation with maintenance of high urine output and oral phosphate binders such as sevelamer may be sufficient to improve phosphate levels. Hemodialysis may be required for severe hyperphosphatemia not controlled by these methods.

Hypocalcemia: Hypocalcemia will correct without specific intervention as phosphate levels normalize. With the exception of severe symptomatic hypocalcemia, intravenous calcium gluconate can be considered, however, it is otherwise not recommended due to elevated risk of calcium-phosphate precipitation.

Hyperuricemia: may be addressed by pharmacologic therapy to reduce uric acid production or to convert existing uric acid into a more soluble metabolite.

  • Allopurinol, an inhibitor of xanthine oxidase, prevents the production of uric acid although it will have no effect on the existing uric acid that already present. Allopurinol’s therapeutic effect is delayed by 24-72 hours. Dosing begins at 100 – 300 mg every 8 hours. There is a risk of accumulation of the uric acid precursors xanthine and hypoxanthine which may also be nephrotoxic in large quantities.

  • Rasburicase is a recombinant form of urate oxidase, a proteolytic enzyme not found in humans that converts uric acid into an inactive and highly soluble metabolite allantoin. It acts immediately even on already formed urate. FDA-approved dosing is 0.2 mg/kg/day intravenously once daily for up to 5 days. A common off-label dosing in hospitalized patient is a single dose of 0.15 mg/kg followed by as needed doses of rasbicuricase for uric acid level equal or greater than 7.5 mg/dL. This single fixed dose of rasburicase is non inferior to prolonged course. High risk patients should be offered a single of rasbicurase prior to initiation of chemotherapy. Rasbicurase should also be considered in patient with renal impairment or allopurinol allergy.

    Rasburicase is contraindicated in patient with known G6PD deficiency.

It should be noted that urinary alkalinization was previously standard therapy in the prevention and treatment of tumor lysis syndrome, however, it is no longer recommended except in specific instances of uncontrolled metabolic acidosis. Although uric acid is more soluble at a higher pH, alkalinization increases the risk of xanthine and calcium-phosphate crystallization and precipitation. This not only worsens nephropathy, but may also worsen symptomatic hypocalcemia by the consumption and precipitation of calcium.

Patient with intractable fluid overload, hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia are indications for hemodialysis. Nephrology should be consulted for evaluation. Renal replacement therapy should continue until adequate recovery of renal function, resolution of electrolyte imbalance and recovery of urine output. Peritoneal dialysis not recommended for treatment of tumor lysis syndrome.

In addition, measures should be taken to limit excess potassium and phosphorus intake. Low-potassium and low-phosphorus diets should be ordered, and intravenous fluids should not have additional electrolytes present. It may also be prudent to maintain patients on a low-purine diet to reduce uric acid accumulation. These dietary restrictions may help in caring for patient especially in acute setting.

B. Physical Examination Tips to Guide Management.

A careful examination of the lungs, extremities, and jugular venous distension are indicated for monitoring for signs of fluid overload and pulmonary edema with vigorous hydration. Due to risk of allergic reaction and Steven-Johnson syndrome associated with allopurinol, any new evidence of rash and mucosal ulcers should be taken seriously.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

For patients with known or suspected tumor lysis syndrome, LDH and CMP and/or ionized calcium, phosphorus level, uric acid should be performed every 6-8 hours until there is resolution of the metabolic abnormalities. Patients at high risk or who develop complications may need to be monitored more frequently in an intensive care setting.

Given that rasburicase degrades uric acid in blood samples left at room temperature; therefore, uric acid samples for patients receiving rasburicase therapy must be collected into pre-chilled heparin-containing tubes and immediately submersed into an ice bath after collection, and optimally to be analyzed within 4 hours for accurate results.

D. Long-term management.

Hemodialysis may be necessary for patients with severe uncontrolled electrolyte abnormalities or worsening renal insufficiency with severe fluid overload. Continuous renal replacement therapy may be required instead of traditional intermittent hemodialysis in patients with hypotension, heart failure, or other cardiovascular co-morbidities.

E. Common Pitfalls and Side-Effects of Management.

Allopurinol leads to the accumulation of uric acid precursors such as xanthine and hypoxanthine by inhibiting the enzyme xanthine oxidase. High levels of these precursors may be nephrotoxic due to precipitation in the renal tubules. Additionally, allopurinol may cause hypersensitivity reactions including Stevens-Johnson Syndrome. The drug should be discontinued for any signs of rash or other allergic reaction.

Rasburicase is immunogenic and is only recommended for use for one course of therapy due to the risk of sensitization and anaphylaxis during subsequent treatment courses.

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

Patients with chronic renal insufficiency are at higher risk of developing tumor lysis syndrome due to decreased clearance of electrolytes and uric acid at baseline. This patient population should be closely monitored for tumor lysis syndrome when undergoing therapy and early consultation with a nephrologist may be indicated.

Medications should be adjusted based on renal function in patients with chronic kidney disease. Allopurinol dosing should be reduced by 50% to decrease the risk of accumulation of the drug. Rasburicase may be used for a short course of therapy with close monitoring of renal function without dose adjustments.

B. Liver Insufficiency.

Allopurinol has been reported to cause hepatotoxicity in rare instances. For this reason, patients with a history of liver insufficiency receiving this drug should have frequent monitoring of liver function tests.

C. Systolic and Diastolic Heart Failure.

Patients with heart failure are at increased risk of fluid overload during treatment of tumor lysis syndrome. ACE inhibitors, ARBs, direct-renin inhibitors, and potassium-sparing diuretics such as spironolactone should be discontinued to prevent exacerbation of hyperkalemia. In the setting of significant hyperkalemia, telemetry monitoring or transfer to a intensive care unit may be warranted for urgent dialysis.

D. Coronary Artery Disease or Peripheral Vascular Disease.

Thiazide diuretics used for hypertension should be discontinued in patients at risk for tumor lysis syndrome as these drugs may decrease renal uric acid excretion leading to worsening hyperuricemia. Additionally, there are reports of increased risk of hypersensitivity reactions in patients concomitantly receiving thiazides and allopurinol.

E. Diabetes or other Endocrine issues.

Patients with osteoporosis receiving bisphosphonates should have these drugs discontinued to reduce the risk of worsening hypocalcemia and renal failure.

F. Malignancy.

Patients receiving 6-mercaptopurine or azathioprine will need decreased dosing of these medications if they are also receiving allopurinol as allopurinol decreases the metabolism of these purine analogues.

G. Immunosuppression (HIV, chronic steroids, etc.)

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

A low potassium and low phosphate diet should be considered initially in severe metabolic derangement. Phosphate binders may be given with meals to decrease phosphorus absorption. A low purine diet may also be prudent in patients with hyperuricemia, although there is little data to support this recommendation.

J. Hematologic or Coagulation Issues.

Rasburicase is contraindicated in patients with known G6PD deficiency, and patients at higher risk of this deficiency should be screened prior to the initiation of treatment. If hemolysis occurs during treatment, the drug should be discontinued. Methemoglobinemia may also develop during treatment and may be severe.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

For patients with active tumor lysis syndrome or those at risk for the disorder, the sign-out should include when the next metabolic panel is due. The sign-out should also include parameters for treatment of electrolyte and metabolic derangements and should delineate whether or not a repeat dosing of rasburicase is indicated for continued hyperuricemia. Additionally, you should inform your colleagues of known metabolic derangements in order to anticipate needs during a possible emergency situation during cross-cover (i.e., a patient with known hyperkalemia previously in the day may benefit from calcium gluconate during a code situation to stabilize cardiac membranes).

B. Anticipated Length of Stay.

Patients with tumor lysis syndrome are critically ill and length of stay depends on the severity of metabolic derangements and the rapidity of renal function recovery. In addition, these patients may also remain hospitalized for the delivery of future cytotoxic therapies for their underlying malignancy, which result in 1-2 weeks of acute inpatient hospitalization.

C. When is the Patient Ready for Discharge.

Electrolytes imbalance must be corrected and appropriate plan for underlying malignancy should be in placed prior consideration for discharge.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom.

Patients should follow up with their oncologist within 3-7 days of hospital discharge for repeat lab work or further treatment plan. For patients continuing dialysis upon discharge, arrangement of dialysis at outpatient center and/or nephrology follow up need to be arranged prior to discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Repeat lab work to include potassium, phosphorus, calcium, creatinine, and uric acid levels should be performed during or prior to the first outpatient clinic visit and can be beneficial in high risk hematologic malignancy. In most cases, CMP is usually adequate to assess renal function, calcium and potassium level.

E. Placement Considerations.

If a decision is made in conjunction with the oncologist not to pursue further aggressive therapy for malignancy, referral to hospice may be warranted.

F. Prognosis and Patient Counseling.

Prognosis in tumor lysis syndrome depends on the underlying malignancy characteristics. In patients with a hematologic malignancy, the mortality rate for tumor lysis syndrome is approximately 15%. The reported mortality of tumor lysis syndrome in patients with solid malignancies is reported at 36%. This higher than expected mortality may be secondary to decreased recognition of the disorder in this patient population leading to reduced prophylaxis and a delayed initiation of treatment. For patients with acute spontaneous tumor lysis syndrome, inpatient mortality rates exceed 58%. Hyponatremia and hypoalbuminemia at the time of admission are risk factors for increased mortality.

For patients that survive the initial episode of tumor lysis, the long-term prognosis remains guarded. The development of renal insufficiency may limit the ability to dose chemotherapy effectively and may limit options for bone marrow transplantation, therefore, increasing cancer mortality.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patient may be discharged home with allopurinol which was initiated for prophylaxis after initial hospitalization for tumor lysis syndrome.

VII. What's the evidence?

Baeksgaard, L, Sorensen, JB. "Acute tumor lysis syndrome in solid tumors – a case report and review of the literature". Cancer Chemother Pharmacolo. vol. 51. 2003 Mar. pp. 187-92.

Cairo, MS, Bishop, M. "Tumour lysis syndrome: new therapeutic strategies and classification". J Haematol. vol. 127. 2004 Oct. pp. 3-11.

Coiffier, B, Altman, A, Pui, CH, Younes, A, Cairo, MS. "Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review". J Clin Oncology. vol. 28. 2010 Feb. pp. 708.

Darmon, M, Guichard, I, Vincent, F, Schlemmer, B, Azoulay, E. "Prognostic significance of acute renal injury in acute tumor lysis syndrome". Leuk Lymphoma. vol. 51. 2010 Feb. pp. 221-7.

Jones, GL, Will, A, Jackson, GH, Webb, NJ, Rule, S. "British Committee for Standards in Haematology. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology". J Haematol. vol. 169. 2015 Jun. pp. 661-71.

Hsu, HH, Chan, YL, Huang, CC. "Acute spontaneous tumor lysis presenting with hyperuricemic acute renal failure: clinical features and therapeutic approach". J Nephrolol. vol. 17. 2004 Jan-Feb. pp. 5-6.

Salit, RB, Bishop, MR. "The evolving world of tumor lysis syndrome". Oncology (Williston Park). vol. 25. 2011 Apr. pp. 378-380.

Vines, AN, Shanholtz, CB, Thompson, JL. "Fixed-dose rasburicase 6 mg for hyperuricemia and tumor lysis syndrome in high-risk cancer patients". Ann Pharmacother. vol. 44. 2010 Oct. pp. 1529-37.

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