Tumor Tumor LysisLysis Syndrome (TLS)Syndrome (TLS)

ByByByBy

Dr/Mohamed Dr/Mohamed MoustafaMoustafa

�Introduction

� Tumor lysis syndrome (TLS) is an oncologic emergency that is Caused by rapid & massive tumor cell lysis and release of large amount of intracellular contents intracellular contents (potassium, phosphate and nucleic acids) into the systemic circulation phosphate and nucleic acids) into the systemic circulation that overwhelms the kidney’s ability to excrete those products →→→ AKI

� Can occur after the initiation of cytotoxic therapy for high-grade lymphomas (e.g., Burkitt’s) and acute lymphoplastic leukemia.

� Can also be precipitated by radiation therapy, cytotoxic antibody therapy or sometimes glucocorticoid therapy alone can result in the rapid lysis of tumor cells .

Cont.Cont.

� Risk of AKI and life-threatening electrolyte disturbances is caused by the breakdown of nucleic acids →→→ uric acid, which can

precipitate in the renal tubules.precipitate in the renal tubules.

� Hyperphostatemia with precipitation &deposition of calcium phosphate crystals in the renal tubules can also cause AKI.

��MalagnanciesMalagnancies Associated with high risk Associated with high risk of developing of developing TLSTLS

� ALL 63%

� Non-Hodgkin’s Lymphoma 18%� Non-Hodgkin’s Lymphoma 18%

� AML 11%

� Solid Tumors 5% - Neuroblastoma; Medulloblastoma; germ cell tumors; sarcoma

��Risk FactorsRisk FactorsAA-- Certain intrinsic tumorCertain intrinsic tumor--related factors related factors are associated with a higher riskare associated with a higher risk

� High tumor cell proliferation rate.

�� ChemosensitivityChemosensitivity of the malignancy.

�� Large tumor burdenLarge tumor burden, as manifested by bulky bulky �� Large tumor burdenLarge tumor burden, as manifested by bulky bulky disease >disease >10 10 cm cm in diameter and/or a WBC count WBC count >>5050,,000 000 per per microLmicroL..

� pretreatment sr. (LDH) (LDH) ˃ ˃ 2 2 times the (ULN).times the (ULN).

� organ infiltration, or bone marrow involvement.

BB-- clinical features that predispose to clinical features that predispose to the development of TLSthe development of TLS

� Pretreatment hyperuricemiahyperuricemia (serum uric acid >7.5 mg/dL [446 micromol/L]) orhyperphosphatemiahyperphosphatemia.hyperphosphatemiahyperphosphatemia.

� A preexisting nephropathynephropathy or exposure to nephrotoxinsnephrotoxins..

�� OliguriaOliguria and/or acidic urineacidic urine.

�� DehydrationDehydration, volume depletionvolume depletion, or inadequate hydration inadequate hydration during treatment.

��Definition And ClassificationDefinition And Classification

� Although there is a general consensus that TLS represents a set of metabolic complications that arise from treatment of

a rapidly proliferating and drug-sensitive

complicationsa rapidly proliferating and drug-sensitive neoplasm.

� There have been relatively few attempts to specifically define the syndrome.

CairoCairo--Bishop definitionBishop definition

� proposed in 2004, provided specific laboratory criteria laboratory criteria for the diagnosis of TLS

both at presentation and within 7 days of both at presentation and within 7 days of treatment.

� It also incorporated a grading system grading system to

help delineate the degree of severity of TLS.

Cairo Bishop Grading SystemCairo Bishop Grading System

�� Laboratory TLS Laboratory TLS was defined as any two

or more abnormal serum values, as outlined in the following table .in the following table .

� present within 3 days before or 7 daysafter instituting chemotherapy in the setting of adequate hydration (with or without alkalinization) and use of a hypouricemicagent.

Clinical TLSClinical TLS

� Clinical TLS constitutes Laboratory TLSLaboratory TLSplus at least one least one of the following clinical

complication : complication :

A- serum Creatinine > 1.5 x (ULN).

B- cardiac arrythmia / sudden death.

C- seizure.

Clinical TLS & grading systemClinical TLS & grading system

Grade Grade 00 †† Grade IGrade I Grade IIGrade II Grade IIIGrade III Grade IVGrade IV Grade VGrade V

LTLSLTLS NoNo YesYes YesYes YesYes YesYes YesYes

CreatinineCreatinine ‡‡ ≤≤11..5 5 ×× ULNULN 11..5 5 ×× ULNULN>>11..55––33..0 0 ××ULNULN

>>33..00––66..0 0 ××ULNULN >>6 6 ×× ULNULN DeathDeath

NonurgentNonurgent

Symptomatic Symptomatic and and incompletely incompletely

LifeLife--threatening threatening (eg, (eg,

Cardiac Cardiac arrhythmiaarrhythmia ‡‡ NoneNone

Intervention Intervention not needednot needed

NonurgentNonurgentintervention intervention neededneeded

incompletely incompletely controlled controlled medically or medically or controlled controlled with a devicewith a device

(eg, (eg, arrhythmia arrhythmia associated associated with CHF, with CHF, hypotension, hypotension, or shock)or shock)

DeathDeath

SeizuresSeizures ‡‡ NoneNone NoneNone

One brief, One brief, generalized generalized seizure, seizure, seizures seizures controlled controlled with with anticonvulsananticonvulsant drugs, or t drugs, or infrequent infrequent motor motor seizuresseizures

Seizures with Seizures with impaired impaired consciousnesconsciousness, poorly s, poorly controlled controlled seizures, seizures, generalized generalized seizures seizures despite despite medical medical interventionsinterventions

Status Status epilepticusepilepticus

DeathDeath

Risk StratificationRisk StratificationRisk StratificationRisk Stratification

Clinical Manifestations of TLSClinical Manifestations of TLS

� Nausea/Vomiting, diarrhea, anoxerialethargy, syncope.

� Metabolic Abnormalities IncludesHyperuricemiaHyperuricemia → “uric acid nephropathy” = �� HyperuricemiaHyperuricemia → “uric acid nephropathy” = oliguria, renal failure , hematuria.

�� HyperphosphatemiaHyperphosphatemia → hypocalcemia, renal failure.

�� HypocalcemiaHypocalcemia → muscle cramps, tetany, mental status changes , seizures.

�� HyperkalemiaHyperkalemia → weakness, dysrhythmias.

Prevention Prevention -- MonitoringMonitoring

AA--high risk for developing TLS(high risk for developing TLS(children&adultchildren&adult))

� Tested for lab.&clinical TLS parameters(sr. UAUA , Ph.Ph., KK , Cr.Cr., CaCa And LDHLDH) Plus Fluid input &urine output →→ 4-6 hr. after chem.thpy initiation and output →→ 4-6 hr. after chem.thpy initiation and

every 4-8 hr. thereafter.

� All pts. Receving rasburicaserasburicase→→ sr. UA should be

reevaluated 4 hrs. after the first dose, and every 6 to 12 hrs. (depending on the risk and degree of tumor lysis) thereafter until normalization of serum LDHLDH and UA UA levels.

Prevention Prevention –– Monitoring (Cont.)Monitoring (Cont.)

BB-- intermediate risk for TLS(Adult)intermediate risk for TLS(Adult)� monitoring should be maintained for 24 hrs. after

administration of the final agent of the first cycle of therapy.therapy.

� If rasburicase is not used initially, serum electrolytes should be measured 8 hrs. after chemotherapy, and the patient might require a one night hospital stay. If TLS has not occurred within 72 hrs. of multiagent chemotherapy, the likelihood of TLS is very lowvery low.

HydrationHydration

� both children and adults at risk for TLS initiallyinitiallyreceive 2 2 to to 3 3 L/mL/m22/ day / day of IV fluid (or 200 mL/kg /day in children weighing ≤10 kg) .

�� Urine output GoalUrine output Goal 80 80 to to 100 100 mLmL/m/m22 /hr/hr.�� Urine output GoalUrine output Goal 80 80 to to 100 100 mLmL/m/m /hr/hr.(2 mL/kg per hr. for both children and adults,

4 to 6 mL/kg per hr. if ≤10 kg).� DiureticsDiuretics can be used to maintain the urine

output, if necessary, but should not be required in patients with relatively normal renal and cardiac function.

� loop diuretics such as furosemidefurosemide appear preferable because they not only induce diuresis, but may also increase potassium secretion.

Hydration (Cont.)Hydration (Cont.)� The choice of hydration fluid depends upon the clinical

circumstances.

� The expert panel suggests the initial use of 55% dextrose one% dextrose one--quarter normal (isotonic) salinequarter normal (isotonic) saline, probably because ALL patients receive steroid during remission induction, which can cause receive steroid during remission induction, which can cause sodium retention sodium retention and hypertensionhypertension .

� In patients with hyponatremia or volume depletion, isotonic saline isotonic saline should be the initial hydration fluid.

� Due to the risk of hyperkalemia and hyperphosphatemia with calcium phosphate precipitation once tumor breakdown begins, potassiumpotassium and calciumcalcium should be withheldwithheld from the hydration fluids, at least initially.

� Monitor for fluid overload in patients with underlying cardiaccardiacdysfunction or renalrenal insufficiency.

Urinary Urinary AlkalinizationAlkalinization� The role of urinary alkalinization with either

acetazolamide and/or sodium bicarbonate is unclear and controversial.

� . In the past, alkalinization to a urine pH of 6.5 to 7.0 or even higher was recommended to increase uric acid or even higher was recommended to increase uric acid solubility, thereby diminishing the likelihood of uric acid precipitation in the tubules.

However,

� This approach has fallen out fallen out of favor for the following reasons:

1- Experimental study suggested that hydration with saline alone saline alone is as effective as alkalinization in minimizing uric acid precipitation.

Urinary Urinary AlkalinizationAlkalinization (Cont.)(Cont.)

2- Alkalinization of the urine has the potential

disadvantagedisadvantage of promoting calcium phosphate deposition in the kidney, heart, and other organs in patients who develop marked hyperphosphatemiahyperphosphatemia once patients who develop marked hyperphosphatemiahyperphosphatemia once tumor breakdown begins.

� the expert panel concluded that use of sodium sodium bicarbonatebicarbonate was only indicated in patients with metabolic acidosismetabolic acidosis.

� If alkalinization is used, it should be initiated when the serum uric aciduric acid level is highhigh and discontinued when hyperphosphatemiahyperphosphatemia develops.

HyperuricemiaHyperuricemia

HyperuricemiaHyperuricemia

Prevention Prevention -- HypouricemicHypouricemic AgentsAgents

�� AllopurinolAllopurinol –(which reduces urate formation by blocking xanthine oxidase activity),

; takes 22--3 3 days days to be effective.; takes 22--3 3 days days to be effective.

�� UrateUrate OxidaseOxidase/RasburicaseRasburicase – breaks down uric acid to allantoin which is more soluble

in urine; acts within several hours.

� UO has significantly reduced the need for rescue dialysis therapy for TLS.

Prevention Prevention -- AllopurinolAllopurinol

� Decrease production of uric acid

� allopurinol inhibits xanthineoxidase.

�� Adult: Adult: 100mg/m2 /day q8 hr. (max. 800 mg/day)

Xanthine/Hypoxanthine

xanthine oxidase

(max. 800 mg/day)�� In children In children : 50-100 mg/m2/day

q8hr.(max. 300 mg/m2/day ) or

10 mg/ kg /day q8hr.PO/IV� Dose reduction 50 50 %% in AKI.� Treatment is generally initiatedinitiated

2424 to 4848 hrs. beforebefore the start of induction chemotherapy → up to up to 33 to 77 days afterward until normalization of sr.uric acid and other lab.evidence of TLS (eg, elevated Sr. LDH levels).

Uric acid

Allopurinol

Prevention Prevention -- UrateUrate OxidaseOxidase�Present in other mammalian species

�Catalyzes conversion of uric acid to allantoin.

�Allantoin more soluble, easily excreted by kidneys.

�Urine alkalinization

�Recombinant urate oxidase(rasburicase) more effective than allopurinol in prevention and treatment of hyperuricemia.

�Contraindicated

with GG66PD deficiencyPD deficiency, anaphylaxisanaphylaxis, hemolysishemolysis, hemoglobinuriahemoglobinuria,

MethemoglobinemiaMethemoglobinemia, asthmaasthma�Urine alkalinizationunnecessary if used.

�Rasburicase therapy was associated with a much greater reduction in serum uric acid four hrs. four hrs. after the first dose.

MethemoglobinemiaMethemoglobinemia, asthmaasthma

�Serum phosphate concentrations decreased to normal within 48 48 hrshrs, and significant reductions in serum creatinine occurred after 24 24 hrshrs.

�No patient receiving rasburicaserequired dialysis,

�dose of 00..2 2 mg/kg mg/kg once daily for up to five to seven days.

Management of electrolyte abnormalities Management of electrolyte abnormalities Management of electrolyte abnormalities Management of electrolyte abnormalities in TLSin TLS

HyperphosphatemiaHyperphosphatemia

� Malignant cells contain higher concentration of phosphorus ( Four times more than normal cells).

� Hyperphosphatemia causes secondary hypocalcemia .

� when (the calcium phosphate product) exceeds 60 � when (the calcium phosphate product) exceeds 60 mg2/dL2, there is an increased risk of calcium phosphate precipitation in the renal tubules, which can lead to AKI. In addition, precipitation in the heart may lead to cardiac arrhythmias.

� Since the widespread use of hypouricemic agents, calcium phosphate deposition (nephrocalcinosis) rather than hyperuricemia has become the major mechanism of AKI in TLS.

��Treatment of Established TLSTreatment of Established TLS

HyperphosphatemiaHyperphosphatemia

HyperkalemiaHyperkalemia�� Moderate and Asymptomatic Moderate and Asymptomatic (K>6.0 mmol/L): � remove all K from IVF; ECG monitoring.� May give Sodium Polystyrene sulfonate (1 gram/kg) every 4-6 hours

until normalized.�� Severe and/or symptomatic Severe and/or symptomatic (K>7.0 mmol/L); loss of p waves, widened

QRS, peaked T waves): QRS, peaked T waves): � Ca Gluconate (50-100 mg/kg) slow IVP� ( insulin iv + dextrose) • Adult: 10 units regular insulin +100ml (D50)• Pediatric: IV regular Insulin (0.1 unit/kg) and D25 (0.5 gram/kg = 2 ml/kg)

over 30 minutes. Monitor blood glucose level.� NaHCO3 If acidotic• Adult : 45-50 meq/kg• Pediatric: 1-2 meq/kg over 5-10 minutes� Albuterol• Adult: 10 to 20 mg in 4 ml saline nebulized over 20 mint.• Pediatric : 0.1 – 0.3 mg/kg nebulized.� Dialysis

HypocalcemiaHypocalcemia

�� AsymptomaticAsymptomatic : No treatment needed if

�� Symptomatic Symptomatic :

� Administer Calcium Gluconate with ECG monitoring

• Adult : 1 gm • Adult : 1 gm

• Pediatric : (50-100 mg/kg) slow iv infusion

however,

� Hypocalcemia shouldnot be treated with calcium until hyperphoshatemia is corrected unless there is (tetany or arrythmia from hypocalcemia).

Dialysis for Tumor Dialysis for Tumor LysisLysis SyndromeSyndrome

Indications � Oliguria

� Hyperkalemia

� Azotemia

� Hyperphosphatemia

� Refractory Hyperuricemia

• Hemodialysis or continuous veno-venous hemofiltration with dialysis most effective

ReferencesReferences

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