What is Tumor Lysis Syndrome?

Tumor Lysis Syndrome (TLS)

Tumor lysis syndrome is a potentially life-threatening metabolic emergency caused by massive cellular lysis in rapidly proliferating, bulky, or highly chemo-radiosensitive cancers, resulting in hyperuricemia, electrolyte disturbances, renal failure, and potentially fatal organ damage.

Definition and Pathophysiology

Tumor lysis syndrome occurs when large numbers of tumor cells are rapidly destroyed, releasing their intracellular contents into the bloodstream. This typically happens during cytotoxic therapy but can occasionally occur spontaneously. The massive release of cellular components leads to several metabolic derangements:

• Hyperuricemia: Nucleic acids are catabolized to hypoxanthine, then xanthine, and finally to uric acid by xanthine oxidase. When production exceeds renal clearance capacity, uric acid can precipitate in renal tubules 1.
• Hyperkalemia: Rapid release of intracellular potassium can lead to cardiac arrhythmias, ventricular tachycardia, fibrillation, or cardiac arrest 1.
• Hyperphosphatemia: Can lead to secondary hypocalcemia and calcium phosphate precipitation in tissues 1.
• Hypocalcemia: Results from hyperphosphatemia and can cause neuromuscular irritability, tetany, and seizures 1.

Clinical Manifestations

TLS is classified into two categories:

1. Laboratory TLS: Characterized by two or more abnormal laboratory values (uric acid, potassium, phosphate, calcium) occurring simultaneously 1.

2. Clinical TLS: Laboratory TLS plus one or more clinical complications:

   • Renal insufficiency (creatinine ≥1.5 times upper limit of normal)
   • Cardiac arrhythmias
   • Seizures
   • Sudden death 1

The Cairo-Bishop grading system classifies clinical TLS severity from grade 0-5 based on creatinine levels, cardiac arrhythmias, and seizures 1.

Risk Factors

High-Risk Malignancies:

• Burkitt's lymphoma
• B-cell acute lymphoblastic leukemia (B-ALL)
• High-grade non-Hodgkin lymphomas
• Acute myeloid leukemia (AML) with high white blood cell count

Intermediate-Risk Malignancies:

• Other non-Hodgkin lymphomas
• Chronic lymphocytic leukemia (CLL) treated with targeted agents
• Multiple myeloma

Tumor-Related Factors:

• High tumor burden
• High proliferation rate
• High sensitivity to chemotherapy
• Extensive bone marrow involvement
• Elevated LDH levels
• WBC count >50,000/mm³ 1

Patient-Related Factors:

• Pre-existing renal impairment
• Elevated pre-treatment uric acid
• Dehydration
• Advanced age
• Tumor infiltration in kidney
• Obstructive uropathy 1

Prevention and Management

Prevention is the cornerstone of TLS management. The approach should be stratified based on risk:

High-Risk Patients:

• Aggressive hydration: 2-3 L/m²/day to maintain urine output >100 mL/m²/hour
• Rasburicase: Recommended as first-line therapy (converts existing uric acid to allantoin, which is 5-10 times more soluble) 1
• Close monitoring: Electrolytes, renal function, uric acid levels every 4-6 hours

Intermediate-Risk Patients:

• Hydration: 2-3 L/m²/day
• Allopurinol: 300-600 mg/day (adults) or rasburicase if baseline hyperuricemia
• Monitoring: Electrolytes, renal function every 8-12 hours

Low-Risk Patients:

• Hydration: Standard IV fluids
• Allopurinol: Oral administration
• Monitoring: Daily laboratory tests 1

Management of Established TLS:

1. Aggressive hydration and diuresis: Maintain high urine output
2. Rasburicase: For hyperuricemia (0.15-0.2 mg/kg/day) 2
3. Electrolyte correction:
   • Hyperkalemia: Calcium gluconate, insulin/glucose, sodium polystyrene sulfonate
   • Hyperphosphatemia: Phosphate binders
   • Hypocalcemia: Calcium supplementation only if symptomatic
4. Renal replacement therapy: Indications include:
   • Severe oliguria or anuria
   • Persistent hyperkalemia
   • Hyperphosphatemia with symptomatic hypocalcemia
   • Volume overload unresponsive to diuretics
   • Uremia 1

Important Considerations

• Urine alkalinization is no longer recommended, especially when using rasburicase 1
• Rasburicase is contraindicated in patients with G6PD deficiency due to risk of hemolysis 2
• Allopurinol prevents formation of new uric acid but does not reduce existing uric acid levels 1
• Monitoring should continue for 24-48 hours after completion of chemotherapy in high-risk patients
• TLS can occur spontaneously before treatment initiation, particularly in highly proliferative malignancies 3
• Novel targeted agents for CLL (venetoclax, ibrutinib, idelalisib) can also cause TLS, requiring appropriate prophylaxis 4

Common Pitfalls to Avoid

1. Delayed recognition: Early identification of high-risk patients is crucial
2. Inadequate hydration: Maintain aggressive hydration in high-risk patients
3. Inappropriate use of diuretics: Avoid in hypovolemic patients
4. Calcium administration in asymptomatic hyperphosphatemia-induced hypocalcemia (can worsen calcium phosphate precipitation)
5. Urine alkalinization when using rasburicase (can promote calcium phosphate precipitation)
6. Overlooking rasburicase contraindications: Screen for G6PD deficiency in high-risk populations
7. Inadequate monitoring: High-risk patients require frequent laboratory assessments

Early recognition, risk stratification, and appropriate prophylactic measures are essential to prevent the potentially fatal complications of tumor lysis syndrome.