Tumor lysis syndrome occurs when cancer cells release their contents into the bloodstream, causing electrolyte imbalances like hyperkalemia, hyperuricemia, and hyperphosphatemia that can damage organs. It is diagnosed when a patient develops acute kidney injury, arrhythmias, or seizures from their electrolyte changes. Treatment involves rapid hydration, uric acid-lowering drugs like allopurinol or rasburicase, and dialysis for severe electrolyte abnormalities or kidney injury. With advances in prevention and management, the prognosis for tumor lysis syndrome has improved in recent years.

1. TUMOR LYSIS SYNDROME
Presenter: Dr. Monica P
MD Radiation Oncologist

2. TUMOR LYSIS SYNDROME:
o Tumor lysis occurs when cancer cells release their contents into the blood stream, either spontaneously or following
antineoplastic therapy  leading to an influx of electrolytes and nucleic acids into the circulation.
o The sudden development of hyperkalemia, hyperuricemia and hyperphosphatemia can have life-threatening end-organ
effects on the myocardium, kidneys and CNS.
o Hypocalcemia is a consequence of hyperphosphatemia in TLS.

3. PRESENTATION:
 SYMPTOMS-
variable from the metabolic derangements of TLS
 Clinical TLS : it is diagnosed when one or more of 3
conditions arise : Acute renal failure, arrhythmias and
seizures.
o ARF: defined as a rise in creatinine to 1.5times or more the
upper limit of normal that is not attributable to medications.
It can manifest as a decrease in urine output, uraemia-related
altered sensorium, crystalline obstructive uropathy.
o Arrhythmias include sudden cardiac death
o Arthralgia can arise from gout flare.

4.  TLS is more common in the rapidly proliferative hematologic malignancies like ALL, AML, Burkitt lymphoma; in
solid tumors like SCLC, germ cell tumors, inflammatory breast cancer and melanoma.
 Liver metastases may increase TLS risk.
 Treatment-provoked TLS occurs in:
o following chemotherapy,
o Treatment with single-agent corticosteroids in patients with sensitive tumors
o Radiation
o Surgery
o Ablation procedures.
 Onset of TLS can be delayed by days to weeks in a patient with a solid malignancy.

5. High-Risk Tumors Intermediate-Risk Tumors Low-Risk Tumors
•Advanced Burkitt lymphoma
•Advanced leukemia
•Early-stage leukemia or Burkitt lymphoma
with elevated lactate dehydrogenase
•ALL with a WBC of >100,000/µL, or if the
increase of LDH from the baseline is two
times the upper limit of normal
•Diffuse large B-cell lymphoma (DLBCL)
and bulky disease with a baseline lactate
dehydrogenase two times the upper limit of
normal
•AML with a WBC of ≥10,000/µL
•Early-stage leukemia and Burkitt
lymphoma with a lactate
dehydrogenase of less than twice the
upper limit of normal
•AML with WBC between 25,000 and
100,000/µl
•ALL with a WBC <100,000/µL
and LDH of less than twice the upper
limit of normal
•DLBCL with a baseline increase in
lactate dehydrogenase of twice the upper
limit of normal but the non-bulky disease
•Solid cancers
•Multiple myelomas
•Indolent lymphomas
•Chronic lymphocytic leukemia
•Chronic myeloid leukemia
•AML with a WBC count <25,000/µL
and a lactate dehydrogenase elevated to less
than two times the upper limit of normal
An international panel of experts has stratified tumors based on the risk of developing tumor lysis syndrome.

6. o Rarely, tumor lysis syndrome is associated with the administration of steroids, biological immunomodulators, and
monoclonal antibodies. Agents that are associated with the development of tumor lysis syndrome include:
•Thalidomide
•Bortezomib
•Hydroxyurea
•Paclitaxel
•Fludarabine
•Etoposide
•Zoledronic acid
o In rare instances, tumor lysis syndrome has been observed in patients under general anesthesia undergoing surgery.
o Other rare occurrences of tumor lysis syndrome are seen in pregnancy or high fever.

7. Electrolyte Imbalance
o Hyperkalemia
 The concentration of potassium within the cell is about 120 to 130 meq/L.
 The lysis of tumorous cells leads to a massive release of intracellular potassium.
 The excess potassium is usually taken up by the liver and skeletal muscle. The rest is excreted via the gastrointestinal
system or the kidney.
 Obstructive uropathy from uric acid salts can limit the excretion of potassium.
 Sometimes the hyperkalemia from the solid tumor can reach a potentially life-threatening level. The risk of
hyperkalemia is cardiac arrest from arrhythmia.

8. o Hyperphosphatemia
 Hyperphosphatemia is another electrolyte imbalance associated with tumor lysis syndrome.
 The nucleic acid has a phosphate group, and the breakdown of the tumor cell will lead to the release of a
significant amount of phosphorus into the bloodstream.
 Most of the phosphorus is renally excreted. This ability of the kidney to handle a high load of phosphorus is
inhibited by acute kidney injury or chronic kidney disease.
 Hyperphosphatemia is less common in spontaneous tumor lysis syndrome than in those induced by
chemotherapy.
 It leads to the chelation of calcium, causing hypocalcemia. The deposition of calcium and phosphorus salts in
the kidney and soft tissues can also occur.

9. o Hypocalcemia
 Hypocalcemia in tumor lysis syndrome is mostly secondary to the chelation of phosphorus.
 This condition is more potentially life-threatening than hyperphosphatemia.
 Possible complications from hypocalcemia include arrhythmia, tetany, seizure, and death.
 The calcium level might still be relatively low even after the normalization of the phosphorus level because of a
deficiency of 1, 25 Vitamin D.

10. o Histopathology
 The histopathological findings in tumor lysis syndrome are associated with the deposition of uric acid,
calcium phosphate, and xanthine in the lamina of the distal kidney tubules.
 Crystals of uric acid can also deposit kidney tubular epithelial cells as well as the medulla.
 The factors that favour the formation of crystals include low urine flow, low solubility, and high levels of
solutes.
 The deposition of crystals in the renal pelvis, calyxes, and the ureter can cause inflammation leading to
obstruction of urinary flow.
 Longstanding obstruction creates hydroureter, hydronephrosis, and subsequent acute kidney failure.

11. History and Physical
 The history and physical examination of patients with tumor lysis syndrome should be focused on the primary
causes of the tumor lysis.
 Time of onset of malignancy should be elicited with attention to the presence of constitutional symptoms like
weight loss or anorexia.
 The presence of respiratory symptoms dyspnea, orthopnea, and tachypnea can be a sign of airway compression
from a primary tumor.
 Urinary symptoms such as dysuria, flank pain, and hematuria
 Signs and symptoms that can be associated with hypocalcemia include nausea, vomiting, seizure, tetanic spasm,
and change in mental status.
 Other clinical manifestations of tumor lysis syndrome include, but are not limited to, syncopal attack, palpitation
lethargy, pitting edema, facial edema, abdominal distention, and other sign of fluid overload.

12. Physical Examination
• The physical examination should focus on the electrolyte abnormalities that are associated with tumor lysis
syndrome. The physical findings associated with these abnormalities are listed below.
• The signs and symptoms of tumor lysis syndrome can develop spontaneously or about 72 hours after the initiation
of chemotherapy.
Hypocalcemia Uremia for hyperuricemia and obstructive uropathy
1.Carpal spasm
2.Pedal spasm
3.Tetany
4.Chvostek sign
5.Trousseau’s sign
6.Wheezing associated with
bronchospasm
7.Seizure
1.Weakness
2.Lethargy
3.Malaise
4.Nausea
5.Vomiting
6.Metallic taste in the mouth
7.Irritability
8.Generalized pruritis
9.Rales and Ronchi from volume overload
10.Muffled heart sound from pericarditis secondary to uremia
11.Joint pain
12.Renal colicky pain
13.Calcium phosphate crystal deposits in the skin
14.Pruritis
15.Gangrene

14. DIAGNOSIS OF TLS:

15. In the evaluation of tumor lysis syndrome, the following studies are necessary:
o Imaging
X-Ray and CT scan of the chest to evaluate the presence of mediastinal mass and the presence of a concomitant pleural
effusion
CT scan and an ultrasound of the abdomen and retroperitoneal structure if the mass lesion is located in the abdomen or
retroperitoneum. Care must be taken with intravenous (IV) contrast because of the presence of AKI in tumor lysis
syndrome.
o Electrocardiography (ECG)
ECG is part of the workup for patients with tumor lysis syndrome to check for findings associated with hyperkalemia
and hypocalcemia. Hyperkalemia is a potential cause of fatal arrhythmia in tumor lysis syndrome.
o Complete Blood Count (CBC)
CBC helps in the diagnosis of malignancy associated with tumor lysis syndrome. The hallmark of most malignancy is
leukocytosis with anemia and thrombocytopenia.

16. o Comprehensive Metabolic Panel (CMP)
The metabolic derangement associated with tumor lysis syndrome are hyperkalemia, hypocalcemia,
hyperphosphatemia, and hyperuricemia.
Blood urea nitrogen (BUN), creatinine, and lactate dehydrogenase are also elevated in tumor lysis syndrome.
CMP must be monitored between two to three times daily before and after initiation of therapy.
Elevated laboratory value might be indicative of the beginning of tumor lysis syndrome.
o Urine Analysis
Precipitation of uric acid salt can cause obstructive uropathy.
In the treatment of tumor lysis syndrome, Alkalinisation of urine with sodium bicarbonate is the standard of care.
Frequent urine analysis with an assessment of urine pH, specific gravity, and output is mandatory.

17. Treatment
o Rapid Expansion of Intravascular Volume
Treatment of tumor lysis syndrome starts with rapid volume expansion.
It is recommended to use crystalloids in volume expansion as this will help to increase the glomerular filtration rate
(GFR) quickly.
Improved GFR helps with the excretion of solutes associated with tumor lysis syndrome.
The drawback to this is that the kidney functions should still be intact.
Intravenous fluid should be initiated 48 hours before the start of chemotherapy and should be continued for 48 hours
after chemotherapy.
Hydration with about 3 to 3.5 liters/m2 per day or 4 to 5 liters per day might be needed to provide adequate
hydration. This will provide a urine output of about 3 liters per day.

18. Medications
o Allopurinol
 This is a structural isomer of hypoxanthine.
 Xanthine oxidase converts allopurinol to oxypurinol. This is the active metabolite, and it is excreted primarily by the
kidney. CKD or AKI impair the elimination of oxypurinol.
 Allopurinol can decrease the production of uric acid in tumor lysis syndrome but is ineffective in the treatment of
hyperuricemia associated with tumor lysis syndrome.
 Allopurinol is a very useful agent to prevent the development of tumor lysis syndrome.

19.  The use of allopurinol is associated with the development of skin rash, eosinophilia, and acute hepatitis. The
combination of these symptoms is called allopurinol hypersensitivity syndrome.
 In the treatment of tumor lysis syndrome, clinicians should be aware of potential drug-to-drug interaction with
azathioprine, immunosuppressive drug use in patients with solid organ transplant, and autoimmune disorder.
 Allopurinol inhibits xanthine oxidase, thus decreasing uric acid production, and can be given preventively starting
up to 48 hours before treatment at doses of 100 mg/m2 every 8 hours (maximum daily dose: 800 mg).

20. o Recombinant Urate Oxidase (Rasburicase)
 Allopurinol does not alter uric acid that has already formed and is not recommended as prophylaxis for patients with
pre-treatment uricemia of 7.5 mg/dL or greater.
 In such patients, rasburicase can be given at dosages of 0.15 to 0.2 mg/kg/day for up to 5 or 7 days.
 A recombinant version of urate oxidase is a drug that is used to treat hyperuricemia in patients with leukemia,
lymphoma, and solid tumor who are undergoing chemotherapy.
 It is derived from Aspergillus by recombinant technology. The drug's mechanism of action is the catalyzes of uric acid to
allantoin, carbon dioxide, and hydrogen peroxide.

21.  Hydrogen peroxide is a potent oxidizing agent and can cause severe methemoglobinemia or hemolytic anemia in
patients with glucose 6 phosphate dehydrogenase G6PD deficiency.
 The Food and Drug Administration approved recombinant urate oxidase in 2009
 This medication can be administered intramuscularly. It can also be given intravenously at doses of between 50 to
100 U/kg per day.
 Rasburicase is contraindicated in pregnancy and in patients with glucose-6-phosphate dehydrogenase (G6PD)
deficiency.

22. The electrolyte complications of TLS are not directly remedied by allopurinol or rasburicase.
o Hyperkalemia can be treated with loop diuretics.
• Immediate reduction in serum potassium through intracellular shifting can be achieved by the injection of 10 U of
regular insulin, followed immediately by 50 mL of 50% dextrose and then an hour-long infusion of 50 to 75 mL of
10% dextrose to prevent hypoglycemia.
• Inhaled beta-agonists, such as 20 mg of nebulized albuterol, can quickly and durably lower potassium.
o Hyperphosphatemia is managed by a phosphorous restricted diet or by short-term use of oral phosphate binders like
aluminium hydroxide (300 mg with meals), aluminium carbonate (30 mL every 6 hours), or calcium acetate (two 667-
mg capsules with each meal, which should be avoided in patients with hypercalcemia).

23. o Calcium
 Calcium chloride and calcium gluconate can be administered parenterally to treat hypocalcemia.
 In tumor lysis syndrome hypocalcemia is secondary to hyperphosphatemia; therefore, administration of calcium
can potentiate the deposition of calcium phosphate crystals in soft tissues and the kidney making AKI worse.
 This might sometimes necessitate the use of hemodialysis.
 A 1000-mg infusion of calcium gluconate can stabilize myocyte membranes and reverse electrocardiographic
changes such as first-degree atrioventricular block and a widened QRS.

24. o Hemodialysis
 This is an option that is available to use in dire situations if the level of potassium and phosphorus is too high in the face
of tumor lysis syndrome associated AKI.
 In tumor lysis syndrome, there is an ongoing liberation of intracellular ions.
 If intermittent hemodialysis is utilized for extracorporeal clearance, rebound hyperkalemia or hyperphosphatemia might
develop. Because of this, continuous renal replacement therapy is the best modality for solute removal.
 This is done with a high flow rate for the dialysate or replacement fluid.
 For life-threatening hyperkalemia, early hemodialysis is recommended.
 For severe hyperphosphatemia, continuous renal replacement therapy might also be the best treatment modality.
 Dialysis may ultimately be necessary to treat any refractory, life-threatening electrolyte derangements, especially in the
context of volume overload and renal insufficiency.

25. o Febuxostat
 This medication is also a xanthine oxidase inhibitor that is relatively new to the market.
 It is more expensive than allopurinol. It does not cause the hypersensitivity reaction that is associated with
allopurinol.
 In the clinical trial, the Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies
(FLORENCE), febuxostat provides better control of hyperuricemia of tumor lysis syndrome with a good safety
profile and preservation of renal functions.

28. Prognosis
 Data on the prognosis of tumor lysis syndrome, whether before the start of chemotherapy or after successful
completion, is limited.
 However, using a recombinant urate oxidase has significantly decreased the incidence of acute renal failure
requiring hemodialysis.
 An increase in the knowledge of the pathophysiology of tumor lysis syndrome has led to better outcomes.
 Management protocol and treatment are being modified based on a better understanding of the disease
process. This has lead to a significant decrease in poor outcomes with tumor lysis syndrome.