Tumor lysis syndrome (TLS) describes metabolic derangements that occur from rapid tumor breakdown associated with cytotoxic therapy. It is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. TLS requires immediate intervention as it can overwhelm homeostatic mechanisms. It occurs primarily in hematologic malignancies with high proliferation rates that are sensitive to therapy. Prevention through hydration, hypouricemic agents, and monitoring of at risk patients is important to manage TLS.

1. Tumour Lysis Sydrome
Dr Deepika Malik
Resident Radiation Oncology

2. Introduction
• Tumor lysis syndrome (TLS) describes the metabolic
derangements that occur from rapid tumor breakdown
associated with the initiation of cytotoxic therapy of
malignancy in both children and adults.
• The syndrome is characterized by a tetrad of
abnormalities -----
-hyperuricemia
-hyperkalemia
-hyperphosphatemia
- hypocalcemia

3. • It should be considered an oncologic emergency.
• The abrupt release of intracellular ions, nucleic
acids, proteins, and their metabolites results from
the rapid destruction of malignant cells and the
release of their intracellular contents into the
extracellular space after the initiation of therapy.
• Cell lysis can overwhelm the body's normal
homeostatic mechanisms and cause severe
metabolic disturbances that require immediate
clinical intervention

4. Incidence
• Primarily observed in patients with acute lymphocytic
leukemia and high-grade non-Hodgkin's lymphomas, in
particular Burkitt's lymphoma.
• Also recognized in a variety of other malignancies,
both hematologic and solid. These malignancies share
the characteristics of a high proliferative rate and a
relative sensitivity to cytotoxic therapy.
• Hematologic malignancies --acute myeloid leukemia,
chronic lymphocytic leukemia, chronic myeloid
leukemia, and low-grade and intermediate-grade non-
Hodgkin's lymphomas.
• Solid tumors -- breast cancer, ovarian and testicular
cancer, neuroblastoma, and small cell carcinoma of the
lung

5. Incidence
• The overall incidence of TLS is not well established
• Has only been closely studied in high-grade non-
Hodgkin's lymphomas
• In a retrospective study of 102 patients with high-grade
non-Hodgkin's lymphoma, the incidence of TLS was
reported to be 42% as determined by serial laboratory
testing. The incidence of clinically significant TLS was
only 6% in the same group of patients.
• Part of the difficulty in obtaining the true incidence of
TLS is that there is no unifying definition or grading
system.

6. • Recent proposals define TLS by both
laboratory (LTLS) and clinical (CTLS) criteria
and use these criteria to develop a grading
system (Cairo-Bishop )

7. Cairo-Bishop Definition of Laboratory
Tumor Lysis Syndrome
Uric acid ≥8.0 mg/dL or 25% increase from baseline
Potassium ≥6.0 mEq/L or 25% increase from baseline
Phosphorus ≥6.5 mg/dL (children)
≥4.5 mg/dL (adults)or 25% increase from
baseline
Calcium ≤7.0 mg/dL or 25% decrease from baseline
LTLS defined as either a 25% change or level above or below normal, as defined
above, for any two or more serum values of uric acid, potassium, phosphate, and
calcium within 3 days before or 7 days after the initiation of chemotherapy. This
assessment assumes that a patient has or will receive adequate hydration and a
hypouricemic agents(s).

8. Cairo-Bishop Definition of Clinical
Tumor Lysis Syndrome
• 1. Renal failure (creatinine[*]: ≥1.5 ULN[†] [age >12 yr or
age adjusted])
• 2. Cardiac arrhythmia/sudden death[*]
• 3. Seizure[*]
*Not directly or probably attributable to a therapeutic agent (e.g., rise in creatinine after amphotericin
administration).
† Patients will be considered to have elevated creatinine if their serum creatinine is 1.5 times greater
than the institutional upper limit of normal (ULN) below age/gender defined ULN. If not specified
by an institution, age/sex ULN creatinine may be defined as: >1 <12 years, both male and female,
61.6 mol/L; ≥12 <16 years, both male and female, 88 μmol/L; ≥16 years, female, 105.6 μmol/L; ≥16
years, male, 114.4 μmol/L.
•

9. • Clinical tumor lysis syndrome (CTLS) assumes
the laboratory evidence of metabolic changes
and significant clinical toxicity that requires
clinical intervention.
• CTLS is defined as the presence of laboratory
tumor lysis syndrome (LTLS) and any one or
more of the above-mentioned criteria

10. Cairo-Bishop Grading System forTLS

11. • Clinical tumor lysis syndrome (CTLS) requires
one or more clinical manifestations along with
criteria for laboratory tumor lysis syndrome
(LTLS). Maximal CTLS manifestation (renal,
cardiac, neuro) defines the grade

12. Does TLS occur only with i/v chemo?
• TLS is not limited to systemic administration of
agents; it has been observed with intrathecal
administration of chemotherapy and with
chemo-embolization.

13. Does TLS occur only with chemo?
• The development of TLS is not limited to the
administration of chemotherapy alone.
• TLS has been associated with the
administration of radiation therapy,
corticosteroids, hormonal agents, biologic
response modifiers, monoclonal antibodies,
and more recently, the low-molecular-weight
inhibitor, imatinib mesylate, better known as
Gleevec

14. • It is extremely important clinically to note that TLS can
occur spontaneously, before the initiation of any
intervention. The identification of patients at risk for the
development of TLS is the most important aspect of
management, so that prophylactic measures can be
initiated before the initiation of therapy. Most of the
complications can be readily managed when they are
recognized early; however, delay in recognition and
initiation of treatment of TLS can be life-threatening. In
addition, a recent cost analysis looking at acute renal
failure, length of stay, and total cost demonstrated that
those patients who went on to develop acute renal failure
requiring dialysis had up to two to three times the length of
stay and more than five times the cost.

15. Pathophysiology
• The majority of agents that are used in the treatment of
malignancies are dependent on the proliferative rate of
malignant cells for their activity.
• In tumors with a high proliferative rate, a relatively large
mass, and a high sensitivity to cytotoxic agents, the
initiation of therapy often results in the rapid release of
intracellular anions, cations, and the metabolic products of
proteins and nucleic acids into the bloodstream.
• The increased concentrations of uric acid, calcium,
phosphates, potassium, and urea can overwhelm the
body's natural mechanisms to process and excrete these
materials and result in the clinical spectrum associated with
TLS

16. Hyperuricaemia
• Hyperuricemia and its associated complications are the
most frequently recognized manifestations of TLS
• predisposes to many of the other clinical
derangements in TLS.
• Cause of Hyperuricemia -results from rapid release
and catabolism of intracellular nucleic acids.
• Purine nucleic acids are catabolized to hypoxanthine,
then xanthine, and finally to uric acid by xanthine
oxidase. In humans, who lack urate oxidase, uric acid is
the final endpoint of purine catabolism

17. • Uric acid clearance is renal, and in normal circumstances
approximately 500 mg of uric acid are excreted through the
kidneys each day.
• Uric acid has a pKa of 5.4 to 5.7 and is poorly soluble in
water.
• At normal concentrations and at physiologic blood pH,
more than 99% of uric acid is in the ionized form
• The concentration of uric acid has been noted to be
elevated in patients with acute leukemias and lymphomas
before the initiation of therapy.
• The high concentrations of uric acid increase the risk for
urate crystal precipitation in the renal collecting ducts and
distal tubules, which are sites of urinary acidification

18. clinical manifestations of hyperuricaemia..
• General clinical manifestations of hyperuricemia include nausea,
vomiting, diarrhea, and anorexia.
• Uric acid crystal precipitation within renal tubules results in a decline in
glomerular filtration and the subsequent development of acute renal
failure.
• The risk of acute renal failure caused by uric acid precipitation may be
increased by
-dehydration, which is often present at the time of diagnosis;
-ureteral obstruction by tumor;
-a history of renal insufficiency;
- possible need for nephrotoxic antibiotics, such as aminoglycosides, in
patients with active infections.
• If the hyperuricemia results in acute obstructive uropathy, other clinical
manifestations may include hematuria, flank pain, hypertension, azotemia,
acidosis, edema, oliguria, anuria, lethargy, and somnolence

19. Pathophysiology- hyperphosphataemia
• Cause- Hyperphosphatemia results from the rapid release of intracellular
phosphates from malignant cells, which may contain as much as four
times the amount of organic and inorganic phosphates as normal cells
• Initially , the kidneys are able to respond to the increased concentration of
phosphorus from tumor lysis by increased urinary excretion and decreased
tubular absorption of phosphorus.
• Eventually, however, the tubular transport mechanism becomes saturated
and is unable to maintain normal serum phosphorus concentrations.
• The development of hyperphosphatemia may be further exacerbated by
acute renal insufficiency associated with uric acid precipitation, resulting
in obstructive uropathy or other complications of tumor therapy.
Hyperphosphatemia can lead to the development of acute renal failure
after precipitation with calcium in renal tubules during TLS.

20. Clinical manifestations of Hyperphosphatemia
• nausea, vomiting, diarrhea, lethargy, and
seizures.
• More importantly, it may result in tissue
precipitation of calcium-phosphate crystals,
resulting in hypocalcemia, metastatic
calcification, intrarenal calcification,
nephrocalcinosis, nephrolithiasis, and
additional acute obstructive uropathy.

21. Hypocalcemia
• The serum concentration of calcium rapidly
decreases as precipitation with phosphate occurs.
• Hypocalcemia is one of the most serious clinical
manifestations of TLS and has been associated
with the development of severe muscle
cramping, tetany, and cardiac arrhythmias.
• In addition to the kidneys, other tissues such as
muscle may be sites of precipitation of calcium
and phosphorus

22. Hyperkalemia
• Hyperkalemia may also be a life-threatening
consequence of TLS.
• Cause- Hyperkalemia results from the kidneys’
inability to clear the massive load of
intracellular potassium released by lysed
tumor cells.
•

23. Clinical manifestations of hyperkalemia
• General clinical manifestations of hyperkalemia
may include nausea, anorexia, vomiting, and
diarrhea.
• More specific complications include
neuromuscular and cardiac abnormalities.
• Neuromuscular signs and symptoms may include
muscle weakness, cramps, paresthesias, and
possible paralysis.
• Cardiac manifestations may include asystole,
ventricular tachycardia or fibrillation, syncope,
and possible sudden death.

24. Uraemia
• Increases in blood urea nitrogen and creatinine levels occur as a result of renal
impairment associated with acute uric acid crystal nephropathy, calcium-
phosphate crystals and nephrocalcinosis, or a combination of both, leading to an
acute obstructive uropathy syndrome
• A correlation with the pretreatment serum lactate dehydrogenase (LDH)
concentration and the development of azotemia has been reported, and the blood
urea nitrogen level will generally rise in parallel with the rise in the serum
phosphorus concentration.
• Acute clinical manifestations may include uremia resulting in nausea, vomiting,
and lethargy; oliguria or anuria leading to fluid retention; edema, hypertension,
congestive heart failure, metabolic disturbances, and exacerbations of
hyperphosphatemia and/or hyperkalemia ; flank or back pain; hematuria; and
severe acidosis.
• Extreme elevations in blood urea nitrogen concentrations can result in a platelet
function defect, cellular immunodeficiency, and inflammatory pericarditis.
Furthermore, acute obstructive uropathy may precipitate acute renal failure
(anuria), confusion, somnolence, seizures, and/or coma.

25. Treatment of TLS

26. Prevention is the best medicine!!
• The ability to prevent TLS is highly dependent on the
immediate recognition of patients at risk for its
development
• Patients at high risk include those with tumors with a
high proliferative rate, large tumor masses including
elevated leukocyte counts, extensive adenopathy and
splenomegaly, pre-existing renal insufficiency, and
elevated levels of phosphorus, uric acid, or both before
the initiation of therapy

27. Risk for Tumor Lysis Syndrome by
Tumor Type
• Burkitt's lymphoma Frequent cases
• Lymphoblastic lymphoma
• Acute leukemia
• Large cell lymphoma
• Low-grade lymphoma treated with chemotherapy, radiotherapy or
steroids Recognized complication but few occurrences
• Breast carcinoma treated with chemotherapy or hormonal therapy
• Small cell lung carcinoma
• Seminoma
• Neuroblastoma
• Low-grade lymphoma treated with interferon Case reports only
• Merkel's cell carcinoma
• Medulloblastoma
• Adenocarcinoma of the gastrointestinal

29. Initial Management of Patients at Risk for Tumor
Lysis Syndrome
1. Identification of the patient at risk
2. Admit to intensive care or hematology/oncology unit.
3. Alert dialysis team of existence of patient and potential
emergent need of assisted renal support.
4. Establish adequate venous access.
5. Perform baseline electrocardiogram and continuous cardiac
monitoring.
6. Determine baseline and serial WBC, serum LDH, uric acid,
Na+, K+, creatinine, BUN, phosphorous, and Ca++ levels. Repeat
every 4–6 hours.
7. Provide intravenous hydration with hypotonic or isotonic
saline solution at 2500 to 3000 mL/m2/24 hours.
8. Given allopurinol, 300 mg/m2/day orally, or rasburicase, 0.20
mg/kg/day intravenously, over 30 minutes for up to 3 days

30. • The elevation of the serum LDH level before the initiation of therapy has
also been associated with the recognition of patients at risk for TLS.
• Cytotoxic therapy should be delayed in patients at high risk for
development of TLS until prophylactic measures can be initiated.
•
• Unfortunately, a delay in therapy is not possible for many patients because
of the aggressive nature of their underlying malignancy. In this clinical
situation, a decision must be made regarding the relative risks in the delay
of tumor therapy versus the risk of development or exacerbation of TLS
and its associated complications including acute renal failure.
• Regardless of time constraints, the patient should have reliable venous
access and be treated in an intensive care or oncology special care unit
with personnel who are trained and familiar with the complications
associated with TLS. The unit should have, at a minimum, the capability of
continuous cardiac monitoring and preferably the capacity for
hemodialysis.

31. • The patient's vital signs, weight, urinary output, and fluid intake must be
carefully monitored.
• Serum creatinine, blood urea nitrogen, sodium, potassium, calcium,
phosphorus, LDH, and uric acid concentrations should be determined
before therapy and every 4 to 6 hours for the first 48 to 72 hours after the
initiation of tumor therapy.
• The LDH concentration serves as an excellent marker for tumor
proliferation and response to therapy.
• Patients should have a baseline electrocardiogram and continuous cardiac
monitoring until the completion of treatment.

32. Hydration
• Ideally, all patients should receive intravenous hydration 24 to 48 hours before the initiation
of tumor therapy.
• Intravenous hydration, preferably with a hypotonic or isotonic saline solution at 2500 to 3000
mL/m2/24 hr, should ideally begin 24 to 48 hours before the initiation of therapy and
continue for 48 to 72 hours after completion of chemotherapy.
• Care must be taken to prevent severe hyponatremia, especially when hypocalcemia is
present, because the risk of seizures is increased. A hypotonic saline solution should be used
when the urinary sodium concentration is less than 150 mEq/L, to reduce the risk of uric acid
supersaturation.
• The rate and amount of fluid is dependent on each patient's cardiovascular function.
• Administration of mannitol may be considered if sufficient diuresis cannot be achieved with
intravenous hydration alone. A test dose of 200 to 500 mg/kg may be given intravenously and
discontinued if an appropriate increase in urine output is not observed. Careful attention
must be given to the administration of both intravenous fluids and mannitol to avoid fluid
overload and the potential for congestive heart failure

33. Hypouricemic agents
• It is necessary to administer a hypouricemic
agent, either allopurinol or rasburicase, before
the initiation of therapy.

35. Allopurinol
• Allopurinol is a potent inhibitor of xanthine
oxidase and blocks the conversion of
hypoxanthine and xanthine to uric acid
• Whereas hypoxanthine is more soluble than
uric acid is at physiologic pH, xanthine is less
soluble than uric acid. This may result in the
formation of xanthine crystals in the kidney
and lead to obstructive uropathy.
• Although allopurinol prevents new uric acid
formation, it does not reduce the amount of
uric acid already present.
• Thus allopurinol requires administration for 2
to 3 days before the serum uric acid
concentration begins to fall and therefore
needs to be initiated 2 to 3 days before the
initiation of cytotoxic therapy.
• Dose of at least 300 mg/m2/day

36. Allopurinol…
Cautions for Allopurinol
• Allopurinol is known to interfere with the degradation of 6-
mercaptopurine, 6-thioguanine, and azathioprine through inhibition
of the P450 pathway; thus, the dose of allopurinol should be
reduced 50% to 75% in patients receiving these chemotherapeutic
agents.
• Should be used with caution in patients with underlying renal
insufficiency, because it can cause a syndrome consisting of rash,
hepatitis, eosinophilia, and worsening renal function
• Previously, urine alkalinization was recommended to increase uric
acid solubility and promote uric acid excretion in patients treated
with allopurinol. However, it is not currently recommended because
of the risk of decreasing ionized calcium concentrations, decreasing
phosphate excretion, and increasing serum phosphate
concentrations

37. Allopurinol…
• A previous limitation of allopurinol has been
the requirement for administration by the oral
route.
• For some critically ill patients or young infants
who may be unable to tolerate oral
medications during the prevention or
treatment of TLS, there is an intravenous
preparation of allopurinol available

38. Rasburicase
• Concept- promote the catabolism of uric
acid to allantoin by uric acid oxidase.
• Allantoin is 5 to 10 times more soluble in
the urine than uric acid.
• Urate oxidase is an endogenous enzyme
commonly found in many mammalian
species but not in humans
• .Urate oxidase, extracted from Aspergillus
flavus, has been demonstrated to rapidly
and significantly reduce uric acid levels in
patients at high risk for TLS.
• Recently, the gene encoding urate oxidase
was identified and expressed in yeast to
yield large quantities of the pure
recombinant form of urate oxidase
Rasburicase

39. Rasburicase…
• In a multicenter trial, 52 pediatric patients with hematologic malignancy at high
risk for TLS were randomly assigned to receive allopurinol or rasburicase. Uric acid
levels significantly decreased by 85% with rasburicase as compared with 12% with
allopurinol within 4 hours of drug administration
• Pui and colleagues administered rasburicase IV at doses up to 0.2 mg/kg in 131
pediatric patients with newly diagnosed leukemia or lymphoma. They found a
rapid drop in uric acid levels from 9.7 to 1 mg/dL within 4 hours of treatment in
patients with hyperuricemia and further reductions to 0.5 mg/dL within 24 hours
after rasburicase administration. Serum phosphorus and creatinine concentrations
also decreased significantly within 1 to 3 days
• There were very few adverse reactions after administration, and all of these were
mild, making this an excellent therapeutic option.
• Coiffier and associates investigated the safety and efficacy of rasburicase in 100
adult patients with non-Hodgkin's lymphoma over a 1-year period. Of these
patients, 66% had elevated LDH levels and 11% were hyperuricemic with
concentrations higher than 7.56 mg/dL. Rasburicase was given to all subjects and
uric acid levels then measured at 4 hours. All of the patients responded to
rasburicase with normalization of uric acid, and none exhibited increased
creatinine levels or required dialysis

40. • Hyperkalemia should be treated expediently with standard measures such
as the administration of sodium polystyrene sulfonate, a potassium-
binding resin, at a dose of 15 to 60 g/day given orally or rectally.
• There should be little hesitation about initiating hemodialysis to correct
this electrolyte abnormality.
• Aluminum hydroxide, given orally or through a nasogastric tube at a dose
of 15 mL (50–150 mg/kg/24 hr) every 4 to 6 hours, should be used to treat
hyperphosphatemia.
• The degree of tumor lysis declines after the first 48 to 72 hours of
treatment, and a decline in the serum LDH level serves as an excellent
marker for a decrease in tumor lysis. However, close monitoring of the
patient should continue until treatment is completed
• Treatment of asymptomatic hypocalcemia is generally not recommended.
In patients with symptomatic hypocalcemia, intravenous calcium
gluconate (50–100 mg/kg per dose) may be administered to correct the
clinical symptoms; however, this may increase the risk of calcium and
phosphorus deposition and acute obstructive uropathy.

41. Approach to the Management and
Treatment of Tumor Lysis Syndrome
Decreased
urine
output(<50ml
/hr)
hyperkalemia Uraemia hypocalcemia hyperuricemi
a
hyperphosph
atemia
Primary
intervention
Mannitol
challenge
Potassium
binding raisin
Diuretic Cautious
replacement
Allopurinol or
Rasburicase
Aluminum
hydroxide
(200–500
mg/kg)
Clinical
manifestation
Renal
insufficiency
or fluid
overload
Arrythmia Pericarditis or
platelet
dysfunction
Arrythmia or
Tetany
Renal
insufficiency
Renal
insufficiency
Secondary
intervention
haemodialysi
s
Treat
arrythmia
Haemodialysi
s
Treat
arrythmia
haemodialysi
s
haemodialysi
s

42. • For patients who have acute renal failure, significant
uremia, or severe electrolyte abnormalities associated
with TLS, the general consensus is that hemodialysis
should be initiated as soon as possible.
• Continuous hemofiltration has been used to correct
fluid overload and electrolyte abnormalities associated
with TLS in children
• The failure to promptly initiate hemodialysis for acute
renal failure may turn a potentially reversible clinical
situation into an irreversible one
•

43. Conclusion
• Successful management and treatment of TLS is highly
dependent on the prompt identification of clinical and
laboratory characteristics, signs, and symptoms of
patients at risk.
• Establishment of vascular access and the initiation of
prophylactic measures, especially hydration and
administration of allopurinol or rasburicase, are vital.
• The early recognition and treatment of metabolic
abnormalities usually prevents the severe and life-
threatening complications associated with TLS.

44. • Thank you.