Tumor Lysis Syndrome Treatment & Management

Approach Considerations

Management of tumor lysis syndrome requires the initiation of preventive measures in

high-risk patients prior to cancer treatment, as well as the prompt initiation of
supportive care for patients who develop acute tumor lysis syndrome during
treatment. Conservative management and prevention of tumor lysis syndrome are
similar.) Identify high-risk patients before treatment by assessing the extent of tumor
burden, histopathologic findings, and renal function.
Patients with evidence of pretreatment acute tumor lysis syndrome should be started
immediately on therapy for it. If possible, cancer treatment should be withheld until
all parameters are corrected.
Cancer patients with acute manifestations of tumor lysis syndrome or those at high
risk should be treated by personnel who are experienced with the conditions
complications and treatment. An oncology unit or intensive care unit (ICU) with
readily available, continuous cardiac monitoring and hemodialysis capabilities is the
preferred treatment setting.[26]
If basic supportive care measures are ineffective in controlling electrolyte
disturbances or renal function, nephrology and critical care consultants should be
accessible to assist in further management.
Laboratory turnover time must be rapid so that metabolic derangements can be
addressed before life-threatening problems arise.
Diet

Dietary restrictions are highly dependent on the status of the individual patient.
However, patients who are not restricted to a nothing-by-mouth diet could
theoretically benefit from restriction of intake of foods that contain high levels of
potassium, phosphorus, or uric acid.
Consultations

If initial supportive care measures fail to control electrolyte disturbances or renal

failure, nephrology and critical care consultations are important for assistance in
further management.
Patients with tumor lysis syndrome may need surgical intervention for central venous
line placement or for the placement of a dialysis catheter in cases of extreme
hyperkalemia or renal failure.
Severe manifestations of tumor lysis syndrome can be prevented only through
meticulous laboratory monitoring and careful clinical observation. Necessary cardiac
studies include baseline ECG with follow-up studies or continuous cardiac monitoring
during treatment. Appropriate renal surveillance and fluid status determinations
require baseline and daily weights, regular vital sign checks, and frequent
measurements of both fluid intake and urine output.
Patients at high risk and those with evidence of tumor lysis syndrome should have the
following levels monitored at least three times daily:
Blood urea nitrogen (BUN)
Creatinine
Uric acid
Potassium
Calcium
Phosphate
Lactate dehydrogenase (LDH)
Monitoring should continue for the first 48-72 hours after chemotherapy initiation.
Some patients may need to be placed on dialysis prior to the initiation of therapy.
Control of Hyperuricemia
Allopurinol

Allopurinol is a xanthine oxidase inhibitor; it is administered to reduce the conversion

of nucleic acid byproducts to uric acid in order to prevent urate nephropathy and
subsequent oliguric renal failure. It is usually given orally at 600 mg daily for
prophylaxis and 600-900 mg daily (up to a maximum of 500 mg/m 2 daily) for
treatment of tumor lysis syndrome. Patients unable to take oral medications can be
given IV allopurinol.
Adverse effects include mild-to-severe rash, xanthine stone-induced urolithiasis, acute
interstitial nephritis, pneumopathy, fever, and eosinophilia. Moreover, the inhibition of
uric acid synthesis promotes an increase of xanthine in plasma and the renal system;
although reported to be rare, xanthine has the capacity to precipitate in the renal
tubules.
Dose reduction is necessary in renal insufficiency or if the medication is given
concomitantly with mercaptopurine, 6-thioguanine, or azathioprine (since allopurinol
interferes with the metabolism of these agents).
Rasburicase

Rasburicase (recombinant urate oxidase) can be used when uric acid levels cannot be
lowered sufficiently by standard approaches. Rasburicase is useful in cases of
hyperuricemia and has been shown to be safe and effective in both pediatric and adult
patients. It also has a more rapid onset of action than allopurinol.
Humans do not express urate oxidase, which catalyses the conversion of poorly
soluble uric acid to soluble allantoin. By converting uric acid to water-soluble
metabolites, urate oxidase effectively decreases plasma and urinary uric acid levels.
Unlike allopurinol, uricase does not increase excretion of xanthine and other purine
metabolites; therefore, it does not increase tubule crystallization of these compounds.
Rasburicase is administered by intramuscular injection or IV infusion at dosages
ranging from 50-100 U/kg daily. It is contraindicated in glucose-6-phosphate
dehydrogenase (G6PD) deficiency and pregnancy.
In G6PD deficiency, excess hydrogen peroxide accumulates as rasburicase breaks
down uric acid and accelerates catabolism of its precursors xanthine and
hypoxanthine; this accumulation places patients at risk for hemolytic anemia and

methemoglobinemias. Some authorities recommend screening for G6PD deficiency

prior to administration of the drug.
In addition, because humans do not express urate oxidase, rasburicase can potentially
elicit an immune response.
Rasburicase is approved by the US Food and Drug Administration (FDA) for the
initial management of plasma uric acid levels in pediatric and adult patients with
leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer
therapy expected to result in tumor lysis and hyperuricemia. Rasburicase is indicated
only for a single course of treatment.[34]
Febuxostat

Febuxostat (Uloric) is a novel xanthine oxidase inhibitor that does not appear to have
the hypersensitivity profile of allopurinol. In addition, this agent does not require
dosing modification for renal impairment.[10] Initial studies suggested that febuxostat is
effective and safe for preventing tumor lysis syndrome. [35]
The Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies
(FLORENCE) trial found that febuxostat provided better control of serum uric acid
compared with allopurinol, with comparable renal function preservation and safety
profile. In FLORENCE, 346 patients with hematologic malignancies at intermediate
to high risk for tumor lysis syndrome were randomized to receive 120 mg of
febuxostat or 200-600 mg of allopurinol daily, starting 2 days before induction
chemotherapy, for 7-9 days. Mean area under curve for serum uric acid was was 514.0
225.71 mgxh/dl for febuxostat versus 708.0 234.42 mgxh/dl for allopurinol
(P <0.0001).[36]
Febuxostat is much more expensive than allopurinol. However, in patients with renal
impairment or hypersensitivity to allopurinol, febuxostat may be a reasonable choice
for prophylaxis of tumor lysis syndrome, pending the publication of further clinical
trial results.[10]
Hydration

Volume depletion is a major risk factor for tumor lysis syndrome and must be
corrected vigorously. Aggressive IV hydration not only helps to correct electrolyte
disturbances by diluting extracellular fluid, it also increases intravascular volume.

Increased volume enhances renal blood flow, glomerular filtration rate, and urine
volume to decrease the concentration of solutes in the distal nephron and medullary
microcirculation.
Ideally, IV hydration in high-risk patients should begin 24-48 hours prior to initiation
of cancer therapy and continue for 48-72 hours after completion of chemotherapy.
Continuous infusion rates as high as 4-5 L daily (or 3 L/m2 daily), yielding urine
volumes of at least 3 L daily, should be given unless the patient's cardiovascular status
indicates impending volume overload.
Diuresis

The use of furosemide or mannitol for osmotic diuresis has not proven to be beneficial
as front-line therapy. In fact, these modalities may contribute to uric acid or calcium
phosphate precipitation in renal tubules in a volume-contracted patient.
Diuretics should be reserved for well-hydrated patients with insufficient diuresis, and
furosemide alone should be considered for the normovolemic patient with
hyperkalemia or for the patient with evidence of fluid overload.
Urinary alkalinization

The use of isotonic sodium bicarbonate solutions intravenously to promote alkaline

diuresis has the potential benefit of solubilizing, and thus minimizing, intratubular
precipitation of uric acid. The goal is to increase urinary pH to 7.0 to maximize uric
acid solubility in renal tubules and vessels.
Drawbacks to systemic alkaline therapy include magnification of clinical
hypocalcemia by shifting ionized calcium to its nonionized form. An increased
likelihood of calcium phosphate precipitation in renal tubules is an additional
drawback. For these reasons, routine urine alkalinization is controversial, and if it is
employed, it must include close monitoring of urinary pH, serum bicarbonate, and
uric acid levels to guide therapy and avoid overzealous alkalinization. Consider
withdrawing sodium bicarbonate from IV fluid solutions once serum bicarbonate
levels reach 30 mEq/L, urinary pH exceeds 7.5, or serum uric acid levels have
normalized.

If urinary alkalinization is not achieved with exogenous bicarbonate solutions despite

increasing serum bicarbonate levels, IV acetazolamide at doses of 250-500 mg daily
(5 mg/kg daily) may be added to decrease proximal tubule bicarbonate reabsorption,
thereby increasing urinary pH.
Treatment of Hyperkalemia

Aggressively treat and monitor hyperkalemia. Immediately restrict dietary potassium

and remove potassium from IV fluids. Acute treatment modalities include IV infusion
of glucose plus insulin to promote redistribution of potassium from the extracellular to
the intracellular space, and IV calcium gluconate as cardioprotection for potassium
levels greater than 6.5 mmol/L or for patients with electrocardiographic alterations.
IV hydration with alkaline fluid can also increase intracellular uptake of potassium.
Potassium-wasting diuretics may be employed with caution since these may worsen
renal precipitation in the volume-contracted patient. Long-term therapy, such as oral
potassium-exchange resins, should be given immediately because of the transient
effectiveness of acute treatment modalities. If these measures fail to control serum
potassium, dialysis should be initiated promptly.
Treatment of Hyperphosphatemia and Hypocalcemia

Hyperphosphatemia is managed with oral phosphate binders and the same solution of
glucose plus insulin used for the control of hyperkalemia. Hyperphosphatemia may
lead to hypocalcemia, which usually resolves as phosphate levels are corrected.
In some cases, depressed serum 1,25-dihydroxycholecalciferol levels contribute to
hypocalcemia, and administration of calcitriol may correct calcium levels. Such
therapy, however, should not be undertaken until serum phosphate levels have
normalized to avoid metastatic calcium phosphate calcifications. As a rule, do not
correct hypocalcemia unless evidence of neuromuscular irritability exists, as indicated
by a positive Chvostek or Trousseau sign.
Dialysis

If the previously described therapies for the complications of tumor lysis syndrome
fail, consider early initiation of dialysis. Dialysis prevents irreversible renal failure
and other life-threatening complications. Indications for dialysis include persistent

hyperkalemia or hyperphosphatemia despite treatment, volume overload, uremia,

symptomatic hypocalcemia, and hyperuricemia.
Hemodialysis is preferred over peritoneal dialysis because of better phosphate and
uric acid clearance rates. Continuous hemofiltration also has been used and is
effective in correcting electrolyte abnormalities and fluid overload.
Because hyperkalemia can recur after dialysis is initiated and because of the high
phosphate burden in some patients with tumor lysis syndrome, electrolyte levels must
be monitored frequently and dialysis repeated as needed.
Prevention

The National Comprehensive Cancer Network advises that tumor lysis syndrome is
best managed if it is anticipated and treatment is started before initiation of
chemotherapy. Treatment centers on the following [37] :
Rigorous hydration
Management of hyperuricemia
Frequent monitoring of electrolytes and aggressive correction
of abnormalities
The NCCN recommends allopurinol for first-line treatment and retreatment for
hyperuricemia. Allopurinol is begun 23 days prior to chemotherapy and continued
for 1014 days
Alternatively, the NCCN recommends rasburicase when allopurinol is ineffective, and
for patients with any of the following risk factors:
Presence of any high-risk feature
Urgent need to initiate therapy in a patient with high-bulk
disease
Situations where adequate hydration may be difficult or
impossible
Acute kidney injury

High-risk features for tumor lysis syndrome include the following [37] :
Hematologic malignancies strongly associated with tumor lysis
syndrome (eg, acute lymphoblastic leukemia, Burkitt
lymphoma, lymphoblastic lymphoma)
Elevated white blood cell count
Bone marrow involvement
Pre-existing hyperuricemia
Renal disease or renal involvement by tumor
British guidelines include the following recommendations for prevention of tumor
lysis syndrome[38] :
Patients due to receive chemotherapy for any hematological
malignancy should be assessed for risk of tumor lysis
syndrome
Low-risk patients can be managed with careful monitoring of
fluid status and laboratory results, with a low threshold for
recourse to intravenous fluids and consideration of allopurinol
therapy
Intermediate-risk patients should be offered up to 7 days of
allopurinol prophylaxis, along with increased hydration once
cancer treatment is initiated, or until risk of tumor lysis
syndrome has resolved
High-risk patients should be offered prophylaxis with
rasburicase, along with increased hydration
In patients with glucose-6-phosphate dehydrogenase (G6PD)
deficiency, do not use rasburicase; treat such patients with
fluids and allopurinol and monitor them carefully
Urinary alkalinization is not recommended for tumor lysis
syndrome prophylaxis

Guideline recommendations on the use of rasburicase for prevention are listed

below[38] :
Most high-risk adults can be treated with a single fixed dose of
3 mg rasburicase, but this must be followed by careful
monitoring of clinical and biochemical parameters, with repeat
dosing if required
Most high-risk children can be treated with a single dose of
0.2 mg/kg rasburicase, followed by close laboratory and clinical
monitoring; use of a fixed dose of 3 mg seems reasonable, but
cannot be firmly recommended on the basis of current
evidence
The addition of allopurinol is unnecessary and has the potential
to reduce the effectiveness of rasburicase
Urate assays taken while patients are receiving rasburicase
must be sent to the laboratory on ice, to prevent falsely low
assay results