Tu mor Lysis Syndrome

Helen H. Chung, MD*, Elina Tsyvkin, MD

KEYWORDS
 Tumor lysis syndrome  Oncologic emergencies  Rasburicase  Acute kidney injury

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Tumor lysis syndrome (TLS) can occur as a consequence of tumor-targeted

therapy (chemotherapy/another pharmacologic antitumor treatment, emboli-
zation therapy, and radiation therapy) or spontaneously. Hematologic cancers
constitute many TLS cases because of their rapid division rate and sensitivity
to chemotherapy.
2. Central to pathogenesis is the rapid release of intracellular potassium, phos-
phorus, and uric acid from dying cancer cells into the extracellular space over-
whelms existing homeostatic mechanisms, potentially leading to acute kidney
injury (AKI), arrhythmia, neurologic deficits, and death.
3. Spontaneous TLS is in the differential diagnosis of any patient with AKI of un-
known cause. It requires a high index of suspicion because it can be the initial
presentation leading to the diagnosis of cancer.
4. Every hospitalized patient with cancer, especially if receiving chemotherapy,
needs to be stratified for the risk of TLS.
5. Patients at highest risk for developing TLS can have hematologic malig-
nancies, advanced or metastatic disease, bulky tumor, and/or tumors with a
high Ki-67 (a marker of cell proliferation). These patients may already be in
spontaneous tumor lysis.
6. Patients with compromised renal function or with risk factors for renal
dysfunction are at increased risk for TLS.
7. The ideal management of TLS is prevention. Prevention strategies include hy-
dration and prophylactic rasburicase in high-risk patients, hydration plus allo-
purinol or rasburicase for intermediate-risk patients, and hydration and
optional allopurinol and close monitoring for low-risk patients.

CONTINUED

Disclosure: The authors have nothing to disclose.

Hospital Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center,
1275 York Avenue, New York, NY 10065, USA
* Corresponding author.
E-mail address: chungh@mskcc.org

Hosp Med Clin 5 (2016) 425438

http://dx.doi.org/10.1016/j.ehmc.2016.02.004
2211-5943/16/$ see front matter 2016 Elsevier Inc. All rights reserved.
426 Chung & Tsyvkin

CONTINUED
8. Potential complications of rasburicase include anaphylaxis, hemolytic anemia,
methemoglobinemia. Rasburicase is contraindicated in patients with glucose-
6-phosphate dehydrogenase deficiency.
9. If hyperkalemia is asymptomatic, treatment with Kayexalate or furosemide (as
long as the patients renal function is normal) should be prioritized.
10. Hypocalcemia should not be treated unless the patient is symptomatic.
11. In hyperphosphatemia, use sevelamer, and not calcium acetate, to bind phos-
phate, because the latter can increase serum calcium levels and cause
calciphylaxis.
12. Patients with established TLS or at high risk, especially in the context of renal
insufficiency or with renal involvement by their malignancy, should be moni-
tored in the intensive care unit.
13. Indications for renal replacement therapy are urate nephropathy, metabolic
acidosis, severe electrolyte abnormalities, calcium-phosphorus product of
70 mg2/dL2 or more, oliguria, volume-overloaded state preventing effective
diuresis without cardiopulmonary compromise, symptomatic uremia with en-
cephalopathy, or pericarditis.

DEFINITIONS

What is tumor lysis syndrome (TLS)?

TLS is a potentially preventable oncologic emergency triggered by the rapid release of
intracellular contents from lysing malignant cells. The rapid shift of potassium, phos-
phorus, and nucleic acids from cancer cells into the extracellular space can over-
whelm existing homeostatic mechanisms, leading to acute kidney failure,
arrhythmia, neurologic deficits, and potentially death.

What is the pathophysiology of TLS?

In malignancies with a large tumor burden, high proliferative rate, and high sensitivity to
treatment, the initiation of tumor-targeted therapy can cause rapid lysis of tumor cells,
leading to hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia.
Hyperuricemia is the result of nucleic acid catabolism. Purine nucleic acids are
catabolized to hypoxanthine, then xanthine. Xanthine oxidase then metabolizes
xanthine to uric acid (Fig. 1). A high burden of uric acid both supersaturates and
directly obstructs renal tubules; uric acid crystallization injures tubules and microvas-
culature.14 Renal vasoconstriction ensues via decreased release of nitric oxide (NO)
and local granulomatous inflammation. This process may explain the paradoxic lack of
benefit of diuretics in the management of acute kidney injury (AKI) associated with
TLS. In a retrospective review of 83 patients with non-Hodgkin lymphoma, the relative
risk of developing TLS or renal events correlated with uric acid level.5
Phosphorus levels in malignant cells can be up to four times higher than those found
in normal cells.3,6,7 Release of phosphorous from lysing cells overwhelms tubular
transport mechanisms, leading to increased serum phosphorus levels. AKI caused
by uric acid may further exacerbate hyperphosphatemia. When the calcium-
phosphorus multiple exceeds 70 mg2/dL2, calcium phosphate precipitation risk in
renal tubules increases, potentially exacerbating renal failure.1,810 Calcium
 Tumor Lysis Syndrome 427

Fig. 1. Uric acid metabolism. Purine nucleic acids are broken down into both hypoxanthine
and xanthine. Allopurinol competitively inhibits xanthine oxidase, preventing the formation
of uric acid. Rasburicase is a recombinant form of urate oxidase, the enzyme absent in hu-
mans that converts uric acid to the five to ten times more soluble allantoin.

phosphate precipitate can deposit in tissues indiscriminately, known as calciphylaxis

(most commonly seen in the skin in patients with end-stage renal disease on dialysis).
Once calcium is deposited in the vasculature it cannot be extracted or made soluble to
reverse the damage, even if electrolyte levels are normalized.
Release of the major intracellular ion, potassium, can lead to hyperkalemia, which
has been addressed in a prior edition of Hospital Medicine Clinics.

What are laboratory and clinical criteria for defining TLS?

No standard definition of TLS exists. In 1993, Hande and Garrow11 defined laboratory
TLS (LTLS). However, it requires defining TLS according to a future event (the admin-
istration of chemotherapy), and excludes spontaneous TLS from the classification. In
2004, Cairo and Bishop1 created the commonly used Cairo-Bishop criteria (Table 1),
defining both LTLS, which included parameters for patients presenting in autolysis, as
well as creating criteria for clinical TLS (CTLS).

Table 1
Cairo-Bishop definition of laboratory TLS

Uric acid  476 mmol/L (>8.0 mg/dL) or 25% increase from baseline
Potassium  6.0 mmol/L or 25% increase from baseline
Phosphorus  1.45 mmol/L (>4.0 mg/dL) or 25% increase from baseline
Calcium  1.75 mmol/L (<7.0 mg/dL) or 25% decrease from baseline

Adapted from Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-
Hodgkins lymphoma. Am J Med 1993;94:1339.
428 Chung & Tsyvkin

LTLS is defined by simultaneous occurrence (within 24 hours) of two or more of the

four classic metabolic derangements (see Table 1), either three days before or up to
seven days after the initiation of cytotoxic therapy. CTLS is defined as LTLS plus one
or more of the following: serum creatinine level greater than 1.5 times the upper limit of
normal (ULN) for patient age and sex, cardiac arrhythmias, seizures, or death.
The distinction between LTLS and CTLS is largely academic because most guide-
lines recommend aggressive treatment of laboratory abnormalities before clinical
sequelae such as arrhythmia develop.

UNDERSTANDING EPIDEMIOLOGY HELPS WITH RISK ASSESSMENT, AND THUS

MANAGEMENT

Ideal TLS management prevents its occurrence. Therefore, it requires a high index of
suspicion and much of the work of management is risk stratification, identifying those
patients at risk, and risk quantification. Several disease-related, treatment-related,
and host-related factors influence the risk and severity of TLS.

Which cancers put patients at high risk of developing TLS spontaneously or with
treatment?
Patients with hematologic malignancies and metastatic advanced solid tumors are at
highest risk. High-risk hematologic malignancies are inherently characterized by a
high proliferation rate, are especially chemosensitive, or involve bulky disease. Tumor
burden is defined by being greater than 10 cm on imaging, lactate dehydrogenase
(LDH) level greater than two times the ULN, or and increased white blood cell (WBC)
count greater than 25,000/mL, or an increased Ki67 level, a marker for cell proliferation
on histopathology. Burkitt lymphoma, stage III or IV diffuse large B-cell lymphomas,
anaplastic large-cell lymphomas, acute leukemia, chronic lymphocytic leukemia, and
lymphomas with transformed physiology are frequently implicated (Table 2). Treatment
may include steroids, radiation therapy, tumor embolization, and newer targeted ther-
apies such as rituximab, a CD-20 antibody, or venetoclax, ABT-199, a bcl-2 inhibitor.
These inherently aggressive hematologic malignancies may autolyse or lyse impres-
sively even to nonspecific steroid treatment. To our knowledge, no prospective
studies monitoring the development of spontaneous TLS exist, limiting understanding
of its risk factors.
Patients with underlying renal dysfunction, or those who are predisposed to its
development, are at additional risk for TLS development, including patients who
have gout, take nonsteroidal antiinflammatory drugs (NSAIDs) or other nephrotoxic
agents chronically, or are, to any degree, hypovolemic. It is important to optimize renal
function before the administration of chemotherapy if possible.2,9,12

Should hospitalized patients with cancers routinely be screened for TLS

Although all hospitalized patients with cancers are not routinely screened for TLS, it
should be considered in the differential diagnosis of any patient with AKI of unknown
cause and a significant burden of malignant disease (regardless of prior treatment status),
particularly in the setting of hyperuricemia, hyperkalemia, and hyperphosphatemia.

What are the most critical complications of TLS associated with morbidity and
mortality?
TLS has a significant mortality of 5% to 20%.1,10,11,13,14 Advanced solid tumors that have
an independently high mortality by their refractory and metastatic nature partially account
 Tumor Lysis Syndrome 429

Table 2
Risk factors for TLS

Characteristic Risk Factor

Tumor type
Tumor burden/extent
of disease
Renal function
Baseline uric acid
Effective and rapid
cytoreductive therapy
Burkitt lymphoma
Lymphoblastic lymphoma
Diffuse large-cell lymphoma
ALL
Solid tumors with high proliferative rates and rapid response
to therapy
Bulky disease (>10 cm)
Increased LDH (>2 ULN)
Increased WBC (>25,000/mL)
Increased Ki67
Preexisting renal failure
Oliguria
Baseline serum/plasma uric acid level >450 mmol/L (7.5 mg/dL)
Disease-specific therapy, varies according to tumor type

Tumors that are large or bulky, have a high proliferative rate, and are highly chemosensitive are at
risk for TLS. Initial treatment with aggressive polychemotherapeutic agents or targeted therapies,
as well as underlying renal insufficiency, increases risk for TLS occurrence.
Abbreviations: ALL, acute lymphoblastic leukemia; LDH, lactate dehydrogenase.
From Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tu-
mor lysis syndrome: an evidence-based review. J Clin Oncol 2008;26(16):276778. Reprinted with
permission. 2016 American Society of Clinical Oncology. All rights reserved.

for the higher end of this estimate. The untreated complications of TLS that account for
morbidity and mortality are arrhythmias, renal failure, calciphylaxis, and seizures.
Development of AKI associated with TLS is a strong predictor of death. Among 63
patients with hematologic malignancies and TLS, 6-month mortality was 21% among
those without AKI and 66% among those with AKI.15,16 This relationship held after
multivariable adjustment (P 5 .0006). Prevention of AKI may be possible with prompt
recognition of TLS and appropriate therapy.13,14,17

MANAGEMENT

What are clinical manifestations of TLS?

Clinical manifestations of TLS include signs and symptoms associated with its four
cardinal laboratory abnormalities: hyperkalemia, hyperphosphatemia, hyperuricemia,
and hypocalcemia (Table 3). Detailed description of clinical presentation associated
with these common metabolic abnormalities is beyond the scope of this article. A
summary of these clinical manifestations is provided later.
The Cairo-Bishop criteria allow grading of TLS severity. TLS grades are based on
the severity of clinical complications experienced (grades range from 0 with no evi-
dence of TLS to V in case of death).1 Treatment guidelines do not vary by grade
and are therefore not discussed here.

What is the best approach to prevent clinical manifestations of TLS?

The best approach is risk stratification because this life-threatening condition may
occur rapidly and is often preventable. Effective management involves having a high
430 Chung & Tsyvkin

Table 3
TLS laboratory values and corresponding clinical manifestations

Laboratory Values Clinical Manifestations

Potassium 25% >baseline, or >6.0 mmol/L Arrhythmia, syncope, sudden death
Uric acid 25% >baseline, or >8.0 mg/dL Renal failure, congestive heart failure
Phosphorus 25% >baseline, or >4.0 mg/dL Seizures, nausea, vomiting, calciphylaxis
Calcium 25% <baseline, or <7.0 mg/dL Mental status changes, arrhythmia,
calciphylaxis, tetany, muscle cramps

LTLS is defined by 2 or more changes in test results within 3 days before or 7 days after initiation of
cytotoxic therapy. Clinical TLS is LTLS with at least 1 of the following: arrhythmia, seizure or wors-
ened renal function as reflected by increased creatinine level.

index of suspicion on the part of clinicians, assigning risk to disease and patients, and
enacting prophylactic management early. Prevention of AKI and other complications
that may delay or dose reduce chemotherapy that is clinically determined to be urgent
optimizes opportunity and therapy for patients with cancers, and can thereby have
significant implications for prognosis, potentially saving lives.

How do clinicians risk stratify TLS?

When LTLS is effectively managed, CTLS does not develop. This point underscores an
increasing need for a standardized way to assess risk to identify patients who need
aggressive up-front management. Instituting guidelines for risk classification helps
cultivate clinicians high index of suspicion, which is perhaps the most important skill
to develop in the management of TLS.
Risk assessment guidelines have been proposed by Cairo and colleagues.9 Patients
are stratified into low, intermediate and high risk groups (Box 1). After identifying pa-
tients with LTLS, patients are grouped based on type of malignancy. Leukemias are
then stratified based on WBC count and lactate dehydrogenase (LDH) level, which
are markers of tumor burden. Chronic lymphocytic leukemias are further risk stratified
by the anticipated type of therapy. Lymphomas are categorized based on LDH, stage,
and bulk. Final TLS risk designation is determined by the absence or presence of renal
dysfunction, with the latter increasing risk by 1 level.

What is the cornerstone of TLS management?

Intravenous fluid hydration is the cornerstone. All patients at risk for TLS should get
hydration and allopurinol when treatment is being initiated. Because rapid clearance
of liberated intracellular solutes is the key to prevention of AKI, methods that increase
glomerular filtration rate and urine output are appropriate regardless of risk category
(Box 2). Patients who are identified to be intermediate or high risk for developing
TLS should be admitted to start aggressive intravenous hydration, ideally at least
24 hours before the start of chemotherapy, and for close monitoring. The standard
recommendation is for crystalloid intravenous fluid at 3 L/m2/24 h. The aim is for a
urine output of 100 mL/kg/h, to maximize phosphorus and uric acid excretion. Di-
uretics can be used to achieve this, sometimes known as forced diuresis, but only if
patients are at least euvolemic. Otherwise, underfilling can lead to a prerenal state,
thereby causing or increasing the severity of TLS.1,57,9,10
Often, patients develop edema, but this risk is acceptable given the benefit of preser-
ving and optimizing renal function. Edema can be relieved after the risk of TLS has passed
 Tumor Lysis Syndrome 431

Box 1
Risk classification as proposed by Cairo and colleagues

Low risk
 AML with WBC count less than 25,000/mm3 and LDH level less than 2  ULN
 CLL with a WBC count less than 50,000/mm3 and treated with only alkylating agents
 Multiple myeloma
 CML, chronic phase
 Hodgkin lymphoma; small lymphocytic, follicular, MALT, marginal zone B-cell, mantle cell
(nonblastoid variant), and cutaneous T-cell lymphomas
 Anaplastic large-cell, diffuse large B-cell, peripheral T-cell, transformed, mantle cell (blastoid
variant) and serum LDH level WNL
 Most solid tumors
Intermediate risk
 CLL treated with targeted and biologic therapies (eg, fludarabine or rituximab) and/or those
with high WBC count (50,000/mm3)
 ALL with WBC count less than 100,000/mm3 and LDH level less than 2 ULN
 AML with WBC count greater than or equal to 25,000/mm3 or less than 100,000/mm3
 AML with WBC count less than 25,000/mm3 and LDH level greater than or equal to 2 ULN
 Early lymphoblastic lymphoma with LDH level less than 2 ULN
 Adult T-cell, diffuse large B-cell, peripheral T-cell, transformed or mantle cell lymphoma,
nonbulky, with LDH level greater than ULN
 Rare bulky solid tumors that are sensitive to chemotherapy (eg, small cell lung cancer, germ
cell cancer)
 Low-risk disease with renal dysfunction and/or renal involvement
High risk
 ALL with WBC count greater than or equal to 100,000/mm3 or less than 100,000/mm3 and
LDH level greater than or equal to 2 ULN
 AML with WBC count greater than or equal to 100,000/mm3
 Burkitt lymphoma
 Stage III or IV lymphoblastic lymphoma or early stage lymphoblastic lymphoma with LDH
level greater than or equal to 2 ULN
 Any adult T-cell lymphoma; diffuse large B-cell, peripheral T-cell, transformed and mantle cell
lymphomas with bulky tumor mass and LDH level greater than ULN
 Intermediate-risk disease with renal dysfunction and/or renal involvement
 Intermediate-risk disease with normal renal function and uric acid, and either potassium or
phosphate levels greater than the ULN

Patients with low-risk disease are intermediate risk for TLS when renal dysfunction and/or renal
involvement are present. Patients with intermediate-risk disease are high risk for TLS when
renal dysfunction and/or renal involvement are present or uric acid, phosphate, or potassium
levels are increased.
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic
lymphocytic leukemia; CML, chronic myeloid leukemia; MALT, mucosa-associated lymphoid tis-
sue; ULN, upper limit of normal; WNL, within normal limits.
From Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and
prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases:
an expert TLS panel consensus. Br J Haematol 2010;149(4):57886; with permission.
432 Chung & Tsyvkin

Box 2
TLS prophylaxis backbone

 Aggressive intravenous hydration ideally 24 to 48 hours before initiation of cytotoxic therapy

is vital
 Patients at low, intermediate, and high risk should be started on allopurinol at least 24 to
48 hours before tumor-targeted therapy (including radiation, embolization)
 In high-risk patients, and in those whose initial uric acid level is greater than 8.0 mg/dL, use
rasburicase prophylactically18
 Avoid potentially nephrotoxic substances
 Alkalinization of urine is not currently recommended

Prevention strategies require hydration and uric acid control in order to preserve renal
function.

or TLS is resolved. Note that aggressive hydration may be difficult in patients with under-
lying cardiac or renal disease, and places such patients at higher risk of developing vol-
ume overload. Such patients should be monitored closely, perhaps in the intensive care
unit (ICU), in concert with a nephrology consultant. If signs of fluid overload appear, loop
diuretics can be used (with the additional benefit of their hypokalemic effect).
Avoid potentially nephrotoxic substances, including vasoconstrictive substances,
such as NSAIDs, and iodinated contrast.

What is in the armamentarium to treat hyperuricemia?

Allopurinol: a xanthine oxidase inhibitor, allopurinol is metabolized by xanthine oxi-
dase to oxypurinol, the active form of the drug. Oxypurinol is excreted in the kidneys,
thus the dose of allopurinol should be reduced in patients with renal failure.19
Maximum dosage of oral allopurinol is 800 mg/d. Dose adjustments may be necessary
if allopurinol is used with other drugs (eg, 6-mercaptopurine, azathioprine, cyclophos-
phamide, thiazide and loop diuretics, and warfarin).20 It can cause hypersensitivity
allergic reactions, and is associated with Stevens-Johnson syndrome and toxic
epidermal necrolysis.21,22
Allopurinol is widely used, well tolerated, and effective in reducing and stabilizing
uric acid levels. However, it has no effect on already existing hyperuricemia. Thus, it
is a good choice for prophylaxis of patients at risk for TLS, but may be less effective
to treat TLS. Allopurinol can be administered intravenously in patients who cannot
tolerate oral medication.
Febuxostat: patients who cannot tolerate allopurinol or have a prohibitive level of
chronic kidney disease can receive febuxostat, a novel xanthine oxidase inhibitor
that is metabolized to inactive metabolites in the liver. Febuxostat has not been spe-
cifically studied in patients at risk of TLS.9
Rasburicase: rasburicase has been approved by the US Food and Drug Administra-
tion for adults since 2009. Rasburicase is a recombinant form of urate oxidase that
humans have lost. It converts uric acid to allantoin, which is five to ten times more sol-
uble in urine. It was originally a nonrecombinant form made from an Aspergillus flavus
strain. However, because of reports of anaphylaxis and hypersensitivity, rasburicase is
now available as a recombinant form made from a Saccharomyces cerevisiae
strain.13,23,24 It is rapid, effective and well tolerated. Although cost analysis has yet
to be formally studied, it is thought that, when the cost of hospitalization and poten-
tially preventable complications of TLS that rasburicase can effectively abrogate,
 Tumor Lysis Syndrome 433

such as kidney failure with attendant electrolyte abnormalities, ICU stays, increasing
length of stay, and possible dialysis, are factored in, using prophylactic rasburicase
is more cost-effective, despite the large cost differential between rasburicase and allo-
purinol with aggressive hydration. In addition, although the efficacy and rapidity of ras-
buricase in lowering uric acid levels and preventing AKI has been shown, mortality
benefit has not been proved, which has been attributed to the overall low incidence
of TLS.5,13,14,18,20,23,25
Using rasburicase as prophylaxis in high-risk patients, or for treatment of TLS, is
standard (Box 3). Rasburicase should be given 4 hours before chemotherapy. The
dosage of rasburicase is based on the underlying risk of TLS.
Many institutions use lower flat dosages (3 mg or 6 mg) based on data from small
studies or retrospective experience.26,27 A single dose of rasburicase may be
repeated for a uric acid level increase to 7.5 mg/dL or greater.28 If repeat dosing is
required, consider a nephrology consultation. At a cost of $850 per 1.5 mg of rasburi-
case, this is considerably more economic and equally effective, perhaps even limiting
potential side effects. The half-life elimination of rasburicase is approximately 12 and
16 hours with the 0.15 mg/kg and 0.2 mg/kg dosing, respectively, with no apparent
accumulation when the area under the curve was evaluated.6,7
Use of rasburicase is contraindicated in patients with glucose-6 phosphate dehy-
drogenase (G6PD) deficiency, known hypersensitivity reactions, hemolytic anemia,
or methemoglobinemia (Box 4). Allopurinol should be substituted in these patients.
Thus the authors recommend checking G6PD level before initiation of therapy, pro-
vided time allows, although it is not a requirement of any published guidelines.
Alkalinization: note that alkalinization by sodium bicarbonate has historically been
used as part of the strategy to treat hyperuricemia. The impressive ease of use,
rapidity, and efficacy of rasburicase has made this all but obsolete, except in cases
in which adverse events and financial considerations are significant. The administra-
tion of sodium bicarbonate makes uric acid more soluble but conversely decreases
the solubility of hypoxanthine and xanthine, potentiating the formation of urinary
xanthine crystals, in addition to creating a more favorable environment for calcium
phosphate precipitation.3,6,9,10,20

How can TLS be prevented in patients at intermediate and high risk for TLS?
Patients at intermediate and high risk for TLS should be more closely monitored in a
hospital and potentially in an ICU. They should be admitted for aggressive intravenous

Box 3
Recommended rasburicase dosing

 High-risk patients or a baseline uric acid level greater than 7.5 mg/dL (446 mmol/L):
rasburicase 0.2 mg/kg
 Intermediate-risk patients with baseline uric acid level less than or equal to 7.5 mg/dL:
rasburicase 0.15 mg/kg
 Low-risk patients with baseline uric acid less than or equal to 7.5 mg/dL rasburicase 0.10 mg/kg

Daily versus twice-daily dosing and number of days depend on plasma uric acid levels and clin-
ical judgment.18
Blood samples to check uric acid levels after administration of rasburicase should be sent in
chilled, heparinized vials, and processed within 4 hours of collection, because the enzyme re-
mains active at room temperature.15
434 Chung & Tsyvkin

Box 4
Toxicities associated with rasburicase

 Anaphylaxis
 Antibody formation with repeated use
 Hemolytic anemia associated with G6PD deficiency
 Methemoglobinemia associated with G6PD deficiency

hydration at least 24 hours before initiation of cytotoxic therapy. Rasburicase should

be used prophylactically in patients at high risk of developing TLS and when baseline
uric acid levels are higher than 7.5 mg/dL (446 mmol/L)17 (Fig. 2). Avoid nephrotoxic
substances, including kidney vasoconstrictive substances (such as NSAIDs) and
iodinated contrast.

How should patients at intermediate and high risk for TLS be monitored?
Patients at high and intermediate risk for TLS should have the following laboratory
tests checked every six to eight hours, starting four hours after initiation of chemo-
therapy, tumor-targeted therapy or radiation therapy: sodium, potassium, chloride,
calcium, bicarbonate, blood urea nitrogen, creatinine, uric acid, LDH, and phos-
phorus. After biomarkers have peaked, laboratory checks can be spaced out to every

Fig. 2. Treatment algorithm for the prevention and management of hyperuricemia. The
treatment approach for low-risk patients is observation. Rasburicase is recommended if hy-
peruricemia develops despite prophylactic treatment with allopurinol in patients at inter-
mediate risk. Aggressive action is necessary for the high-risk group, with vigorous
hydration and rasburicase administration.
 Tumor Lysis Syndrome 435

12 hours and then daily, using clinical judgment. Monitoring for TLS should continue
for at least 72 hours.9 Patients are at highest risk at the initiation of a particular treat-
ment regimen, whether it is for newly diagnosed or relapsed disease, when tumor
burden is highest or tumor is naive to a particular cytotoxic agent. Clinical judgment
should guide management on an individualized basis.

How and when should hyperkalemia, hypophosphatemia, and hypocalcemia be

treated?
Rigorous and continuous maintenance of phosphorus and calcium hemostasis is
important. A phosphate binder should be started if phosphate levels are abnormally
high. Aluminum hydroxide or sevelamer hydroxide is recommended rather than cal-
cium carbonate or calcium acetate. Calcium carbonate and calcium acetate may
increase calcium levels, increasing the risk of calciphylaxis. Severe hyperphosphate-
mia requires renal ultrafiltration. If the calcium-phosphorus multiple is greater than or
equal to 70 mg2/dL2, it is important to ensure that hydration is maintained and that the
nephrology service is consulted.
Hypocalcemia should not be repleted unless the patient is symptomatic. A serum
ionized calcium level rather than a simple calcium level should be measured for thor-
ough risk stratification of TLS during assessment.

When can prophylaxis be discontinued?

Prophylaxis can be discontinued after completion of cancer-targeted treatment once
uric acid, potassium, phosphorous, calcium, and creatinine levels are within normal
limits for at least 2 consecutive measurements. Patients should be monitored for at
least 24 hours after discontinuation of TLS prophylaxis.2932

When do patients need to be in an ICU?

Because TLS can progress rapidly, patients with high risk features of LTLS with or
without cardiac or renal comorbidities, and all patients with CTLS, should be managed
in an ICU (Box 5). The ICU should be notified early in the course even before TLS oc-
curs. The clinical manifestations would be emergent in the context of any underlying
cause, and require acute treatment.
Often, ICU-level care is necessary when a patients deteriorating renal function
needs to be balanced with cardiac and pulmonary fluid overload, potentially requiring
renal replacement therapy as well as intubation.

Box 5
Indications for ICU management

Patients at high risk for TLS

Patients with laboratory TLS and cardiac or renal comorbidities
Patients with clinical TLS
Patients potentially requiring renal replacement therapy

ICU consult should be obtained early in the hospital course for the indications listed here. Renal
consult should be obtained for oliguria, refractory hyperkalemia, symptomatic hypocalcemia,
calcium-phosphorus product of 70 or more, metabolic acidosis, volume overload state prevent-
ing effective diuresis without cardiopulmonary compromise, symptomatic uremia.
436 Chung & Tsyvkin

When should a renal consult be considered?

Hemodialysis may be required in patients who are oliguric or anuric, or have refractory
hyperkalemia, symptomatic hypocalcemia, or calcium-phosphorus product of
70 mg2/dL2 or more. Although dialysis usage has been reduced since the introduction
of rasburicase, as many as 5% of adult patients require this procedure.22

PERFORMANCE IMPROVEMENT
 Every hospitalized patient with cancer, especially if receiving chemotherapy,
needs to be stratified for the risk of TLS.
 There is a need to develop a standardized way to assess risk and institute guide-
lines for management.
 Low-risk patients can be monitored (fluid status, laboratory results) with a low
threshold to initiate intravenous fluids and allopurinol.
 Intermediate-risk patients should be given prophylaxis with rasburicase or up to
7 days of allopurinol along with aggressive hydration after the initiation of
treatment.
 High-risk patients should be given prophylaxis with rasburicase, along with
aggressive hydration.
 Allopurinol is useful in the prophylactic setting, but is not the drug of choice in es-
tablished TLS except in the presence of G6PD deficiency or allergy to
rasburicase.
 The management of established TLS requires a multidisciplinary approach with
involvement of oncologists, nephrologists, and intensive care physicians.

CLINICAL GUIDELINES

No formal society has published guidelines for TLS. Advice exists from expert
panels.9,19

REFERENCES

1. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and
classification. Br J Haematol 2004;127(1):311.
2. Ejaz AA, Mu W, Kang DH, et al. Could uric acid have a role in acute renal failure?
Clin J Am Soc Nephrol 2007;2(1):1621.
3. Flombaum CD. Metabolic emergencies in the cancer patient. Semin Oncol 2000;
27(3):32234.
4. Friedman M, Patel PR, Rondelli D. A focused review of the pathogenesis, diag-
nosis, and management of tumor lysis syndrome for the interventional radiologist.
Semin Intervent Radiol 2015;32(2):2316.
5. Cairo MS. Prevention and treatment of hyperuricemia in hematological malig-
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