Lisis Tumoral
Lisis Tumoral
Lisis Tumoral
review article
current concepts
T
From the Department of Oncology and he tumor lysis syndrome is the most common disease-related
International Outreach Program, St. Jude emergency encountered by physicians caring for children or adults with
Children’s Research Hospital (S.C.H.,
C.-H.P.), and the Department of Pediatrics, hematologic cancers.1-4 Although it develops most often in patients with
University of Tennessee Health Sciences non-Hodgkin’s lymphoma or acute leukemia, its frequency is increasing among
Center, College of Medicine (S.C.H., D.P.J., patients who have tumors that used to be only rarely associated with this compli-
C.-H.P.) — both in Memphis. Address re-
print requests to Dr. Howard at St. Jude cation.5-8 The tumor lysis syndrome occurs when tumor cells release their contents
Children’s Research Hospital, 262 Danny into the bloodstream, either spontaneously or in response to therapy, leading to
Thomas Place, Barry-Longinotti Bldg., the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia,
MS 721, Memphis, TN 38105-2794, or at
[email protected]. and hypocalcemia.1-3 These electrolyte and metabolic disturbances can progress to
clinical toxic effects, including renal insufficiency, cardiac arrhythmias, seizures,
This article was updated on August 23, and death due to multiorgan failure.
2018, at NEJM.org.
Although optimal methods of risk classification and treatment have been dif-
N Engl J Med 2011;364:1844-54. ficult to define, uniform standards for management of the tumor lysis syndrome
Copyright © 2011 Massachusetts Medical Society. are beginning to evolve. Indeed, several groups have advocated guidelines for risk
stratification and made recommendations for evaluating risk and for prophylactic
therapy for the tumor lysis syndrome.2,9 This review of the tumor lysis syndrome
summarizes current strategies for risk assessment, prophylaxis, and therapy. The
following case illustrates the clinical challenges.
C a se r ep or t
* In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be present during the same 24-hour
period within 3 days before the start of therapy or up to 7 days afterward. Clinical tumor lysis syndrome requires the
presence of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or death.
† The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × (4 − albumin
in grams per deciliter).
‡ Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 μmol per liter)
or a period of oliguria lasting 6 hours or more. By definition, if acute kidney injury is present, the patient has clinical
tumor lysis syndrome. Data about acute kidney injury are from Levin et al.11
acid and has low solubility regardless of urine pH, ability of patient cohorts and lack of standard cri-
can lead to xanthine nephropathy or urolithiasis teria have contributed to a wide range of reported
(Fig. 1).20,27 incidences (see Table 1 in the Supplementary Ap-
Calcium phosphate can precipitate throughout pendix, available with the full text of this article
the body (Fig. 2). The risk of ectopic calcification at NEJM.org).28 The greater the cancer mass, the
is particularly high among patients who receive greater the quantity of cellular contents released
intravenous calcium.13 When calcium phosphate after the administration of effective anticancer
precipitates in the cardiac conducting system, therapy. Cancers with a high potential for cell lysis
serious, possibly fatal, dysrhythmias can occur. include high-grade lymphomas, acute leukemias,
Acute kidney injury developed in our patient as and other rapidly proliferating tumors. However,
a result of the precipitation of uric acid crystals the potential for cell lysis must be considered
and calcium phosphate crystals and was exacer- along with the effectiveness of therapy, as high-
bated by dehydration and acidosis that developed lighted by a case of tumor lysis syndrome in an
because the tumor lysis syndrome had not been adult who died after treatment with cetuximab for
suspected and no supportive care was provided. metastatic colon carcinoma, a cancer in which the
tumor lysis syndrome had not been previously re-
Epidemiol o gy ported.5 Indeed, the tumor lysis syndrome in-
creasingly has been reported in patients with can-
The incidence and severity of the tumor lysis syn- cers that previously had been rarely associated
drome depend on the cancer mass, the potential with this complication, such as endometrial can-
for lysis of tumor cells, the characteristics of the cer, hepatocellular carcinoma, chronic lympho-
patient, and supportive care (Table 2). The vari- cytic leukemia, and chronic myelogenous leuke-
A B
Inosine Guanine
Hypoxanthine Acute
kidney injury
D Xanthine oxidase
Allopurinol Xanthine
Xanthine oxidase
Rasburicase
Allantoin Uric acid Phosphate Potassium
Figure 1. Lysis of Tumor Cells and the Release of DNA, Phosphate, Potassium, and Cytokines. COLOR FIGURE
The graduated cylinders shown in Panel A contain leukemic cells removed by leukapheresis fromDraft 12
a patient with 4/25/11
T-cell
Author Howard
acute lymphoblastic leukemia and hyperleukocytosis (white-cell count, 365,000 per cubic millimeter). Each cylinder con-
Fig # 1
tains straw-colored clear plasma at the top, a thick layer of white leukemic cells in the middle, and a thin layer of red
Title
cells at the bottom. The highly cellular nature of Burkitt’s lymphoma is evident in Panel B (Burkitt’s lymphoma of the
ME
appendix, hematoxylin and eosin). Lysis of cancer cells (Panel C) releases DNA, phosphate, potassium, Hastings
and cytokines.
DE Campion
DNA released from the lysed cells is metabolized into adenosine and guanosine, both of which are converted
Artist Knoper
into xan-
thine. Xanthine is then oxidized by xanthine oxidase, leading to the production of uric acid, which isAUTHOR
excreted by the kid-
PLEASE NOTE:
neys. When the accumulation of phosphate, potassium, xanthine, or uric acid is more rapid than excretion,
Figure has been redrawnthe tumor
and type has been reset
Please check carefully
lysis syndrome develops. Cytokines cause hypotension, inflammation, and acute kidney injury, which increase
Issue date 5/12/11 the risk
for the tumor lysis syndrome. The bidirectional dashed line between acute kidney injury and tumor lysis syndrome indi-
cates that acute kidney injury increases the risk of the tumor lysis syndrome by reducing the ability of the kidneys to
excrete uric acid, xanthine, phosphate, and potassium. By the same token, development of the tumor lysis syndrome
can cause acute kidney injury by renal precipitation of uric acid, xanthine, and calcium phosphate crystals and by crystal-
independent mechanisms. Allopurinol inhibits xanthine oxidase (Panel D) and prevents the conversion of hypoxanthine
and xanthine into uric acid but does not remove existing uric acid. In contrast, rasburicase removes uric acid by enzymati-
cally degrading it into allantoin, a highly soluble product that has no known adverse effects on health.
mia.5-8,29-32 Characteristics of patients that confer The adequacy of fluid management affects
high risk include preexisting chronic renal insuf- both the development and the severity of the tu-
ficiency, oliguria, dehydration, hypotension, and mor lysis syndrome. Thus, disastrous cases of the
acidic urine. tumor lysis syndrome occurred in patients with
A B C
2µm 100 µm
D E
nonhematologic cancer who received effective dramatic difference that supportive care can
anticancer treatment but no intravenous fluids make, even when other risk factors for the tumor
or monitoring because the tumor lysis syndrome lysis syndrome are the same.33 This was seen in
was not anticipated.5,32 In contrast, in many coun- the 8-year-old boy in the vignette.
tries, patients with a bulky Burkitt’s lymphoma
who have a high potential for lysis have a low risk R isk a sse ssmen t
of clinical tumor lysis syndrome because they
routinely receive aggressive treatment with hydra- Acute kidney injury is associated with high mor-
tion and rasburicase, a recombinant urate oxidase bidity and mortality,34 and its prevention requires
enzyme that is a highly effective uricolytic agent an awareness of the patient’s a priori risk of the
(Table 1 in the Supplementary Appendix). Chil- tumor lysis syndrome and careful monitoring for
dren with Burkitt’s lymphoma who received ras- early signs of it. Models that predict the risk of
buricase were a fifth as likely to undergo dialysis the tumor lysis syndrome have been developed for
as those who received allopurinol, illustrating the adults with acute myeloid leukemia35,36 and chil-
(e.g., phosphorus, uric acid) that can crystallize and cause nephropathy.
Acidic urine Uric acid has a lower solubility in acidic urine and therefore crystallizes more rapidly. A patient who presents
with acidic urine and hyperuricemia usually already has uric acid crystals or microcrystals in the renal tubules.
Downloaded from nejm.org at UNIV OF SO DAKOTA on September 1, 2018. For personal use only. No other uses without permission.
xanthine to uric acid. It does not remove existing uric acid and does increase urinary excretion of xanthine,
which can crystallize and cause nephropathy. Rasburicase is an enzyme that rapidly removes uric acid by
converting it to allantoin, which is highly soluble and readily excreted in the urine. The longer the uric acid
level remains high, the greater the risk of crystal formation and acute kidney injury.
1849
The n e w e ng l a n d j o u r na l of m e dic i n e
Measure serum potassium, phosphorus, calcium, creatinine, uric acid, and urine output
Assess patient
presentation
Preexisting nephropathy
Dehydration
Acidosis
Hypotension
Nephrotoxin exposure
No Yes
ter (3.3 mmol per liter) in the allopurinol group creases in phosphorus levels and decreases in
(and mean uric acid levels decreased by 12%, to creatinine levels among 131 patients who were at
5.7 mg per deciliter [339.0 μmol per liter] at 48 high risk for the tumor lysis syndrome and were
hours).41,42 The serum creatinine level improved treated with rasburicase. Finally, in a multicenter
(decreased) by 31% in the rasburicase group but study involving pediatric patients with advanced-
worsened (increased) by 12% in the allopurinol stage Burkitt’s lymphoma, in which all patients
group. Pui and colleagues40 documented no in- received identical treatment with chemotherapy
and aggressive hydration, the tumor lysis syn- levels (every 4 to 6 hours), continuous cardiac
drome occurred in 9% of 98 patients in France monitoring, and the administration of oral sodi-
(who received rasburicase) as compared with 26% um polystyrene sulfonate are recommended in
of 101 patients in the United States (who received patients with the tumor lysis syndrome and acute
allopurinol) (P = 0.002).33 Dialysis was required in kidney injury. Hemodialysis and hemofiltration
only 3% of the French patients but 15% of the effectively remove potassium. Glucose plus insu-
patients in the United States (P = 0.004). At the lin or beta-agonists can be used as temporizing
time of the study, rasburicase was not available in measures, and calcium gluconate may be used to
the United States. reduce the risk of dysrhythmia while awaiting
Urinary alkalinization increases uric acid solu- hemodialysis.
bility but decreases calcium phosphate solubil- Hypocalcemia can also lead to life-threatening
ity (Fig. 1a in the Supplementary Appendix). dysrhythmias and neuromuscular irritability; con-
Because it is more difficult to correct hyper- trolling the serum phosphorus level may prevent
phosphatemia than hyperuricemia, urinary al- hypocalcemia. Symptomatic hypocalcemia should
kalinization should be avoided in patients with be treated with calcium at the lowest dose re-
the tumor lysis syndrome, especially when ras- quired to relieve symptoms, since the administra-
buricase is available.13 Whether urine alkalini- tion of excessive calcium increases the calcium–
zation prevents or reduces the risk of acute kid- phosphate product and the rate of calcium
ney injury in patients without access to rasburicase phosphate crystallization, particularly if the prod-
is unknown, but the animal model of urate ne- uct is greater than 60 mg2 per square deciliter
phropathy suggested no benefit.39 If alkaliniza- (Fig. 2D and 2E). Hypocalcemia not accompanied
tion is used, it should be discontinued when hy- by signs or symptoms does not require treatment.
perphosphatemia develops. In patients treated Despite the lack of studies that show the efficacy
with rasburicase, blood samples for the measure- of phosphate binders in patients with the tumor
ment of the uric acid level must be placed on ice lysis syndrome, this treatment is typically given.
to prevent ex vivo breakdown of uric acid by ras- The role of renal phosphate leak in renal lithiasis
buricase and thus a spuriously low level. Patients and the use of phosphate binders have recently
with glucose-6-phosphate dehydrogenase deficien- been reviewed in the Journal.48,49
cy should avoid rasburicase because hydrogen per-
oxide, a breakdown product of uric acid, can cause Management of severe acute kidney injury
methemoglobinemia and, in severe cases, hemo- Despite optimal care, severe acute kidney injury
lytic anemia.43,44 Rasburicase is recommended as develops in some patients and requires renal re-
first-line treatment for patients who are at high placement therapy (Table 3 in the Supplementary
risk for clinical tumor lysis syndrome.9 Because of Appendix). Although the indications for renal-
cost considerations and pending pharmacoeco- replacement therapy in patients with the tumor
nomic studies, no consensus has been reached on lysis syndrome are similar to those in patients with
rasburicase use in patients who are at intermediate other causes of acute kidney injury, somewhat
risk for the tumor lysis syndrome; some have ad- lower thresholds are used for patients with the
vocated use of a small dose of rasburicase in such tumor lysis syndrome because of potentially rapid
patients.45,46 Patients who are at low risk can usu- potassium release and accumulation, particularly
ally be treated with intravenous fluids with or in patients with oliguria. In patients with the tu-
without allopurinol, but they should be monitored mor lysis syndrome, hyperphosphatemia-induced
daily for signs of the tumor lysis syndrome. symptomatic hypocalcemia may also warrant di-
alysis. Phosphate removal increases as treatment
Prevention of cardiac dysrhythmias time increases, which has led some to advocate
and neuromuscular irritability the use of continuous renal-replacement therapies
Hyperkalemia remains the most dangerous com- in patients with the tumor lysis syndrome, includ-
ponent of the tumor lysis syndrome because it can ing continuous venovenous hemofiltration, con-
cause sudden death due to cardiac dysrhythmia. tinuous venovenous hemodialysis, or continuous
Patients should limit potassium and phosphorus venovenous hemodiafiltration.50 These methods
intake during the risk period for the tumor lysis of dialysis use filters with a larger pore size, which
syndrome.47 Frequent measurement of potassium allows more rapid clearance of molecules that are
not efficiently removed by conventional hemodi- and those at low risk should undergo such moni-
alysis (Table 3 in the Supplementary Appendix). toring daily. Monitoring should continue over the
One study that compared phosphate levels among entire period during which the patient is at risk
adults who had acute kidney injury that was treat- for the tumor lysis syndrome, which depends on
ed with either conventional hemodialysis or con- the therapeutic regimen. In a protocol for acute
tinuous venovenous hemodiafiltration showed that lymphoblastic leukemia, which featured up-front,
continuous venovenous hemodiafiltration more ef- single-agent methotrexate treatment,53 new-onset
fectively reduced phosphate.51 Much less is known tumor lysis syndrome developed in some patients
about the dialytic clearance of uric acid, but in at day 6 or day 7 of remission-induction therapy
countries where rasburicase is available, hyperuri- (after the initiation of combination chemother-
cemia is seldom an indication for dialysis.40,44,52 apy with prednisone, vincristine, and daunoru-
In our patient, once the tumor lysis syndrome was bicin on day 5 and asparaginase on day 6).
identified, treatment with intravenous fluids,
phosphate binders, and rasburicase prevented Decreasing the rate of tumor lysis
the need for dialysis. Despite a potassium level with a treatment prephase
of 5.9 mmol per liter, he had no dysrhythmia or Patients at high risk for the tumor lysis syndrome
changes on electrocardiography, but had he pre- may also receive low-intensity initial therapy. Slow-
sented 1 day later, the tumor lysis syndrome may er lysis of the cancer cells allows renal homeo-
have proved fatal. static mechanisms to clear metabolites before they
accumulate and cause organ damage. This strate-
Monitoring gy, in cases of advanced B-cell non-Hodgkin’s lym-
Urine output is the key factor to monitor in pa- phoma or Burkitt’s leukemia, has involved treat-
tients who are at risk for the tumor lysis syndrome ment with low-dose cyclophosphamide, vincristine,
and in those in whom the syndrome has devel- and prednisone for a week before the start of in-
oped. In patients whose risk of clinical tumor lysis tensive chemotherapy. Similarly, many groups sub-
syndrome is non-negligible, urine output and fluid scribe to a week of prednisone monotherapy for
balance should be recorded and assessed frequent- childhood acute lymphoblastic leukemia.
ly. Patients at high risk should also receive inten-
Supported in part by grants (CA21765 and U01 GM92666)
sive nursing care with continuous cardiac monitor- from the National Institutes of Health and by the American
ing and the measurement of electrolytes, creatinine, Lebanese Syrian Associated Charities.
and uric acid every 4 to 6 hours after the start of Dr. Howard reports receiving consulting fees from EnzymeRx
and Sanofi-Aventis.
therapy. Those at intermediate risk should un- Disclosure forms provided by the authors are available with
dergo laboratory monitoring every 8 to 12 hours, the full text of this article at NEJM.org.
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