acute tumor lysis syndrome

Acute Tumor Lysis Syndrome

Arnold Altman

A CUTE TUMOR lysis syndrome (ATLS), considered a true oncologic emergency, is

precipitated by spontaneous or chemotherapy-induced rapid lysis of malignant cells. The resultant release of intracellular products and ions into the systemic circulation exceeds the excretory capac-

ity of the kidney, producing life-threatening electrolyte abnormalities and metabolic derangements. The pathophysiology, clinical features, and predic-

tive factors for patients likely to experience ATLS are described below.

Patients with large tumor burdens and/or rapidly

proliferating malignancies exquisitely sensitive to chemotherapy or radiation typically are at greatest risk for ATLS. Release of massive amounts of potassium, phosphate, and uric acid quickly ensues following exposure to cytotoxic therapy.1-3 Malig-

nant lymphoid cells, in particular, are thought to contain four times the amount of phosphate in comparison to their mature cell counterparts.4 Ly

sis of these and other tumor cells results in release of intracellular potassium and phosphate ions and leads to potentially clinically significant hyperkalemia and hyperphosphatemia and associated hy-

pocalcemia. Additionally, rapidly dividing cells contain significant amounts of nulceic acid purines. In the absence of malignant disease along with normal renal function, purine nucleic acids are catabolized to uric acid and excreted renally. In

the presence of tumors with rapidly dividing cells, nucleic acid production is much higher than normal, excretory capacity of the renal tubule is ex- ceeded, and hyperuricemia occurs. Ultimately, pa-

tients may develop acute renal failure either because of acute uric acid precipitation in the renal tubules and/or from severe hyperphosphatemia/hypocalcemia-induced nephrocalcinosis.

PATHOPHYSIOLOGY AND CLINICAL FEATURES

Potassium

The acute redistribution of the intracellular cat- ion, potassium, into the systemic circulation may pose the first life-threatening abnormality in ATLS (Table 1). Hyperkalemia can occur within 6 to 72 hours of initiation of cytotoxic therapy.1 The immediate concern is the depressant effects

Seminars in Oncology, Vol 28, No 2, Suppl 5 (April), 2001: pp 3-8

on the cardiac conduction system leading to ven- tricular arrhythmias, syncope, and sudden death. Despite the awareness of ATLS and its etiology, cardiac fatalities continue to be reported.5 Rigor-

ous serum potassium monitoring should routinely take place along with evaluation for clinical symptomatology such as muscle weakness, lethargy, and paresthesias. Common electrocardiographic

changes include peaked T-waves and QRS widening. Immediate correction of hyperkalemia with routine treatment modalities is essential.

A phenomenon known as pseudohyperkalemia has been described. This is an artificial increase in potassium caused by cell lysis after blood draws in patients with elevated white blood cell and plate-

let counts. In these circumstances, it is recommended to follow plasma potassium versus serum levels. Also, it should be noted that electrocardiographic changes are absent in pseudohyperkalemia.6

Phosphate and Calcium

Tumor lysis with release of phosphate from intracellular stores may result in profound hyperphosphatemia, subsequent hypocalcemia, and hyperphosphaturia. Precipitation of calcium phos-

phate in soft tissues is the primary cause of hy pocalcemia. It is also thought hypocalcemia may be caused by inadequate production of 1,25-dihy- droxyvitamin D3 (calcitriol). Calcitriol deficiency

may play a role in sustained hypocalcemia in ATLS.7 Phosphate and calcium metabolic alter- ations may occur within 24 to 48 hours of the start of chemotherapy.* Ultimately, acute renal failure

resulting from precipitation of calcium phosphate crystals in the renal tubules (acute nephrocalcinosis) may occur.1T3 Both serum phosphate and cal-

cium should be routinely monitored at baseline and frequently postcytotoxic therapy. In addition

From the Department of Hematolog-y/Onc&gy , Connecticut Chik dren’s Medical Center, Hartford, CT.

Address reprint requests to Arnold A&an, MD, Department of Hematology/Oncology, Connecticut Children’s Medical Center, 282 Washington St, Hmtfwd, CT 06106.

Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2802-0502$35.00/O doi:10.1053/sonc.2001.21181

4 ARNOLD ALTMAN

Abnormality Laboratory Parameters* Symptomatology

Hyperkalemia

Hyperphosphatemia

Hypocalcemia

Hyperuricemia

Renal failure

Within first 6-72

hours of therapy

24-48 hours

24-118 hours

24-I8 hours

48-72 hours

>6.0 mEq/L

> IO mg/dL

<6 mg/dL

> IO mg/dL

Elevated blood urea nitrogen/

creatinine (2 times baseline)

Lethargy, muscle weakness, paresthesia,

electrocardiogram changes (QRS

widening), bradycardia, lethal cardiac

arrhythmias, syncope, sudden death

Oliguia, anuria, azotemia, acute renal

failure, exacerbation of pre-existing

renal compromise

Muscle cramps, tetany, paresthesias,

cardiac arrhythmias, syncope, sudden

death, seizures

Nausea, vomiting, lethary, acute uric

acid nephropathy, renal failure

Oliguria, uremia-induced nausea,

vomiting and lethargy, fluid overload-

induced hypertension, congestive

heart failure, seizures

+ Laboratory parameters at which immediate action should be taken.

Data from Flombaum’ and Zusman et a1.s

to parameters indicating acute renal compromise, symptomatology of decreased calcium levels in-

cluding muscle cramps, tetany, cardiac arrhythmias, and seizures should be further evaluated.

Uric Acid

Hyperuricemia is common in ATLS and is the single greatest clinical finding in patients with the

syndrome who ultimately develop acute renal failure. 2 In particular, neoplasms such as leukemias and lymphomas have a high nucleic acid turnover.

High cell turnover or lysis results in excess production of purines. These purine nucleotides are catabolized in the liver through oxidation of hypoxanthine and xanthine to the end product, uric acid (Fig 1). Patients are considered hyperuricemic when the serum uric acid concentration exceeds 7

to 8 mg/dL. At this level or greater, plasma sodium urate is saturated. In the urine, sodium urate is protonated and converted to uric acid. As the uric acid becomes less ionized, it in turn becomes less soluble.3 Uric acid is relatively insoluble at urinary acidic pH, and, thus, will crystallize. Acute uric acid nephropathy and subsequent renal failure may develop secondary to uric acid crystals in the distal tubules, collecting ducts, and renal parenchyma. Typically, elevating urine pH will improve the solubility of uric acid, however, caution must be

exercised as urinary alkalinization may conse-

quently decrease the solubility of phosphate and hypoxanthine.

One theoretical concern of elevated uric acid is the potential for inhibition of antitumor response from chemotherapy. In vitro, urate inhibits doxorubicin-induced DNA damage.9 Therefore, a log

ical but unanswered concern is the potential for hyperuricemia to compromise antitumor efficacy of doxorubicin.

Renal Failure

Acute renal failure in ATLS can be attributed

to uric acid precipitation in the urine and subsequent acute uric acid nephropathy. Hyperphos- phatemia-induced calcium phosphate precipitation in the renal tubules also may be implicated as a primary cause of acute renal failure in the patient with ATLS.’

The presence of pre-existing volume depletion has been noted to be a factor in the development of acute renal compromise as well.3 Finally, it has been estimated that up to two thirds of patients with pre-existing renal dysfunction experiencing ATLS will ultimately develop acute renal failure. Chemotherapy will further predispose this patient population to acute renal failure.lO

ACUTE TUMOR LYSIS SYNDROME

OH

I I OH

I OH

,/\ N I I I

I ;-Cm, ’ Xanthine

/ Oxidase

Xanjhine . ~“c’~Y{CvoH

Oxidase I 1

\ I /

H I H I \

I H H

HYPOXANTHlNE URIC ACID

CHYDROXYPYRAZOLO PYRIMIDINE 4,6-DIHYDROXYPYRAZOLO PYRIMIDINE

(ALLOPURINOL) (OXIPURINOL)

Fig I. Final steps in purine degradation pathway to uric acid are mediated by xanthine oxidase. Allopurinol is converted to oxipurinol by the action of xanthine oxidase. Oxipurinol binds tightly to xanthine oxidase and blocks the conversion of hypoxanthine

and xanthine to uric acid.

PATIENTS AT RISK

Neoplastic Diseases

Individuals at greatest risk for the development of ATLS are primarily those with hematologic malignancies with high proliferative fractions and large tumor burdens. A landmark report charac- terizing ATLS in Burkitt’s Lymphoma was the first to formalize the syndrome.ll Since that time, the occurrence of ATLS in other hematologic malig nancies has been well described, in addition to individual cases with solid tumors (Table 2). Al- though the precise incidence is not well defined, it is clear that of the hematopoietic malignancies, ATLS is most commonly associated with

Burkitt’s Lymphoma followed by other non- Hodgkin’s lymphomas, acute, and chronic leukemias.12113

Overall, occurrence with solid tumors is relatively rare and limited to individual case reports. At the present time, of the solid tumor types, ATLS precipitated by small cell lung cancer, breast carcinoma, and neuroblastoma have ap- peared in the literature with a frequency greater than a single case report.‘4-‘7 Otherwise, descrip- tions of solid tumor-induced cases are primarily limited to isolated case reports and include metastatic medulloblastoma,18 rhabdomyosarcoma,lg vulvar carcinoma,zO ovarian carcinoma,21 thy-

Table 2. Neoplastic Diseases Associated With Acute Tumor Lysis Syndrorne’,*,‘*-24.26,35

Hematological Malignancies Solid Tumors

Burkitt’s Lymphoma

Lymphoblascic Lymphoma

Acute Lymphocytic Leukemia

Chronic Lymphocytic Leukemia

Small Cell Lung Cancer

Breast Carcinoma

Neuroblastoma

Metastatic Medulloblastoma

Metastatic Melanoma

Metastatic Seminoma

Ovarian Cancer

Rhabdomyosarcoma

6 ARNOLD ALTMAN

moma,zz soft tissue sarcomas,23 Merkel cell carcinoma.24 and metastatic seminoma.15

Drug--Induced Acute Tumor Lysis Syndrome

Chemotherapy and other various drug therapies, most notably corticosteroids, have been associated with ATLS (Table 3).25-34 As more active chemo- therapeutic regimens and immunotherapies be-

come available for the management of solid tumors, previously untreatable malignancies are becoming highly responsive to treatment and sub- ject to the same concerns and precautions seen

with the highly proliferative hematopoietic diseases, specifically tumor lysis syndrome.35 A recent literature review conducted by Yang et a136 evaluated immunotherapy-induced ATLS. To date,

only rituximab and interferon alpha have been reported to cause ATLS when used as mono- therapy. Interestingly, ATLS only occurs following the first dose of rituximab with no recurrence

following subsequent doses. Thus, tumor lysis syndrome prophylaxis should be considered before initiation of rituximab therapy in lymphoprolifera- tive disorders such as high-grade non-Hodgkin’s lymphoma. While it has been recommended to consider decreasing the initial dose of rituximab by greater than 90% to 31.25 mg/m2 in patients at

high risk of ATLS (eg, chronic lymphocytic leukemia patients with lymphocyte counts greater than 5 to 10 x 109/L), this only delays the onset

and lessens the severity of ATLS. Also, it is not known whether a dose reduction may be accom- plished without a compromise in efficacy and/or

clinical outcomes.36

1 Chemotherapy Immunotherapy Other I

Amsacrine Interferon alpha Corticosteroids

Cisplatin Interleukin-2 Tamoxifen

Monoclonal antibody

Cladribine R24

Cytosine Tumor necrosis

arabinoside factor alpha

Etoposide Rituximab

Fludarabine

lntrathecal

methotrexate

Paclitaxel

Extensive disease (large tumor mass)

Increased lactate dehydrogenase levels (> I500 U/L)

Advanced disease with abdominal involvement

Pre-existing volume depletion

Pre-existing renal dysfunction

Post-treatment acute renal failure

Acidic urine

Concentrated urine

Young (age < 25 yr)

Male

Data from Flombaum,’ Arrambide and Toto,l and Harrison’s

Principles of Internal Medicine6

Radiation

Radiation as part of the preparative regimens for

bone marrow transplantation regimens as well as splenic irradiation has been associated with ATLS.37Ja

Other

Case reports describing surgery-induced ATLS are reported39 as well as one case precipitated by a prolonged episode of fever.4O Acute spontaneous tumor lysis syndrome, ATLS unrelated to chemo-

therapy, steroids, or radiotherapy, also have been documented.4l

Clinical Status of Patient

Numerous clinical risk factors have been asso-

ciated with an increased risk for ATLS (Table 4). Because renal clearance is a primary mechanism for excretion of uric acid, phosphate, and potassium, it is not unforeseen that pre-existing renal dysfunction will predispose the patient to ATLS as does post-chemotherapy induced renal compro-

mise. 123 Also, acidic urine and concentrated urine are implicated3 in increasing the risk of ATLS.

Factors relating to tumor size and involvement are predictive as well. In general, advanced disease with large tumor masses and abdominal involvement, typically accompanied by elevated lactate dehydrogenase levels impose a greater risk of ATLS the patient. 113 However, cases have been reported in patients with no evidence of bulk disease.42

ACUTE TUMOR LYSIS SYNDROME 7

SUMMARY

The electrolyte abnormalities and metabolic derangements associated with ATLS are a serious consequence in patients with both hematologic malignancies and solid tumors. While concern is primarily for those with highly proliferative he-

matopoietic disorders following treatment with exquisitely responsive chemotherapy, the practi- tioner should consider ATLS a potential conse-

quence for any patient with a neoplastic disease. Vigilant monitoring and appropriate therapy for patients with laboratory parameters and/or clinical symptomatology suggestive of ATLS should be instituted without delay. Aggressive therapeutics

and monitoring may avert serious consequences, and in some cases, fatalities, resulting from this true oncologic emergency.

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acute tumor lysis syndrome

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