Management of Acute Tumor Lysis Syndrome

Stephen Sallan

A CUTE TUMOR lysis syndrome (ATLS) is a well recognized oncologic emergency. Rapid

release of cellular constituents into the systemic circulation yields electrolyte abnormalities and

metabolic derangements.lJ Typically seen in pa- tients with large tumor burdens and/or highly proliferative malignancies,3 toxic concentrations

of potassium, phosphate, and uric acid can en- sue following chemotherapy114 and/or radiation.5 Acute tumor lysis syndrome also may occur spon- taneously6 or may result from nonchemotherapeu- tic drug-induced causes.7 The syndrome consists of

hyperkalemia, hyperphosphatemia, and subse- quent hypocalcemia. Hyperuricemia can result be- cause of accelerated purine catabolism with the

production of uric acid exceeding the excretory capacity of the renal tubules. Acute renal failure

WW 1s a rimar concern resulting from urate P Y nephropathy and/or calcium phosphate deposi-

tion. Additionally, hyperkalemia- and/or hypocal- cemia-induced fatal cardiac arrhythmias have been reported.8 The consequences of ATLS are

severe and deleterious to the patient. Therefore, prevention of ATLS is paramount. Strategies for prevention of ATLS, as well as treatment regimens to counteract the potential electrolyte abnormal-

ities and metabolic derangements should they oc- cur, are subsequently described. Since its early description and characterization, prevention of ATLS has become the cornerstone of manage- ment. Early preventative therapies have shown an improvement in decreasing the morbidity and

mortality associated with ATLS.9

PREVENTION

Identification of Patients at Risk

Patients with large tumor burdens and/or rapidly

dividing tumors are at greatest risk for ATLS. Acute tumor lysis syndrome has been most com- monly associated with Burkitt’s and other high- grade non-Hodgkin’s lymphomas and with the acute and chronic leukemias.3JO Although re- ported to occur with solid tumors, the incidence is

relatively rare.11 Patients with highly differenti- ated hematologic malignancies should be the pri* mary group targeted as high risk and should un- dergo intense scrutiny for additional risk factors predisposing them to ATLS.

Seminars in Oncology, Vol 28, No 2, Suppl 5 (April), 2001: pp 9-12

Minimi~ing/Eliminabng Risk Factors

In addition to identifying patients at risk, it is

also essential to minimize or eliminate any modi-

fiable risk factor (Table 1). These measures should

be instituted before chemotherapy or radiation.

Clinical patient characteristics such as pre-exist-

ing renal disease and/or volume depletion have been linked with an increased likelihood of ATLS.

While renal dysfunction is not a “correctable” risk,

factors that may affect renal function and further

aggravate renal compromise should be carefully

evaluated and minimized or removed where possi-

ble. Therapeutic alternatives to known nephro-

toxic agents, such as aminoglycoside antibiotics,

amphotericin B, non-steroidal anti-inflammatory

drugs, should be considered before initiation of

chemotherapy and/or radiation therapy in the high

risk patient. Volume status should be assessed and

patients intensively hydrated where appropriate.

Another preventative measure is to carefully

examine existing therapies for the potential to contribute to electrolyte abnormalities experi-

enced in ATLS and/or agents that might compro-

mise renal secretion of uric acid and further accel-

erate hyperuricemia.

Hyperkalemia, for example, may be exacerbated

by concomitant administration of exogenous po-

tassium sources such as dietary intake, oral supple-

ments, enteral and parenteral nutrition. Coadmin-

istration of drugs known to interfere with

aldosterone may further intensify the potential for hyperkalemia. When possible, potassium-sparing

diuretics such as amiloride, triamterene, or spi-

ronolactone should be avoided. Also the angioten-

sin converting enzyme inhibitors,‘2 the angioten-

sin II receptor blockers,13 and heparinl4 have all

been reported to cause hyperkalemia. The use of

From the Department of Pediatic Oncology, Dana Farber Can- cer Center, Boston, MA.

Address reprint requests to Stephen Sal& MD, Department of Pediatric Oncology, Dana Farber Cancer Center, 44 Binney St, Boston, MA 02115.

Copyright 0 2001 by W.B. Saunders Company 0093.7754/01/2802-0503$35.00/O doi:10.1053/sonc.2001.2ll83

9

IO

Renal Function

Correct volume depletion

Avoid concomitant administration of known nephrotoxins

(eg, aminoglycosides, amphotericin B, nonsteroidal anti-

inflammatory agents)

Potassium

Evaluate patient for excess exogenous potassium sources

(ie, diet, oral supplements, enterallparenteral nutrition)

Avoid concomitant administration of agents know to

interfere with aldosterone (eg, sprironolactone,

triamterene, angiotensin converting enzyme inhibitors,

heparin)

Phosphate

Evaluate patient for excess exogenous phosphorous

sources (ie. diet, oral supplements, enterallparenteral

nutrition)

Uric Acid

Alkalinize to promote uric acid solubility

Avoid drugs that block tubular reabsorption of uric acid

(eg, probenicid, aspirin, thiazides)

Administer allopurinol to inhibit uric acid formation from

purine catabolism

these medications should be minimized and avoided where appropriate.

As with potassium, exogenous sources of phos- phate (dietary intake, enteral and parenteral nu- trition) can contribute to hyperphosphatemia as- sociated with ATLS.

Finally, drugs that block the tubular reabsorp-

tion of uric acid should be avoided. These agents promote renal excretion of uric acid decreasing its solubility and increasing the risk of renal calculi.

These uricosuric agents such as probenecid, sulfin- pyrazone, aspirin, radiocontrast agents,l and thia- zide diuretics are not recommended for concomi- tant use and should be eliminated from medication regimens when possible.

Preventative Treatment Regimens

While it is crucial to minimize or eliminate conditions that may impose a greater risk of ATLS to the patient, prophylactic treatment regimens consisting of intensive hydration, urinary alkalin- ization, and allopurinol have reduced the magni-

tude and severity of ATLS (Table 2).9 In partic- ular, hyperuricemia is a target and its incidence is significantly reduced with prophylactic treatment

STEPHEN SALLAN

regimens of fluids, urine alkalinization, and allo- purinol.

Standard supportive care guidelines at the Dana

Farber Cancer Institute and Children’s Hospital (Boston, MA) for patients with lymphoma and leukemia from the time of admission and suspected diagnosis include: hydration with D5W in 0.5 nor-

mal sodium bicarbonate at 3 L/m’/d and allopuri- no1 (200 to 400 mg/m2/d) at least 12 to 24 hours before the initiation of chemotherapy. Intravenous allopurinol (versus oral) is preferred. Intravenous

administration is mandatory if there is any evi- dence of vomiting or abnormal gastrointestinal absorption. Forced diuresis with furosemide also

may be used to maintain urine flow and may be needed in patients with pre-existing renal compro- mise. In these patients, care should be taken to avoid fluid retention and intravascular volume overload. Furosemide also may be beneficial in

preventing hyperkalemia by increasing urinary po- tassium excretion.15 Intensive prophylactic regi- mens such as these have decreased the incidence

of hyperuricemia and ATLS alike. Prophylactic dialysis has been studied on a lim-

ited basis, specifically with continuous arterio- venous hemofiltration (CAVH) before induction chemotherapy. In one high risk, undifferentiated

lymphoblastic lymphoma patient, prophylactic con- tinuous arteriovenous hemofiltration prevented hyperuricemia, hyperphosphatemia, and renal fail- ure.16 It has been suggested that preventative di-

Hydration

D5W 0.5 normal saline at 3 Um’ld to maintain urine flow

> I50 to 200 mL/hr

Alkalinization

50 to IO0 mEq sodium bicarbonate per liter fluid to

maintain urine pH > 6.5 to 7.0

Allopurinol

200 to 400 mg/m*/d intravenous* or oral

Forced Diuresis

Furosemide: 20 to IO0 mg intravenous pyelogram or I to 2

mglkg intravenous every 6 to 8 h if urine flow is not

achieved by hydration alone

Mannitol: 0.5 g&kg intravenous every 6-8 h if urine flow is

not achieved by hydration + furosemide

* Intravenous allopurinol is recommended if there is any evi-

dence of vomiting or abnormal gastrointestinal absorption.

MANAGEMENT OF ACUTE TUMOR LYSIS SYNDROME

alysis may be a consideration for the patient at high risk of ATLS with pre-existing renal compro-

mise and hyperkalemia. However, the risk versus benefit including cost effectiveness has not been formally evaluated.

While the incidence and severity of ATLS has markedly decreased with the intensive preventa-

tive strategies and prophylactic treatment regi- mens, it is essential to monitor patients considered high risk, especially during initial course(s) of treatment. Routine studies such as serum potas-

sium, phosphate, uric acid, blood urea nitrogen, and creatinine should be regularly monitored. The primary goals of therapy are to prevent or rapidly

correct electrolyte abnormalities and associated metabolic disorders and to prevent renal failure.

TREATMENT

Hyperkalemia

Mild hyperkalemia (potassium < 6.0 mEq/L)

can usually be managed with sodium poystytrene. Sodium poystytrene, a cation exchange resin, causes the release of sodium in place of other cations and can be administered orally or via a

rectal retention enema. In general, the effects are not immediate, and thus, sodium poystytrene should not be used for acute toxicities such as life-threatening cardiac arrhythmias. Calcium glu-

conate may be used for severe cardiac toxicities. In general, calcium gluconate, lo%, 10 to 30 mL is infused over 1 to 5 minutes. While cardiac protec- tion may be immediate, the effects are transient and should be used only in those patients with

significant electrocardiographic changes. Also, calcium will not correct any underlying abnormal- ity caused by elevated potassium. Other treatment

modalities for severe hyperkalemia with or without electrocardiographic changes include hypertonic glucose and insulin, loop diuretics, and bicarbon- ate. Hypertonic glucose and insulin will shift po- tassium from the extracellular to the intracellular space. Sodium bicarbonate shifts potassium intra-

cellularly and a slight alkalinization favors distal tubule secretion as well. Loop diuretics promote potassium excretion.

Hyperphosphatemia/Hypocalcemia

Phosphate binders such as the aluminum antac- ids will decrease the gut absorption of phosphate. Generally, 30 mL of aluminum hydroxide or alu-

I I

minum carbonate at 30 mL four times daily is used. Usually treatment of hyperphosphatemia will self correct any related hypocalcemia. Calcium itself should not be administered as it may precipitate

metastatic calcifications.

Hyperuricemia

Hyperuricemia is best managed by prevention; however, treatment of elevated uric acid levels is

similar to prophylactic measures. Intensive intra- venous hydration to maintain good urine outflow is essential in ensuring urine volume greater than

3 L/d. Alkalinization with sodium bicarbonate will favor ionization of uric acid to maximize solubility. Generally, intravenous sodium bicarbonate 100 mEq/d will maintain a urine pH of greater than

7.5, enhancing uric acid solubility. Caution should be exercised not to overly alkalinize patients as elevated urinary pH may decrease the solubility of phosphate complexes leading to massive phos- phate crystalluria and subsequent precipitation of

phosphate.17 The formation of uric acid, the final product in the oxidation of purine nucleotides, is dependent on the enzyme, xanthine oxidase. Al- lopurinol, an inhibitor of xanthine oxidase, should

be administered at dosages ranging from 300 mg to 800 mg daily (200 to 400 mg/m2/d).

Urate oxidase is a nonhuman proteolytic en- zyme that oxidizes human uric acid to allantoins. Allantoins are highly soluble at urinary pH. Com- mercially available in Europe, urate oxidase has

been shown to be efficacious in rapidly decreasing serum levels of uric acid with associated diuresis.18 A recombinant DNA version is currently in clin-

ical trials which appears to be well tolerated and potent as a uricolytic agent.19 The primary advan- tage of urate oxidase is its rapid onset of action. The primary disadvantage is the paucity of data in

the preventative or prophylactic setting. It is cur- rently not available within the United States and further studies are needed to determine its precise role in the management of ATLS.

The availability and routine use of prophylactic allopurinol has markedly reduced the incidence of ARF resulting from acute uric acid nephropathy. Significant hyperphosphatemia with subsequent metastatic intrarenal calcification is often the

more frequent etiology of ARF in ATLS.15 Vol- ume expansion with hydration and forced diuresis

12 STEPHEN SALLAN

has also played a critical prophylactic role in the prevention of ARF caused by hyperuricemia.za

Despite these prophylactic efforts, hemodialysis should be considered for every patient in whom

uric acid, phosphate and/or potassium are exces- sively high, and in those with ARF to control volume and manage uremia.4 In this clinical set- ting, intravenous allopurinol might prevent hyper-

uricemia, subsequent acute uric acid nephropathy, and dialysis in a subset of patients unable to tol- erate oral dosage forms.

Dialysis is indicated when other intensive ther- apeutic measures to correct electrolyte abnormal- ities and establish adequate urinary flow are un- successful. Early dialysis with onset of oliguria is generally justified because the duration of oliguria before dialysis generally determines the length of

postdialysis change. Data comparing the various dialytic modalities

(hemodialysis, peritoneal and continuous hemofil- tration) are lacking. In general, hemodialysis is

preferred as it can rapidly correct any life-threat- ening electrolyte changes. The duration of dialysis should be every 12 hours until renal/hepatic func- tion and urinary volume are restored.1 Also, dial-

ysis every 12 to 24 hours may be necessary in patients presenting with large phosphate bur- dens.15 Peritoneal dialysis is much less efficient than hemodialysis in correcting metabolic abnor- malities and hemodialysis affords much higher clearance rates of both uric acid and phospho-

rous.4J5 Ideally, a primary endpoint for patients at risk of

ATLS is to prevent ARF and the need for dialysis. This in turn will reduce clinical complications,

avoid delays in chemotherapy and consequent in- creased lengths of stay, and increased costs.

SUMMARY

Preventative measures are essential to success- fully avoid or minimize the severity of ATLS in the high risk patient. Certainly, prophylactic

treatment regimens consisting of hydration, alka- linization, and allopurinol play a significant role in the management of these patients. It is also critical

to carefully evaluate individuals for potential risk factors that can be modified or removed. Finally,

should clinical and/or laboratory symptomatology

develop, prompt resolution of electrolyte abnor- malities and metabolic derangements is imperative to the well being of the patient with ATLS.

REFERENCES

1. Jones DP, Mahmoud H, Chesney RW: Tumor lysis syn-

drome: pathogenesis and management. Pediatr Nephrol9:206-

212, 1995

2. Fleming DR, Doukas MA: Acute tumor lysis syndrome in

hematologic malignancies. Leukemia Lymphoma 8:315-318,

1992

3. Hande KR, Garrow GC: Acute tumor lysis syndrome in

patients with high-grade non-Hodgkin’s lymphoma. Am J Med

94:133-139. 1993

4. Arrambide K, Toto RD: Tumor lysis syndrome. Semin

Nephrol 13:273-280, 1993

5. Schifter T, Cohen A, Lewinski UH: Severe tumor lysis

syndrome following splenic irradiation. Am J Hematol 60:75-

76, 1999

6. Sklarin NT, Markham M: Spontaneous recurrent tumor

lysis syndrome in metastatic breast carcinoma. Am J Clin

Oncol 18:71-73, 1995

7. Sparano J, Ramirez M, Wiernik PH: Increasing recogni-

tion of corticosteroid-induced tumor lysis syndrome in non-

Hodgkin’s lymphoma. Cancer 65:1072-1073, 1990

8. Van Der Klooster JM, Van Der Wiel HE, Van Saase JL,

et al: Asystole during combination chemotherapy for non-

Hodgekin’s lymphoma: The acute tumor lysis syndrome. Neth

J Med 56:147-152, 2000

9. Holland I?, Holland NH: Prevention and management of

acute hyperuricemia in childhood leukemia. J Pediatr 358-366,

1968

10. Razis F, Arlin ZA, Ahmed T, et al: Incidence and

treatment of tumor lysis syndrome in patients with acute leu-

kemia. Acta Haematol 91:171-174, 1994

11 I Drakos I’, Bar-& J, Catane R: Tumor lysis syndrome in

nonhematologic malignancies. Am J Clin Oncol 17:502-505,

1994

12. Reardon LC, Macpherson DS: Hyperkalemia in outpa-

tients using angiotensin-converting enzyme inhibitors. Arch

Intern Med 15826-32, 1998

13. Toto R, Shultz I’, Raij L, et al: Efficacy and tolerability

of losartan in hypertensive patients with renal impairment.

Hypertension 31:684-691, 1998

14. Gonzalez-Martin G, Diaz-Molinas MS, Martinez AM, et

al: Heparin induced hyperkalemia: A prospective study. Int

J Clin Pharmacol Ther 29:446-450, 1991

15. Flombaum CD: Metabolic emergencies in the cancer

patient. Semin Oncol 27:322-334, 2000

16. Hene D, Essex-Carter A, Brocklebanck, et al: Contin-

uous arteriovenous hemofiltration in the treatment of tumor

lysis syndrome. Pediatr Nephrol 4:245-247, 1990

17. Stapleton FB, Strother DR, Roy S, et al: Acute renal

failure at onset of therapy for advanced stage Burkitt lymphoma

and B cell acute lymphoblastic lymphoma. Pediatrics 82:863-

869, 1988

18. Leach M, Parsons RM, Reilly JT, et al: Efficacy of mate

oxidase (Uricozyme) in tumour lysis induced mate nephropa-

thy. Clin Lab Haematol 20:169-172, 1998

19. Mahmoud HH, Leverger G, Patte C, et al: Advances in

the management of malignancy-associated hyperuricemia. Br J

Cancer 77:18-20, 1998 (suppl 4)

20. Stokes DN: The tumor lysis syndrome. Anesthesia 44:

133-136, 1989