Tumor Lysis Syndrome Treatment & Management

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. ^{[24, 25, 26]} (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 (see Overview/Etiology.)

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 condition’s 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. ^[27]

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.

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 acute kidney injury. ^[28] It is usually given orally at 600 mg daily for prophylaxis and 600-900 mg daily (up to a maximum of 500 mg/m² 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 kidney 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. ^{[29, 30, 31, 32]} 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. ^{[33, 34]} 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. ^[35] A study by Nauffal in 92 adult patients wtih tumor lysis syndrome found that uric acid levels normalized in 95% of patients after a single 6-mg dose of rasburicase. ^[36]

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. ^[4] Initial studies suggested that febuxostat is effective and safe for preventing tumor lysis syndrome. ^[37]

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 preservation of kidney function 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 mg h/dL for febuxostat versus 708.0 ± 234.42 mg h/dL for allopurinol (P< 0.0001). ^[38]

In a Japanese phase III trial comparing febuxostat with allopurinol for prevention of thyperuricemia in 100 patients with malignant tumors receiving chemotherapy, febuxostat was non-inferior to allopurinol. No differences in safety outcomes with either medication was noted. ^[39]

Febuxostat is much more expensive than allopurinol. However, in patients with kidney 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. ^{[4, 40]}

Ito et al point out that inhibition of xanthine oxidase by febuxostat can cause accumulation of xanthine and urinary excretion of xanthine crystals. They report three cases in which xanthine crystals appeared in the urine of patients with hematologic malignancies who received febuxostat for prophylaxis during tumor lysis syndrome; the crystals were noted when yellowish and pinkish deposits were observed in urinary tract catheters and urine bags. The authors recommend careful observation and management to avoid xanthine nephropathy in this setting. ^[41]

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.

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.

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.

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.

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.

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. High-risk features for tumor lysis syndrome include the following ^[9] :

• Hematologic malignancies strongly associated with tumor lysis syndrome (eg, Burkitt lymphoma, lymphoblastic lymphoma, occasional cases of diffuse large B-cell lymphoma, chronic lymphocytic leukemia)
• Spontaneous tumor lysis syndrome
• Elevated white blood cell count
• Bone marrow involvement
• Pre-existing hyperuricemia
• Kidney disease or kidney involvement by tumor

Treatment of tumor lysis syndrome centers on the following ^[9] :

• 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 2–3 days prior to chemotherapy and continued for 10–14 days. Febuxostat may be used in patients intolerant to allopurinol.

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

The NCCN notes that a single dose of 3–6 mg of rasburicase is frequently adequate. Redosing should be individualized. ^[9]

Guidelines from the British Committee for Standards in Haematology (BCSH) include the following recommendations for prevention of tumor lysis syndrome ^[10] :

• 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

BCSH recommendations on the use of rasburicase for prevention are as follows ^[10] :

• 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.