The National Cancer Institute estimated in 2020 that 1,806,590 new cases of cancer would be diagnosed in the United States that year, resulting in 606,520 related deaths.1 Among the causes of cancer deaths are oncologic emergencies, which can be defined as acute events that threaten the life or health of patients with cancer, whether they result from the cancer itself or from its treatment.2 Tumor lysis syndrome is one such oncologic emergency.

Tumor lysis syndrome occurs when tumor cells rapidly break down and die, releasing their intracellular components into the bloodstream. These components often include the following3, 4:

* potassium, broken down from cytosol

* proteins

* phosphate, broken down from proteins

* nucleic acids

* uric acid, broken down from nucleic acids

PATHOPHYSIOLOGY

Normally, multiple body systems, including the kidneys, liver, muscles, and gastrointestinal tract, work together to eliminate excess amounts of potassium and other electrolytes and byproducts from the bloodstream. In tumor lysis syndrome, however, the rapid release of electrolytes and byproducts from the breakdown of tumor cells can quickly overwhelm the body's natural homeostasis mechanisms.5 As a result, three primary electrolyte abnormalities-hyperkalemia, hyperuricemia, and hyperphosphatemia-occur, as well as hypocalcemia, secondary to the hyperphosphatemia. These abnormalities can result in acute kidney injury, uremia, and systemic end-organ damage, including renal failure and liver failure, potentially causing seizures, cardiac dysrhythmias, and death.3-8

Hyperkalemia is often the first and the most potent of the electrolyte abnormalities to occur in tumor lysis syndrome. It has adverse effects on cardiac and skeletal muscles, which can lead to cardiac arrhythmias or cardiac arrest. Signs of hyperkalemia may be evident within the first 12 to 24 hours of tumor lysis syndrome.3, 4

Hyperphosphatemia and hypocalcemia usually occur simultaneously. Research has shown that phosphate levels are four times higher in cancer cells than in normal cells.4 With this elevated level of phosphate in the bloodstream, the body attempts to compensate by eliminating the excess through the kidneys.5 Excess phosphate binds to extracellular calcium, depleting the calcium supply, causing hypocalcemia, and producing calcium phosphate crystals in the renal tubules, worsening kidney injury.5, 7

Hyperuricemia occurs when nucleic acids are broken down multiple times to form uric acid; this excess uric acid is not easily excreted by the kidneys.7 Human kidneys also lack the enzyme uricase, which can transform uric acid into a more soluble form for excretion.7 When the kidneys become overwhelmed with high levels of uric acid, uric acid crystals form, which create micro-obstructions and can reduce the glomerular filtration rate.4 Hyperuricemia also causes direct kidney injury due to increased vascular resistance in the peritubular capillaries, release of proinflammatory cytokines, and increased use of nitric oxide.5

Definition and classification. Cairo and Bishop have proposed a new way of defining and classifying tumor lysis syndrome based on laboratory criteria.6 (See Table 16, 9 for Cairo and Bishop's tumor lysis syndrome criteria as compared with normal electrolyte values defined by the American Board of Internal Medicine.)

Table 1. Normal Electrolyte Values vs. Electrolyte Values Indicative of Tumor Lysis Syndrome

CLINICAL PRESENTATION

Many of the manifestations associated with tumor lysis syndrome result from electrolyte imbalances. Hyperkalemia presents the most urgent concern because of the life-threatening cardiac arrhythmias it produces. In the presence of hyperkalemia, electrocardiogram (ECG) changes often follow a characteristic pattern. When potassium levels are over 5.5 mEq/L, an initial ECG change that may be seen is a peaked, narrow-based T wave. Other changes may include a widened QRS complex, prolonged PR interval, flattening of P waves, and ST-segment depression.10-12 (See Figure 1.)

Figure 1. ECG Changes Associated with Hyperkalemia

Early recognition of the signs and symptoms of tumor lysis syndrome is important. Symptoms tend to occur within 72 hours after starting chemotherapy treatment, though a delayed presentation after 72 hours may occur.13 (For common signs and symptoms of electrolyte imbalances that occur in tumor lysis syndrome, see Table 2.5, 10-12, 14-17)

Table 2. Common Signs and Symptoms Associated with Electrolyte Abnormalities

EPIDEMIOLOGY AND RISK FACTORS

Tumor lysis syndrome can occur either spontaneously or following intervention with chemotherapy, radiation therapy, or corticosteroid therapy. While it can occur in patients with solid tumors-including breast, gastric, small cell lung, or reproductive cell tumors, such as ovarian or testicular cancers-it occurs more frequently in patients with hematologic malignancies or high-grade lymphomas.3, 18

In children, tumor lysis syndrome most often occurs in those with acute myeloid leukemia; acute lymphoblastic leukemia (ALL); and non-Hodgkin lymphoma, especially Burkitt lymphoma.19

Risk of tumor lysis syndrome varies with the underlying cancer type and specific patient characteristics, including age, hydration status, and kidney function.

Patient characteristics associated with tumor lysis syndrome risk:

* male sex5

* advanced age5

* under one year or over age 10 (in children with ALL)20

* preexisting renal dysfunction5

* dehydration8

* history of hypertension, diabetes, or gout8

* acidosis, hypotension8, 21

* elevated levels of serum creatinine, uric acid, and lactate dehydrogenase8, 21

* splenomegaly8

* central nervous system or renal involvement18

Alcohol consumption and use of certain medications, including levodopa and thiazide diuretics, worsen hyperuricemia by altering excretion of uric acid from the kidneys,22 increasing serum uric acid levels and thus the risk of developing tumor lysis syndrome.17

Cancer characteristics that raise risk. Patients at greatest risk for tumor lysis syndrome are those with a high "tumor burden,"8 or "tumor load," which the National Cancer Institute defines as "the number of cancer cells, the size of a tumor, or the amount of cancer in the body."23 A high tumor burden, for example, would include the following8, 24:

* intermediate or high cancer bulk; that is, solid cancers or lymphomas with tumors greater than 10 cm in diameter

* bone marrow involvement

* metastatic disease

* kidney involvement

* hepatomegaly

* splenomegaly

* elevated white blood cell count in acute leukemia

Treatment-related risk factors. Besides cytotoxic chemotherapy, other cancer treatments can put patients at risk for tumor lysis syndrome. These include radiation; corticosteroids; biologic agents, such as monoclonal antibodies; proteasome inhibitors; targeted therapies, such as tyrosine kinase inhibitors; immunotherapies; and proapoptotic agents, such as lenalidomide.3, 22, 25-27

TUMOR LYSIS SYNDROME INCIDENCE

Incidence rates vary widely among studies of tumor lysis syndrome, depending on the study design, case definitions used, and whether the underlying cancers studied are hematologic or nonhematologic. For patients with hematologic cancers, reported tumor lysis syndrome incidence rates have ranged from 21.1%28 to as high as 75.5%.29 In hematologic cancers of childhood, incidence rates have ranged from 4.4% to 53.6%.19

Spontaneous vs. treatment-related tumor lysis syndrome. While tumor lysis syndrome is most commonly seen after chemotherapy treatment is initiated for hematologic malignancies, there is an increasing incidence of both spontaneous and treatment-related tumor lysis syndrome in patients with solid tumors, most often in those with high-grade tumors or in an advanced stage of disease.30 Tumor lysis syndrome can occur in patients who have cancers not normally associated with tumor lysis syndrome and in those who have not yet started cancer treatment, as well as in patients whose cancer has not yet been diagnosed.3 For these reasons, spontaneous tumor lysis syndrome should be included in the differential diagnosis of patients who present with signs associated with tumor lysis syndrome, such as acute kidney injury and electrolyte abnormalities; conditions such as sepsis, medication toxicities, obstructive renal disease, or rhabdomyolysis31; or who have undergone imaging with the use of contrast dye.3

If tumor lysis syndrome is suspected, intervention should be initiated immediately to prevent further complications because spontaneous tumor lysis syndrome may be more severe than treatment-related tumor lysis syndrome, which is usually pretreated with antihyperuricemic agents to prevent a rise in uric acid.31 While the causes of spontaneous tumor lysis syndrome are not well understood, Parsi and colleagues theorize that it occurs when rapidly expanding tumors outgrow their blood supply, causing necrosis and the release of their intracellular components.32

Although fewer solid tumor patients than hematologic cancer patients develop tumor lysis syndrome, these patients have a higher mortality rate (36%) than patients with hematologic malignancies (15%).32 This may be attributed to delayed treatment as a result of failure to anticipate tumor lysis syndrome development in this patient population. It may also be attributed to failure to recognize patient- and cancer-specific tumor lysis syndrome risks.

It's important for nurses to be aware of both patient and cancer characteristics that put patients at elevated risk for tumor lysis syndrome and to closely observe patients for early signs and symptoms of the condition, which are both subtle and common in oncology patients, and include nausea, vomiting, dyspnea, fatigue, muscle spasm, and paresthesia.5, 11

Awareness of tumor lysis syndrome risk factors, initial signs and symptoms, and time of symptom onset can help nurses differentiate tumor lysis syndrome from other causes. While early signs and symptoms may be evident within a few hours after chemotherapy is started, they more commonly occur 24 to 48 hours following its initiation.18

PREVENTION: NURSING MANAGEMENT OF AT-RISK PATIENTS

Nurses should measure electrolytes, creatinine, and uric acid and evaluate the results every six to eight hours after initiation of cancer treatment. Preventive measures should also include monitoring of patient status, laboratory values, renal function, and response to prescribed medications every eight to 12 hours for patients at intermediate risk, every six to eight hours for patients at high risk, and every four to six hours for patients with tumor lysis syndrome on presentation.19

In children at high risk for tumor lysis syndrome, low-dose corticosteroid monotherapy may be prescribed prophylactically to reduce risk of kidney damage.33

Nurses should monitor prescribed therapies and educate patients and caregivers on any risks associated with their use and with tumor lysis syndrome, reminding them to report any new symptoms.

Adequate hydration helps prevent kidney damage from uric acid and calcium phosphate accumulation in the renal tubules.34 Nurses should encourage patients who are able to increase their oral fluid intake to 1.5 to 2 L daily.27 Hospitalized patients generally receive IV hydration.

In adults, the goal of hydration is to maintain a urine output of at least 3 L/day or more than 100 mL/hr.27 For children, the National Comprehensive Cancer Network guidelines recommend hyperhydration with IV fluids, targeting a urine output of 2 mL/kg/hr.33 Unless the patient's potassium level is low (less than 3.5 mEq/L), the hydration is usually given without potassium.

Monitoring fluid status (intake and output) is vital for preventing volume overload, especially in patients with altered renal or cardiac functioning.13 Nurses should anticipate a consult with a nephrology specialist.

TREATING TUMOR LYSIS SYNDROME AND ITS SEQUELAE

With a diagnosis of tumor lysis syndrome, treatment is usually determined by the severity of electrolyte disturbances and clinical symptoms. Most major cancer centers have treatment guidelines for tumor lysis syndrome.7 Because of the need for close monitoring of laboratory values, urine output, and cardiac function, patients should be considered for ICU or intermediate level care.7 Patients who do not respond to conventional therapies for electrolyte management and have high levels of potassium, phosphate, or uric acid should be evaluated for renal replacement therapy.18 Patients who develop acute renal failure due to tumor lysis syndrome and have volume overload, uremia, and electrolyte imbalances should also be evaluated for dialysis treatment.18 Depending on the severity of the symptoms and electrolyte imbalances, cytotoxic therapy may have to be temporarily delayed.17

Epidemiology and clinical outcomes of tumor lysis syndrome are generally understudied, but Durani and colleagues recently examined outcome data for patients with tumor lysis syndrome for trends.35 They found that in patients diagnosed with tumor lysis syndrome, overall in-hospital mortality was 21% and the median length of stay was 10 days. They also found that 69% of patients experienced a severe complication such as sepsis, dialysis, acute respiratory failure, mechanical ventilation, gastrointestinal hemorrhage, cerebral hemorrhage, seizures, or cardiac arrest.

Reducing uric acid levels. Allopurinol or rasburicase may be prescribed to reduce uric acid levels. Allopurinol is a xanthine oxidase inhibitor that may be administered orally (Zyloprim) or intravenously (Aloprim) usually at a dose of 600 to 800 mg/day. Allopurinol prevents nucleic acids released by cancer cells from transforming into uric acid.27 It should be started two to three days before chemotherapy is initiated and continued for 10 to 14 days or until there are no longer any signs of tumor lysis syndrome.36 Adverse effects of allopurinol may include a mild pruritic rash, diarrhea, leukopenia, and thrombocytopenia, though more severe hypersensitivity reactions, nephritis, and nephropathy have also been reported.27 Febuxostat (Uloric), an oral medication indicated to lower serum uric acid levels in patients with gout, may be used off label as an alternative to allopurinol in patients who have renal dysfunction or resistance to allopurinol; severe hypersensitivity reactions, such as anaphylaxis or Stevens-Johnson syndrome, can occur.27, 37

Rasburicase (Elitek) may be prescribed in patients at high risk for developing tumor lysis syndrome who require a rapid reduction in serum uric acid levels. It can reduce serum uric acid concentrations quickly and safely in both adults and children. Rasburicase should be started four to 24 hours before the initiation of chemotherapy as a 30-minute IV infusion at a recommended dose of 0.2 mg/kg and continued for up to five days or until signs of tumor lysis syndrome are no longer present.36, 38 Adverse effects include nausea and vomiting, fever, edema, headache, pharyngolaryngeal and abdominal pain, constipation or diarrhea, anxiety, low serum phosphate levels, and elevated alanine aminotransferase levels.38 Rasburicase may cause a severe hypersensitivity reaction and should not be given to patients with a glucose-6-phosphate dehydrogenase deficiency.13, 38

Treatment of acute hyperkalemia generally employs the following three strategies10:

* stabilize the threshold of cardiac depolarization

* shift the potassium back into the cells

* support potassium elimination

These treatment strategies usually involve use of hemodialysis and the following agents:

IV calcium gluconate can stabilize the cardiac membrane within minutes and with minimal potassium level reduction, thereby decreasing the potential for cardiac arrhythmias.39 IV calcium, however, is not without risks: both calcium gluconate and calcium chloride may exacerbate digoxin toxicity when administered intravenously and may cause soft tissue injuries if extravasation occurs, though calcium chloride is considered more likely to produce the latter in the case of extravasation.10

Insulin, glucose, and an inhaled [beta]-agonist, such as albuterol (Ventolin), can facilitate the movement of potassium back into the intracellular space.39 Oral or IV sodium bicarbonate may be prescribed to increase urinary excretion of potassium.39 Loop diuretics, such as furosemide (Lasix), may be prescribed to promote urinary output. Thiazide diuretics are usually contraindicated because they raise uric acid levels and interact with allopurinol.27 Although sodium polystyrene sulfonate is often used to treat hyperkalemia, its efficacy has not been established in clinical trials, and it can cause serious gastrointestinal harm, including bowel necrosis.10 Newer potassium-binding agents such as patiromer (Veltassa) and sodium zirconium cyclosilicate (Lokelma) may be safer and more effective.10

The practice of alkalinizing the patient's urine with such medications as sodium bicarbonate was routine in the past but is no longer recommended as standard care. This is because it can cause calcium phosphate and uric acid crystals to form, raising the risk of nephropathy.17 Alkalinization, however, may be used in patients with metabolic acidosis.17

Patient and family education. Patients and their family members should be taught about the risks, signs, and symptoms of tumor lysis syndrome and the importance of informing health care providers in both outpatient and inpatient settings of their condition. Advise patients to follow a low-phosphate, low-potassium diet.17 Oral phosphate binders, such as calcium acetate (Phoslo, Phoslyra), ferric citrate (Auryxia), sevelamer (Renagel, Renvela), and lanthanum carbonate (Fosrenol) may be prescribed.

CONCLUSIONS

Tumor lysis syndrome is one of the most common medical oncologic emergencies. It occurs acutely and can be life-threatening. With the increasing number of effective, cytoreductive cancer therapies, including biological and targeted agents, incidence of tumor lysis syndrome and its associated complications is expected to rise.13

Nurses providing direct patient care, as well as those in ambulatory clinics and on telephone triage, should be familiar with tumor lysis syndrome risk factors and sequelae. Vigilance and frequent monitoring of risk factors, patient symptoms, and laboratory values promote early intervention and prompt implementation of evidence-based management. This, in turn, can reduce the potential for toxicities and other complications, improving patient quality of life and achieving optimal patient outcomes.

REFERENCES