Tumor Lysis Syndrome, Causes, Symptoms, Diagnosis, Prevention and Treatment
Tumor Lysis Syndrome refers to the constellation of metabolic disturbances that occurs when large numbers of neoplastic cells are killed rapidly, leading to the release of intracellular ions and metabolic byproducts into the systemic circulation. Clinically, the syndrome is characterized by rapid development of hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acute kidney injury.
Tumor Lysis Syndrome arises most commonly after the start of initial chemotherapeutic treatment, but spontaneous cases have increasingly been documented in patients with high-grade hematologic malignancies.
Risk Factors of Tumor Lysis Syndrome:
Tumor Lysis Syndrome is the most common disease-related emergency encountered by physicians caring for children or adults with hematologic cancers. Although Tumor Lysis Syndrome develops most often in patients with non-Hodgkin’s lymphoma or acute leukemia, its frequency is increasing among patients who have tumors that used to be only rarely associated with Tumor Lysis Syndrome. Tumor Lysis Syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. These electrolyte and metabolic disturbances can progress to clinical toxic effects, including renal insufficiency, cardiac arrhythmias, seizures, and death due to multiorgan failure.
Although optimal methods of risk classification and treatment of Tumor Lysis Syndrome have been difficult to define, uniform standards for management of Tumor Lysis Syndrome 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.
Not all cancer patients are at equal risk of developing Tumor Lysis Syndrome. Patients with a large “tumor burden” of cancer cells and/or tumors that typically have rapidly dividing cells, such as acute leukemia or high-grade lymphoma, as well as tumors that are highly responsive to therapy, are at greatest risk of developing Tumor Lysis Syndrome. Tumor Lysis Syndrome can occur spontaneously (before cancer treatment) but is more common within a week of starting treatment. Tumor Lysis Syndrome is not limited to patients receiving traditional chemotherapy; it can also occur in patients receiving steroids, hormonal therapy, targeted therapy, or radiation therapy. Patients who are dehydrated and those with existing kidney dysfunction are at higher risk of developing Tumor Lysis Syndrome.
Symptoms of Tumor Lysis Syndrome:
Symptoms of Tumor Lysis Syndrome are generally nonspecific and can include:
- Nausea with or without vomiting
- Lack of appetite and fatigue
- Dark urine, reduced urine output, or flank pain
- Numbness, seizures, or hallucinations
- Muscle cramps and spasms
- Heart palpitations
- Kidney failure and death can occur, especially if Tumor Lysis Syndrome is left untreated.
Diagnosis of Tumor Lysis Syndrome:
Tumor Lysis Syndrome is diagnosed based on blood tests, along with signs and symptoms. Tumor Lysis Syndrome onset may be subtle, with only a few abnormal laboratory values, but Tumor Lysis Syndrome can also present with frank kidney and organ failure.
Tumor Lysis Syndrome should be suspected in patients with large tumor burden who develop acute kidney failure along with hyperuricemia or hyperphosphatemia. (Most other acute kidney failure occurs with uric acid. Acute uric acid nephropathy is associated with little or no urine output. The urinalysis may show uric acid crystals or amorphous urates. The hypersecretion of uric acid can be detected with a high urine uric acid - creatinine ratio, compared to the value for most other causes of acute kidney failure
Prognosis of Tumor Lysis Syndrome:
The rate of mortality from Tumor Lysis Syndrome may vary widely depending on the type of underlying malignancy. However, the occurrence of acute kidney injury is concerning given the high mortality that is generally associated with it
Incidence of Tumor Lysis Syndrome:
The incidence and prevalence of Tumor Lysis Syndrome are not well defined since they vary depending on several tumor-, anticancer therapy-, and patient-related risk factors, as well as prophylactic procedures undertaken. The most epidemiological data about Tumor Lysis Syndrome come mostly from the 90s, with laboratory Tumor Lysis Syndrome described in about 40% adults with hematologic malignancies and even up to 70% of children with acute leukemia and clinical form in <10% . Then, in the first-year decade of the 21st century, we witnessed a rapid growth of highly effective novel anticancer therapies, and the risk of Tumor Lysis Syndrome –at least in certain diseases like chronic lymphocytic leukemia– seemed to be even higher. This early experience resulted in the development of strict preventive measures and step-wise dosing and therapeutic sequencing strategies, which remarkably decreased the incidence of Tumor Lysis Syndrome. It is now much less common, provided the adequate prophylaxis and monitoring; however, it must be kept in mind that the consequences may be fatal if they happen.
Prevention of Tumor Lysis Syndrome:
Certain measures can reduce the chances of developing Tumor Lysis Syndrome. Your clinician will consider results of blood tests and characteristics of the cancer to determine your risk of developing Tumor Lysis Syndrome and which preventive measure(s) to use. Intravenous fluids can help the kidneys to flush out toxins in the urine. Medications such as allopurinol and rasburicase reduce uric acid levels in the blood and may be prescribed.
It is important to prevent life threatening manifestations associated with Tumor Lysis Syndrome which include acute kidney injury, hyperkalemia (which may cause cardiac arrhythmias), and or hypocalcemia (which may cause cardiac arrhythmias and neuromuscular irritability).
Acute Kidney Injury:
Patients at risk for developing Tumor Lysis Syndrome (e.g. patients about to receive chemotherapy for a cancer with a high cell turnover rate, especially lymphomas and leukemias) should receive appropriate intravenous hydration in order to improve blood flow to the kidneys, maximize urine output, and ultimately prevent precipitation of uric acid crystals that can led to acute kidney injury. A diuretic may also be indicated to further increase urine output in addition to intravenous hydration. Another approach to prevent damage to the kidneys is to prevent the build up of uric acid during Tumor Lysis Syndrome, and this can be accomplished with use of allopurinol or rasburicase. Allopurinol (a xanthine oxidase inhibitor, which inhibits uric acid production) works by preventing the formation of uric acid following Tumor Lysis Syndrome. Rasburicase is a synthetic urate oxidase enzyme and acts by degrading uric acid. It is not recommended to alkalinize urine in the management of Tumor Lysis Syndrome.
Monitoring potassium levels in the blood frequently and cardiac monitoring (given the risk of cardiac arrhythmias) are important components in the prevention of adverse consequences in Tumor Lysis Syndrome. Other strategies include limiting oral intake of potassium and excreting potassium through the gastrointestinal tract using agents such as oral sodium polystyrene sulfonate can be beneficial. Insulin therapy (in conjunction with glucose administration) as well as beta-receptor agonists (such as albuterol) can also be used but are temporary interventions and potassium is not excreted from the body. Hemodialysis and hemofiltration can also be used as options to remove potassium from the bloodstream when hyperkalemia is present.
Hyperphosphatemia is a common finding in Tumor Lysis Syndrome and high phosphorus levels can itself contribute to hypocalcemia and therefore phosphate binders may be beneficial in preventing this form of hypocalcemia
Treatment of Tumor Lysis Syndrome:
Even with preventive measures, Tumor Lysis Syndrome can still develop. Patients at high risk of Tumor Lysis Syndrome undergo bloodwork and clinical monitoring before and during therapy to ensure early diagnosis if Tumor Lysis Syndrome develops. Treatment of Tumor Lysis Syndrome is similar to the preventive measures, including intravenous fluids, allopurinol, and especially rasburicase. Patients of Tumor Lysis Syndrome may require admission to the intensive care unit. Bloodwork is repeated frequently to assess electrolyte levels and kidney damage, and the heart rhythm and urine output are closely monitored. Careful correction of electrolyte imbalances is required. Some patients of Tumor Lysis Syndrome with severe kidney injury may require temporary hemodialysis.
Treatment is first targeted at the specific metabolic disorder. In general, rasburicase and hydration are the mainstays of treatment in patients with clinical evidence of Tumor Lysis Syndrome. A loop diuretic may also be indicated to maintain appropriate production of urine by the kidneys. Further treatment is targeted towards the specific metabolic abnormalities present in patients with Tumor Lysis Syndrome. Mild hyperkalemia without symptoms can be treated with a loop diuretic and sodium polystirene, while a temporizing agent such as rapid acting insulin (in conjunction with glucose) and an agent to stabilize cardiac membranes such as calcium carbonate may be given in cases of severe hyperkalemia. Concerning symptoms related to hypocalcemia (e.g. seizures) in Tumor Lysis Syndrome patients can be treated with calcium gluconate. Tumor Lysis Syndrome patients patients may ultimately also require renal replacement therapy such as through hemodialysis if indicated.
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