Hello, this is Janice Zimmerman, and this presentation will cover the Oncologic Emergency of Tumor Lysis Syndrome. As you know, Tumor Lysis Syndrome is a metabolic emergency resulting from the release of potassium, phosphate, and nucleic acids from tumor cells. Although it is most commonly initiated following cytotoxic therapy, it can also occur spontaneously. It's often stated that Tumor Lysis Syndrome is the most common oncologic emergency, but the true incidence is difficult to determine because it depends on the type of malignancy and the definition used. Tumor Lysis Syndrome has been most commonly associated with hematologic malignancies that have a high proliferation rate, such as acute leukemias, Burkitt's lymphoma, and diffuse large B-cell lymphoma. However, there's an increasing association with hematologic malignancies that have lower proliferation rates, such as multiple myeloma and chronic lymphocytic leukemia, as well as solid tumors that can involve any part of the body. A report in 2017 from the National Inpatient Sample found that 20% of Tumor Lysis Syndrome cases were associated with solid tumors. This change in epidemiology of Tumor Lysis Syndrome is related to the development of newer targeted therapies that result in a higher rate of cell death. This includes immune checkpoint inhibitors, kinase inhibitors and BCL-2 inhibitors used in CLL, proteasome inhibitors and pro-apoptotic agents used for myeloma, and of course, there's the expanding use of CAR-T cell therapies. I think it's helpful to review the pathophysiology of Tumor Lysis Syndrome to understand its clinical impact for the patient, as well as the treatment options. Allopurinol results in the electrolyte abnormalities of hyperkalemia, hyperphosphatemia, with its associated hypocalcemia. Calcium phosphate deposition may lead to kidney injury. The breakdown of tumor DNA results in the purines being metabolized by xanthine oxidase to uric acid, and these elevated levels of uric acid can result in deposition in the kidneys and injury. Calcium phosphate, meanwhile, inhibits the xanthine oxidase and prevents the production of uric acid. Uric acid can also be metabolized by rasburicase to a more water-soluble compound called allantoin, but this enzyme is not present in humans. Cairo and Bishop definitions of Tumor Lysis Syndrome are the most widely used diagnostic criteria for this syndrome. They divide the syndrome into Laboratory Tumor Lysis Syndrome and Clinical Tumor Lysis Syndrome. Laboratory Tumor Lysis Syndrome is defined by at least two metabolic abnormalities present in a 24-hour period and includes specific thresholds for hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia. There is also a provision for a greater than 25% change from baseline in these abnormalities, but that is less commonly used. Clinical Tumor Lysis Syndrome is defined as the presence of Laboratory Tumor Lysis Syndrome plus either an increase in creatinine, seizure, arrhythmia, or sudden death, and it can be graded in severity from 0 to 5. Management of Tumor Lysis Syndrome includes both prevention and treatment of the syndrome. It involves three steps, and the first two steps, assessing the risk of Tumor Lysis Syndrome and initiating preventive interventions, often takes place outside the ICU, while treatment of Clinical Tumor Lysis Syndrome requires critical care. Various algorithms and scoring systems exist for determining risk of Tumor Lysis Syndrome in specific cancers, but all involve disease, treatment, and patient factors. Cancer-related factors include a high tumor burden, as with metastatic disease, a high proliferation rate, which is often evidenced by a high LDH, and the sensitivity of the cancer to the proposed treatment. Treatment factors include the specific therapy as well as the intensity of treatment, the hydration status of the patient, and exposure to nephrotoxins. For patient factors, renal dysfunction is the most important in assessing risk. However, hyperuricemia and hyperphosphatemia that is preexisting, or the presence of hypotension and hypovolemia are also risk factors for developing Tumor Lysis Syndrome. The next step is prevention of Tumor Lysis Syndrome in those patients who don't yet meet criteria for Laboratory Tumor Lysis Syndrome, and the recommendations are based on the assessment of risk. All risk categories should receive IV fluids. Low-risk patients, it is recommended to get allopurinol to prevent hyperuricemia, as well as daily laboratory tests. Intermediate-risk patients can receive allopurinol or Rasburocase, but require inpatient monitoring and laboratory tests every 8 to 12 hours. High-risk patients should receive Rasburocase, cardiac monitoring, and laboratory tests are performed every 6 to 8 hours. Next step in managing Tumor Lysis Syndrome is the treatment of Established Laboratory or Clinical Tumor Lysis Syndrome. You'll notice once again that IV fluids are a mainstay of therapy. In those patients with Laboratory Tumor Lysis Syndrome, Rasburocase is often given as a single dose, cardiac monitoring is recommended, and laboratory studies every 6 to 8 hours. In the patients with the most severe form of the syndrome, Clinical Tumor Lysis Syndrome, Rasburocase is given, they require cardiac monitoring, as well as ICU admission, and laboratory tests are done frequently, every 4 to 6 hours. Let's take a closer look at some of the management issues raised by these recommendations. For intravenous fluids, crystalloids are recommended. There are no specific recommendations for using normal saline versus balanced crystalloids, but the goal, regardless of the fluid that's used, is to achieve a urine output of at least 100 milliliters per hour. Urinary alkalinization is not routinely recommended, although alkalinization of the urine may increase uric acid solubility, it actually decreases the solubility of xanthine and hypoxanthine, and also of calcium phosphate. The only circumstance where you may consider urinary alkalinization is when you do not have access to Rasburocase, but if you do alkalinize the urine, you have to monitor the calcium level closely. Loop diuretics may be considered if there's evidence of volume overload or an insufficient urine output. However, you must ensure that intravascular volume is adequate, and they, of course, are contraindicated in the setting of obstructive uropathy. Hyperkalemia should be managed with standard treatment. In the setting of hyperphosphatemia, it's important to pay attention to the calcium phosphate product and try to keep it below 60 to avoid the risk of renal injury. Phosphate binders such as savelimere or aluminum hydroxide can be administered, being sure to avoid calcium-based phosphate binders. Hypokalcemia should be treated only if the patient has significant symptoms, and then use the lowest dose possible to relieve those symptoms. All of urate lowering therapy is to achieve a uric acid less than 8 milligrams per deciliter and prevent renal dysfunction. It's important to recognize that the uric acid level alone doesn't necessarily correlate with renal injury, as there are other factors that contribute to renal injury, including calcium phosphate, xanthine deposition, exposure to nephrotoxins, as well as hypotension. Allopurinol, which can be administered orally or intravenously, blocks the production of uric acid, but does not eliminate preformed uric acid. It is recommended for the prevention of tumor lysis syndrome in low and intermediate risk patients, and the treatment is usually continued for three to seven days. The dose must be adjusted for renal insufficiency. Rasburicase and allopurinol should not be used together, because allopurinol may decrease the substrate for rasburicase, and it may also result in xanthine accumulation. There are hypersensitivity reactions associated with allopurinol, including rash, eosinophilia, and acute hepatitis. Fibuxostat may be an alternative for patients who have reactions to allopurinol or renal insufficiency. It does not have an indication for tumor lysis syndrome, but has been found to be equivalent to allopurinol in decreasing uric acid levels. Dose adjustment due to renal insufficiency is not needed, since it is metabolized in the liver to inactive metabolites. It also has less drug interactions than allopurinol. However, it does carry adverse effects, such as abnormal LFEs, Stevens-Johnson syndrome, the risk of anaphylaxis, and it carries a black box warning for an increase in cardiovascular mortality based on the experience in chronic gout patients. Rasburicase is a recombinant urate oxidase derived from aspergillus. It is recommended for use in patients with high-risk laboratory and clinical tumor lysis syndrome. Based on the manufacturer's recommendations, the cost of treating a 70-kilogram patient for five days would be more than $37,000. This has resulted in a variety of protocols and recommendations for different dosing regimens. The recommended dosing is based on weight. However, multiple reports have reported success using fixed doses ranging from 1.5 to 7.5 milligrams, with 6 milligrams probably being the most commonly used. There are also reports of single dose being highly effective versus five days of treatment. If single dose is used, monitoring must continue to assess the patient for the need for a second dose. Rasburicase is contraindicated in patients with G6PD deficiency due to the risk of methemoglobinemia and hemolysis. So males of African, Asian, and Mediterranean descent should be tested for this abnormality before giving rasburicase. There is also a risk of anaphylaxis with repeat courses of rasburicase. When measuring uric acid levels in a patient who's received rasburicase, the samples must be put on ice and analyzed immediately because there is ongoing metabolism and falsely low levels may be reported. Hemodialysis may often be part of the management of tumor lysis syndrome. The indications are similar to other patients, volume overload, hyperkalemia, hyperphosphatemia, usually with symptomatic hypocalcemia, and then possibly hyperuricemia, although this is seldom a sole indication for the initiation of hemodialysis. The type of dialysis, intermittent versus continuous, will depend on the specific abnormality that's being addressed, as well as the hemodynamic status of the patient. These patients do need a higher dose of dialysis, usually daily intermittent dialysis because of the rapid cell turnover and destruction. In addition, the threshold for initiation may be lower in these patients because of the anticipated worsening of the metabolic abnormalities. In summary, I hope you recognize the changes in the epidemiology of tumor lysis syndrome due to the development of newer cytotoxic therapies. Remember that intravenous fluids are a mainstay of treatment in all patients to increase urine output, whether that be for prevention or treatment of tumor lysis syndrome. To prevent tumor lysis syndrome, a risk assessment is used to determine the appropriate urate lowering therapy. For those patients who already have laboratory and clinical tumor lysis syndrome, RASB-URA case should be administered. In all patients, vigilant monitoring is necessary to assess for complications and modifications of therapy. Thank you very much for listening.

Oncologic Emergency

Tumor Lysis Syndrome

Metabolic Emergency

Hematologic Malignancies

Solid Tumors