Continuing Education Activity

Tumor lysis syndrome is the most common oncologic emergency. This condition is prevalent in both adult and pediatric oncology patients undergoing chemotherapy, though it can also occur spontaneously. Most of the symptoms seen in patients with tumor lysis syndrome are related to the release of intracellular chemical substances that cause impairment in the functions of target organs. This can lead to acute kidney injury (AKI), fatal arrhythmia, and even death. This activity reviews the evaluation and management of tumor lysis syndrome. It highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Objectives:

• Assess the electrolyte abnormalities associated with tumor lysis syndrome.

• Evaluate how tumor lysis syndrome can lead to end-organ failure.

• Interpret how to stratify tumors based on the risk of developing tumor lysis syndrome.

• Communicate how an interprofessional approach is imperative to the effective management of patients with tumor lysis syndrome.

Introduction

Tumor lysis syndrome (TLS) is a clinical condition that can occur spontaneously or after the initiation of chemotherapy associated with the following metabolic disorders: hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia leading to end-organ damage. It is most common in patients with solid tumors.[1][2][3] TLS is a metabolic and oncologic emergency frequently encountered in clinical practice. This condition is prevalent in both adult and pediatric oncology patients undergoing chemotherapy. Most of the symptoms seen in patients with TLS are related to the release of intracellular chemical substances that cause impairment in the functions of target organs. This can lead to acute kidney injury (AKI), fatal arrhythmias, and even death. Cancer is a leading cause of morbidity and mortality in the United States and the second leading cause of death. Cancer, as a disease entity, has a wide range of pathologies. Moreover, the primary origin of cancerous cells is different. This, coupled with the variability in the life cycle of cancerous cells, creates a profound derangement of the host's metabolic response.[4][5] TLS usually develops after the initiation of chemotherapy treatment. However, there are more cases of spontaneous development of TLS with high-grade hematology-oncology malignancies. Because this condition is very lethal, it is imperative to identify patients at high risk for developing TLS and start early preventative therapy. Quick and early recognition of the renal and metabolic derangement associated with TLS and initiation of treatment can save a patient's life.

Etiology

TLS is most common in leukemia patients with a high white blood cell (WBC) count. It can also be seen in high-grade lymphomas, especially after the initiation of aggressive chemotherapy. Other solid tumors that can cause TLS are hepatoblastoma or neuroblastoma.[6][7] There are reports of TLS occurring spontaneously before the initiation of chemotherapy. An international panel of experts has stratified tumors based on the risk of developing TLS. 

High-Risk Tumors

• Advanced Burkitt lymphoma
• Advanced leukemia
• Early-stage leukemia or Burkitt lymphoma with elevated lactate dehydrogenase
• Acute lymphocytic leukemia with a white cell count of more than 100,000/microliters, or if the increase of lactate dehydrogenase from the baseline is 2 times the upper limit of normal
• Diffuse large B-cell lymphoma and bulky disease with a baseline lactate dehydrogenase 2 times the upper limit of normal
• Acute myeloid leukemia with a white cell count more than or equal to 10,000/microliters

Intermediate-Risk Tumors

• Acute myeloid leukemia with A white cell count between 25,000 and 100,000/microliters
• Acute lymphocytic leukemia with a white cell count of less than 100,000/microL and LDH of less than twice the upper limit of normal
• Diffuse large B-cell lymphoma with a baseline increase in lactate dehydrogenase of twice the upper limit of normal but the non-bulky disease
• Early-stage leukemia and Burkitt lymphoma with a lactate dehydrogenase of less than twice the upper limit of normal

Low-Risk Tumors

• Solid cancers
• Multiple myelomas
• Indolent lymphomas
• Chronic lymphocytic leukemia
• Chronic myeloid leukemia 
• Acute myeloid leukemia with a WBC count of less than 25,000/microliters and a lactate dehydrogenase elevated to less than 2 times the upper limit of normal

Rarely TLS is associated with administering steroids, biological immunomodulators, and monoclonal antibodies. Agents that are associated with the development of TLS include:

• Thalidomide
• Bortezomib
• Hydroxyurea
• Paclitaxel
• Fludarabine
• Etoposide
• Zoledronic acid

In rare instances, TLS has been observed in patients under general anesthesia undergoing surgery. Other rare occurrences of TLS are seen in pregnancy or high fever.

Epidemiology

The precise incidence of TLS is not known. There are inherent risk factors that can increase the incidence of TLS, including but not limited to tumor burden, tumors with a high rate of proliferation, tumors with high sensitivity to chemotherapy, and preexisting renal disease or impairment of the patient. The predisposition to TLS is not related to race or sex. In a study that queried the database of the National Inpatient Sample, the most common malignancies associated with TLS include non-Hodgkin lymphoma (30%), solid tumors (20%), acute myeloid leukemia (19%), and acute lymphocytic leukemia (13%). The overall in-hospital mortality was approximately 21%.[8] Cairo et al described the incidence of TLS based on the risk stratification outlined above. The percentage expressed is the reported incidences of TLS based on each specific malignancy, including: 

High-Risk Tumors

• Acute lymphocytic leukemia (5.2% to 23%)
• Acute myeloid leukemia with a WBC count greater than 75,000 (18 %)
• B-cell acute lymphoblastic leukemia (26.4%)
• Burkitt lymphoma (14.9%)

Intermediate-Risk Tumors

• Acute myeloid leukemia with WBC counts between 25,000 and 50,000 (6%)
• Diffuse large B-cell lymphoma (6%)

Low-risk Tumors

• Acute myeloid leukemia with WBC count less than 25,000 (1%)
• Chronic lymphocytic leukemia (0.33%)
• Chronic myelogenous leukemia (Case reports)
• A solid tumor (Case reports)

TLS is most commonly associated with the initiation of cytotoxic chemotherapy. However, there are case reports of TLS precipitated by radiation therapy, including the use of thalidomide, dexamethasone therapy, and the use of newer chemotherapeutic agents like rituximab and bortezomib.

Pathophysiology

The pathophysiology of TLS is complicated. TLS is caused by the massive release of intracellular ions such as potassium, phosphorus, and nucleic acids metabolized to uric acid. The main organ responsible for the excretion of these substances is the kidney. When the kidney's compensatory response is exhausted due to the massive release of intracellular ions, uric acid obstructive uropathy develops, which can then progress to acute kidney injury. Molecules called nucleotides comprise DNA. These nucleotides are units made of a phosphate group, a sugar group, and a nitrogen base. The nitrogen base is adenine, thymine, guanine, or cytosine. Adenine and guanine are purines, while thymine and cytosine are pyrimidines. Ribonucleic acid, however, comprises ribose sugar and a nitrogen base adenine, thymine, and uracil.

The metabolism of the purines adenine and guanine in a stepwise process leads to the production of xanthine. Adenine is metabolized to hypoxanthine, whereas guanine is metabolized to xanthine. Xanthine is then metabolized into uric acid in a reaction catalyzed by xanthine oxidase. Most mammals have the enzyme urate oxidase that can transform uric acid into allantoin, a more soluble substance that the kidney can easily excrete. Human beings lack this enzyme. Due to the rapid turnover of tumor cells, uric acid is overwhelming, which then crystallizes in the renal tubules, causing obstructive uropathy and decreased glomerular filtration rate. In rat models, urate nephropathy causes an increase in both proximal and distal tubule pressure. Peritubular capillary pressure and vascular resistance also increase. Uric acid scavenges nitric oxide, which is a potent vasodilator. The scavenging of nitric oxide produces vasoconstriction and kidney ischemia. Uric acid is also a potential pro-inflammatory agent and can cause the release of other cytokine-like tumor necrosis factor-alpha, protein I. These cytokines attract white blood cells and facilitate further injury to the kidney.

Electrolyte Imbalance

Hyperkalemia

The potassium concentration within the cell is about 120 to 130 meq/L. The lysis of tumorous cells leads to a massive release of intracellular potassium. The liver and skeletal muscle usually take up the excess potassium. The rest is excreted via the gastrointestinal system or the kidney. Obstructive uropathy from uric acid salts can limit the excretion of potassium. Sometimes, the hyperkalemia from the solid tumor can reach a potentially life-threatening level. The risk of hyperkalemia is cardiac arrest from arrhythmia.

Hyperphosphatemia

Hyperphosphatemia is another electrolyte imbalance associated with TLS. The nucleic acid has a phosphate group, and the breakdown of the tumorous cell releases a significant amount of phosphorus into the bloodstream. Most of the phosphorus is renally excreted. The kidney's ability to handle a high load of phosphorus is inhibited by acute kidney injury or chronic kidney disease. Hyperphosphatemia is less common in spontaneous TLS than in those induced by chemotherapy. It leads to calcium chelation, causing hypocalcemia. Calcium and phosphorus salts can be deposited in the kidney and soft tissues.

Hypocalcemia

Hypocalcemia in TLS is mostly secondary to the chelation of phosphorus. This condition is more potentially life-threatening than hyperphosphatemia. Possible complications from hypocalcemia include arrhythmia, tetany, seizure, and death. The calcium level might remain relatively low even after normalizing phosphorus because of a 1 25 vitamin D deficiency.

Histopathology

The histopathological findings in TLS are associated with the deposition of uric acid, calcium phosphate, and xanthine in the lamina of the distal kidney tubules. Uric acid crystals can also deposit kidney tubular epithelial cells and the medulla. The factors that favor the formation of crystals include low urine flow, low solubility, and high levels of solutes. The deposition of crystals in the renal pelvis, calyxes, and the ureter can cause inflammation, leading to obstruction of urinary flow. Longstanding obstruction creates hydroureter, hydronephrosis, and subsequent acute kidney failure.

History and Physical

The history and physical examination of patients with TLS should focus on the tumor lysis's primary causes. The time of onset of malignancy should be elicited with attention to the presence of constitutional symptoms like weight loss or anorexia. The presence of respiratory symptoms, dyspnea, orthopnea, and tachypnea can be a sign of airway compression from a primary tumor. Urinary symptoms such as dysuria, flank pain, and hematuria Signs and symptoms that can be associated with hypocalcemia include nausea, vomiting, seizure, tetanic spasm, and change in mental status. Other clinical manifestations of TLS include but are not limited to, syncopal attack, palpitation lethargy, pitting edema, facial edema, abdominal distention, and other signs of fluid overload.

Physical Examination

The physical examination should focus on the electrolyte abnormalities associated with TLS. The physical findings associated with these abnormalities are listed below.

Hypocalcemia

1. Carpal spasm
2. Pedal spasm
3. Tetany
4. Chvostek sign
5. Trousseau sign
6. Wheezing associated with bronchospasm
7. Seizure

Uremia for hyperuricemia and obstructive uropathy

1. Weakness
2. Lethargy
3. Malaise
4. Nausea
5. Vomiting
6. Metallic taste in the mouth
7. Irritability
8. Generalized pruritis
9. Rales and Ronchi from volume overload
10. Muffled heart sound from pericarditis secondary to uremia
11. Joint pain
12. Renal colicky pain
13. Calcium phosphate crystal deposits in the skin
14. Pruritis
15. Gangrene

The signs and symptoms of TLS can develop spontaneously or about 72 hours after the initiation of chemotherapy.

Evaluation

TLS is diagnosed based on criteria that Cairo and Bishop developed.[7][9] The criteria established by Cairo and Bishop have several limitations. The most crucial drawback is that the definition of TLS based on this criterion requires the initiation of chemotherapy. However, in clinical practice, TLS can develop spontaneously without initiating chemotherapy. The second limitation is creatinine levels greater than 1.5, the upper limit for age and gender. This is not standard, as a patient with CKD (Chronic Kidney Disease) has elevated creatine in the absence of AKI. The Cairo-Bishop criteria also factor in the severity of TLS, which is based on the severity of illness from grade 0 (asymptomatic) to 4 (death).

Laboratory Diagnosis of TLS

Requires 2 or more of the following criteria achieved in the same 24-hour period from 3 days before to 7 days after chemotherapy initiation:

• Uric acid 25% increase from baseline or greater than or equal to 8.0 mg/dL
• Potassium 25% increase from baseline or greater than or equal to 6.0 mEq/L
• Phosphorus 25% increase from baseline or greater than or equal to 4.5 mg/dL (greater than or equal to 6.5 mg/dL in children)
• Calcium 25% decrease from baseline or less than or equal to 7.0 mg/dL

Clinical Diagnosis of TLS

Laboratory TLS plus 1 or more of the following:

• Creatinine greater than 1.5 times the upper limit of normal of an age-adjusted reference range
• Seizure
• Cardiac arrhythmia or sudden death

Other origins of AKI should be excluded.

In the evaluation of TLS, the following studies are necessary:

Imaging

X-ray and CT scan of the chest to evaluate the presence of mediastinal mass and concomitant pleural effusion. CT scan and an ultrasound of the abdomen and retroperitoneal structure are needed to determine if the mass lesion is in the abdomen or retroperitoneum. Care must be taken with intravenous (IV) contrast because of the presence of AKI in TLS.

Electrocardiography (ECG)

ECG is part of the workup for patients with TLS to check for findings associated with hyperkalemia and hypocalcemia. Hyperkalemia is a potential cause of fatal arrhythmia in TLS.

Complete Blood Count (CBC)

CBC helps diagnose malignancy associated with TLS. The hallmark of most malignancies is leukocytosis with anemia and thrombocytopenia.

Comprehensive Metabolic Panel (CMP)

The metabolic derangements associated with TLS are hyperkalemia, hypocalcemia, hyperphosphatemia, and hyperuricemia. Blood urea nitrogen (BUN), creatinine, and lactate dehydrogenase are also elevated in TLS. CMP must be monitored 2 to 3 times daily before and after therapy initiation. Elevated laboratory values might indicate the beginning of TLS.

Urine Analysis

Precipitation of uric acid salt can cause obstructive uropathy. In treating TLS, alkalinization of urine with sodium bicarbonate is the standard of care. Frequent urine analysis with an assessment of urine pH, specific gravity, and output is mandatory.

Treatment / Management

Treatment

Rapid Expansion of Intravascular Volume

Treatment of TLS starts with rapid volume expansion. Crystalloids are recommended for volume expansion to help quickly increase the glomerular filtration rate (GFR). Improved GFR helps with the excretion of solutes associated with TLS. The drawback to this is that the kidney functions should still be intact. Intravenous fluid should be initiated 48 hours before the start of chemotherapy and should be continued for 48 hours after chemotherapy. Hydration with about 3 to 3.5 liters/m2 per day or 4 to 5 liters per day might be needed to provide adequate hydration. This will provide a urine output of about 3 liters per day.[10][11][12]

Medications

Allopurinol

This is a structural isomer of hypoxanthine. Xanthine oxidase converts allopurinol to oxypurinol. This is the active metabolite, and it is excreted primarily by the kidney. CKD or AKI impairs the elimination of oxypurinol. The level of xanthine in the urine and serum can be elevated after the administration of allopurinol because of the inhibition of the conversion of xanthine to uric acid. Xanthine has limited solubility and can crystallize in the renal tubules, worsening the obstructive uropathy associated with TLS. Allopurinol can decrease the production of uric acid in TLS but is ineffective in treating hyperuricemia associated with it. However, it is a very useful agent to prevent the development of TLS. The use of allopurinol is associated with the development of skin rash, eosinophilia, and acute hepatitis. The combination of these symptoms is called allopurinol hypersensitivity syndrome. In the treatment of TLS, clinicians should be aware of potential drug-to-drug interaction with azathioprine, immunosuppressive drug use in patients with solid organ transplants, and autoimmune disorders.

Recombinant Urate Oxidase

A recombinant version of urate oxidase is a drug used to treat hyperuricemia in patients with leukemia, lymphoma, and solid tumors undergoing chemotherapy. It is derived from Aspergillus by recombinant technology. The drug's mechanism of action is the catalyzes of uric acid to allantoin, carbon dioxide, and hydrogen peroxide. Hydrogen peroxide is a potent oxidizing agent and can cause severe methemoglobinemia or hemolytic anemia in patients with glucose 6 phosphate dehydrogenase G6PD deficiency. The Food and Drug Administration approved recombinant urate oxidase in 2009. This medication can be administered intramuscularly or intravenously at doses of 50 to 100 U/kg daily.

Sodium Bicarbonate for Urine Alkalinisation

Normal urine has a pH of about 5. Alkalinizing urine increases the solubility of uric acid about 10-fold. This can be achieved by adding about 40 to 50 mEq/liter of sodium bicarbonate to the fluid used for hydration in TLS. The risk of urine alkalinization is a decrease in ionized calcium level as there is less bonding of calcium to albumin. This can worsen the hypocalcemia associated with TLS, leading to arrhythmia or tetany. Apart from that, the alkalinization of urine can favor the precipitation of calcium and phosphate salts in the kidney tubules, thus making AKI in TLS worse. Therefore, alkalinization of urine with sodium bicarbonate is only advisable if rasburicase is not readily available. Even with that, the level of calcium should be serially monitored.

Calcium

Calcium chloride and calcium gluconate can be administered parenterally to treat hypocalcemia. In TLS, hypocalcemia is secondary to hyperphosphatemia; therefore, administration of calcium can potentiate the deposition of calcium phosphate crystals in soft tissues and the kidney, making AKI worse. This might sometimes necessitate the use of hemodialysis.

Hemodialysis

This option is available to use in dire situations if the potassium and phosphorus levels are too high in the face of TLS-associated AKI. In TLS, intracellular ions are liberated. If intermittent hemodialysis is utilized for extracorporeal clearance, rebound hyperkalemia or hyperphosphatemia might develop. Because of this, continuous renal replacement therapy is the best modality for solute removal. This is done with a high dialysate or replacement fluid flow rate. For life-threatening hyperkalemia, early hemodialysis is recommended. For severe hyperphosphatemia, continuous renal replacement therapy might also be the best treatment modality.

Febuxostat

This medication is also a xanthine oxidase inhibitor that is relatively new to the market. It is more expensive than allopurinol but does not cause the hypersensitivity reaction associated with allopurinol. In the clinical trial, the Febuxostat for TLS Prevention in Hematologic Malignancies (FLORENCE), febuxostat provided better control of TLS hyperuricemia with a good safety profile and preservation of renal functions.

Differential Diagnosis

TLS should be differentiated  from other clinical conditions that can cause:

• Hyperkalemia
• Hyperphosphatemia
• Hyperuricemia

The differential diagnosis of each electrolyte abnormality is listed below:

Hyperkalemia

• Hypocalcemia
• Metabolic acidosis
• Congenital adrenal hyperplasia
• Toxicity from digitalis
• Acute tubular necrosis
• Electrical burn
• Head trauma
• Rhabdomyolysis
• Thermal burns

 Hyperphosphatemia

• Monoclonal gammopathy
• Waldenstrom macroglobulinemia
• Multiple myeloma
• Other differentials to be considered in hyperphosphatemia include:
• Pseudohypoparathyroidism
• Rhabdomyolysis
• Vitamin D intoxication
• Oral saline laxative (Phospho-soda) abuse
• Pseudohyperphosphatemia

Hyperuricemia

• Hyperparathyroidism
• Hypothyroidism
• Nephrolithiasis
• Alcoholic ketoacidosis
• Diabetic ketoacidosis
• Gout
• Pseudogout
• Type 1 a glycogen storage disease
• Hemolytic anemia
• Hodgkins lymphoma
• Uric acid nephropathy

Prognosis

Data on the prognosis of TLS, whether before the start of chemotherapy or after successful completion, is limited. However, recombinant urate oxidase has significantly decreased the incidence of acute renal failure requiring hemodialysis. An increase in the knowledge of the pathophysiology of TLS has led to better outcomes. Management protocol and treatment are being modified based on a better understanding of the disease process. This has led to a significant decrease in poor outcomes with TLS.

Enhancing Healthcare Team Outcomes

TLS is a life-threatening oncologic emergency. It is best managed by an interprofessional team that includes the oncologist, nephrologist, internist, intensivist, and ICU nurses. Because this condition is very lethal, it is imperative to identify patients at high risk for developing TLS and start early preventative therapy. Quick and early recognition of the renal and metabolic derangement associated with TLS and initiation of treatment can save a patient's life. ICU and oncology nurses play a key role in managing these patients.

Prevention

TLS is best prevented rather than managed. The most important factor considered for the management of TLS is the ability to prevent its development based on anticipation. Some guidelines stratify the risk of developing TLS based on the histology of the primary tumor. Multiple clinical trials have not demonstrated the superiority of any particular prophylactic regiment for TLS. For tumors with a high risk of releasing a large amount of intracellular substances after the initiation of chemotherapy, it is recommended to start aggressive hydration before the initiation of treatment. At least 3 liters per day is recommended. Since an adequate glomerular filtration rate promotes the excretion of potassium, phosphorus, and uric acid, a generous amount of fluid is necessary to prevent the development of AKI from TLS and promote solute excretion.

It is also advisable to avoid substances that can cause vasoconstriction of the renal vasculature, like non-steroidal anti-inflammatory drugs (NSAIDs) and iodinated contrast. Patients with moderate to high risk of developing TLS should be prophylactically started on xanthine oxidase inhibitors. For a patient with a high-risk tumor, the overall consensus is to start prophylactic urate oxidase inhibitor therapy before the initiation of chemotherapy. It is advisable to start rasburicase on patients whose hyperuricemia from TLS might delay the initiation of chemotherapy. These patients need full monitoring in an ICU setting, and any deviation in vital signs should be quickly communicated to the clinician. Only with open communication between clinicians can the morbidity and mortality of this disorder be lowered.

Outcomes

The mortality rates for patients with TLS have improved, but the prognosis remains guarded.[13][14]