Tumor lysis syndrome is a clinical condition that can occur spontaneously or after 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.
Tumor lysis syndrome 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 tumor lysis syndrome are related to the release of intracellular chemical substances that causes impairment to the functions of target organs. This can lead to acute kidney injury (AKI), fatal arrhythmia, and even death. This condition is the most common oncological emergency.
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.
Tumor lysis syndrome usually develops after the initiation of chemotherapy treatment. There are more cases of spontaneous development of tumor lysis syndrome with high-grade hematology-oncology malignancies. Because this condition is very lethal, it is imperative to identify patients at high risk for developing tumor lysis syndrome and start early preventative therapy. Quick and early recognition of the renal and metabolic derangement associated with tumor lysis syndrome and initiation of treatment can save a patient's life.
Tumor lysis syndrome is most common in patients diagnosed with leukemia who have a very 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 tumor lysis syndrome are hepatoblastoma or neuroblastoma. There are reports of tumor lysis syndrome occurring spontaneously before the initiation of chemotherapy.
An international panel of experts has stratified tumors based on the risk of developing tumor lysis syndrome.
There are case reports of tumor lysis syndrome associated with the administration of steroids, biological immunomodulators, and monoclonal antibodies. Agents are associated with the development of tumor lysis syndrome include:
In rare instances, tumor lysis syndrome has been observed in patients under general anesthesia undergoing surgery. Other rare occurrences of tumor lysis syndrome are seen in pregnancy or high fever.
The precise incidence of tumor lysis syndrome is not known. There are inherent risk factors that can increase the incidence of tumor lysis syndrome, 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 tumor lysis syndrome 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 tumor lysis syndrome 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%.
Cairo et al. described the incidence of tumor lysis syndrome based on the risk stratification outlined above. The percentage expressed is the reported incidences of tumor lysis syndrome based on each specific malignancy, including:
Tumor lysis syndrome is most commonly associated with the initiation of cytotoxic chemotherapy. However, there are case reports of tumor lysis syndrome precipitated by radiation therapy, including the use of thalidomide, dexamethasone therapy, and the use of newer chemotherapeutic agents like rituximab and bortezomib.
The pathophysiology of tumor lysis syndrome is complicated. Tumor lysis syndrome is caused by the massive release of intracellular ions such as potassium, phosphorus, and nucleic acids that have been metabolized to uric acid. The main organ responsible for the excretions of these substances is the kidney. When the compensatory response of the kidney is exhausted as a result of 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, is made up of a 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 further metabolized into uric acid in a reaction that is catalyzed by xanthine oxidase. Most mammals have the enzyme urate oxidase that can transform uric acid to allantoin which is a more soluble substance that can be easily excreted by the kidney. Human beings lack this enzyme.
Due to the rapid turnover of tumor cells, there is an overwhelming production of uric acid which then crystallizes in the renal tubules causing obstructive uropathy from 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.
The concentration of potassium within the cell is about 120 to 130 meq/L. The lysis of tumorous cells leads to a massive release of intracellular potassium. The excess potassium is usually taken up by the liver and skeletal muscle. The rest is excreted via the gastrointestinal system or the kidney. The 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 is another electrolyte imbalance associated with tumor lysis syndrome. The nucleic acid has a phosphate group, and the breakdown of the tumorous cell will lead to the release of a significant amount of phosphorus into the bloodstream. Most of the phosphorus is renally excreted. This ability of the kidney to handle a high load of phosphorus is inhibited by acute kidney injury or chronic kidney disease.
Hyperphosphatemia is less common in spontaneous tumor lysis syndrome than those induced by chemotherapy. It leads to the chelation of calcium causing hypocalcemia. Deposition of calcium and phosphorus salts in the kidney and soft tissues can also occur.
Hypocalcemia in tumor lysis syndrome 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 still be relatively low even after the normalization of the phosphorus level because of a deficiency of 1, 25 Vitamin D.
The histopathological findings in tumor lysis syndrome are associated with the deposition of uric acid, calcium phosphate, and xanthine in the lamina of the distal kidney tubules. Crystals of uric acid can also deposit kidney tubular epithelial cells as well as 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.
The history and physical examination of patients with tumor lysis syndrome should be focused on the primary causes of the tumor lysis.
Time of onset of malignancy should be elicited with attention to the presence of constitutional symptoms like weight loss or anorexia.
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 tumor lysis syndrome include, but are not limited to, syncopal attack, palpitation lethargy, pitting edema, facial edema, abdominal distention, and other sign of fluid overload.
The physical examination should focus on the electrolyte abnormalities that are associated with tumor lysis syndrome. The physical findings associated with these abnormalities are listed below.
Uremia for hyperuricemia and obstructive uropathy
The signs and symptoms of tumor lysis syndrome can develop spontaneously or about 72 hours after the initiation of chemotherapy.
Tumor lysis syndrome is diagnosed based on criteria that were developed by Cairo and Bishop. The criteria established by Cairo and Bishop have several limitations. The most crucial drawback is that the definition of tumor lysis syndrome based on this criterion requires initiation of chemotherapy. However, in clinical practice, tumor lysis syndrome can develop spontaneously without the initiation of chemotherapy.
The second limitation is the use of creatinine level greater than 1.5 the upper limit for age and gender. This is not standard as a patient with CKD (Chronic Kidney Disease) will have elevated creatine in the absence of AKI.
The Cairo-Bishop criteria also factor the severity of tumor lysis syndrome based on the severity of illness from grade 0 (asymptomatic) to 4 (death).
Laboratory Diagnosis of Tumor Lysis Syndrome
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:
Clinical Diagnosis of Tumor Lysis Syndrome
Laboratory tumor lysis syndrome plus 1 or more of the following:
Other origins of AKI should be excluded.
In the evaluation of tumor lysis syndrome, the following studies are necessary:
X-Ray and CT scan of the chest to evaluate the presence of mediastinal mass and the presence of a concomitant pleural effusion
CT scan and an ultrasound of the abdomen and retroperitoneal structure if the mass lesion is located in the abdomen or retroperitoneum. Care must be taken with intravenous (IV) contrast because of the presence of AKI in tumor lysis syndrome.
ECG is part of the workup for patients with tumor lysis syndrome to check for findings associated with hyperkalemia and hypocalcemia. Hyperkalemia is a potential cause of fatal arrhythmia in tumor lysis syndrome.
Complete Blood Count (CBC)
CBC helps in the diagnosis of malignancy associated with tumor lysis syndrome. The hallmark of most malignancy is leukocytosis with anemia and thrombocytopenia.
Comprehensive Metabolic Panel (CMP)
The metabolic derangement associated with tumor lysis syndrome are hyperkalemia, hypocalcemia, hyperphosphatemia, and hyperuricemia. Blood urea nitrogen (BUN), creatinine, and lactate dehydrogenase are also elevated in tumor lysis syndrome. CMP must be monitored between two to three times daily before and after initiation of therapy. Elevated laboratory value might be indicative of the beginning of tumor lysis syndrome.
Precipitation of uric acid salt can cause obstructive uropathy. In the treatment of tumor lysis syndrome, Alkalinisation 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.
Tumor lysis syndrome is best prevented rather than managed. The most important factor considered for the management of tumor lysis syndrome is the ability to prevent its development based on anticipation. Some guidelines stratify the risk of developing tumor lysis syndrome based on the histology of the primary tumor. Multiple clinical trials have not demonstrated the superiority of any particular prophylactic regiment for tumor lysis syndrome. For tumors with a high risk of releasing situation amount of intracellular substances after the initiation of chemotherapy, it is recommended to start aggressive hydration before 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 tumor lysis syndrome and also to promote the solute excretion.
It is also advisable to avoid substances that can potentially cause vasoconstriction of the renal vasculature like non-steroidal anti-inflammatory drugs (NSAIDS) and iodinated contrast.
Patients with moderate to high risk of developing tumor lysis syndrome should be prophylactically started on xanthine oxidase inhibitors.
For a patient with a high-risk tumor, the overall consensus is to start on prophylactic urate oxidase inhibitor therapy before the initiation of chemotherapy. It is advisable to start rasburicase on patients in which hyperuricemia from tumor lysis syndrome might delay the initiation of chemotherapy
Rapid Expansion of Intravascular Volume
Treatment of tumor lysis syndrome starts with rapid volume expansion. It is recommended to use crystalloids in volume expansion as this will help to increase the glomerular filtration rate (GFR) quickly. Improved GFR helps with the excretion of solutes associated with tumor lysis syndrome. 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
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 impair 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 by itself has limited solubility and can crystallize in the renal tubules making the obstructive uropathy associated with tumor lysis syndrome worse.
Allopurinol can decrease the production of uric acid in tumor lysis syndrome but is ineffective in the treatment of hyperuricemia associated with tumor lysis syndrome. Allopurinol is a very useful agent to prevent the development of tumor lysis syndrome.
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 tumor lysis syndrome, clinicians should be aware of a potential drug to drug interaction with azathioprine, immunosuppressive drug use in patients with solid organ transplant and autoimmune disorder.
Recombinant Urate Oxidase
A recombinant version of urate oxidase is a drug that is used to treat hyperuricemia in patients with leukemia, lymphoma, and solid tumor who are 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. It can also be given intravenously at doses of between 50 to 100 U/kg per day.
Sodium Bicarbonate for Urine Alkalinisation
The normal urine is acidic with a pH of about 5. The solubility of uric acid in urine is increased about 10-fold with the alkalinization of urine. This can be achieved by adding about 40 to 50 mEq/liter of sodium bicarbonate to the fluid use for hydration in tumor lysis syndrome.
The risk of alkalinization of urine is a decrease in the level of ionized calcium as there is less bonding of calcium to albumin. This can worsen the hypocalcemia associated with tumor lysis syndrome leading o arrhythmia or tetany. That apart, the alkalinization of urine can favor the precipitation of calcium and phosphate salts in the kidney tubules thus making AKI in tumor lysis syndrome 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 chloride and calcium gluconate can be administered parenterally to treat hypocalcemia. In tumor lysis syndrome 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.
This is an option that is available to use in a dire situations if the level of potassium and phosphorus is too high in the face of tumor lysis syndrome associated AKI. In tumor lysis syndrome, there is an ongoing liberation of intracellular ions. If intermittent hemodialysis is utilized for extracorporeal clearance, a 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 flow rate for the dialysate or replacement fluid.
For life-threating hyperkalemia, early hemodialysis is recommended.
For severe hyperphosphatemia, continuous renal replacement therapy might also be the best treatment modality.
This medication is also a xanthine oxidase inhibitor that is relatively new to the market. It is more expensive than allopurinol. It does not cause the hypersensitivity reaction that is associated with allopurinol.
In the clinical trial, the Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies (FLORENCE), febuxostat provides better control of hyperuricemia of tumor lysis syndrome with a good safety profile and preservation of renal functions.
Tumor lysis syndrome should be differentiated from other clinical conditions that can cause:
The differential diagnosis of each electrolyte abnormalities are listed below:
Data on the prognosis of tumor lysis syndrome, whether before the start of chemotherapy or after successful completion, is limited. However, the use of a recombinant urate oxidase has significantly decreased the incidence of acute renal failure requiring hemodialysis.
An increase in the knowledge of the pathophysiology of tumor lysis syndrome has led to better outcomes.
Management protocol and treatment are being modified based on a better understanding of the disease process. This has lead to a significant decrease in poor outcomes with tumor lysis syndrome.