Sapino Silvia, Secreto Carolina
Tumor lysis syndrome (TLS) is an important metabolic disorder frequently encountered in the management of a variety of cancers including lymphoma, such as Burkitt's lymphoma, leukemia, and neuroblastoma. Delayed recognition can result in a variety of biochemical abnormalities resulting in life-threatening complications such as renal failure, arrhythmias, and seizures.
Tumor lysis syndrome is characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia brought about by rapid tumor cell destruction that may result in a variety of musculoskeletal, renal, cardiac, and neurologic manifestations. It is one of the few oncologic emergencies that accounts for a significant number of morbidity and mortality events if not recognized early and treated appropriately. Although frequently seen after chemotherapy of rapidly proliferating and bulky hematologic malignancies such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and lymphoma, it has also been described in solid malignancies—particularly small-cell cancer, rhabdomyosarcoma, and neuroblastoma.
The use of newer, more aggressive cytotoxic therapies has seemingly increased the incidence of TLS.
(Tumor lysis syndrome, 2013)
The first description of TLS was made by two Czech physicians, Bedrna and Polcak, in 1929. Crittenden and Ackerman made the first clinicopathologic description of TLS in 1977, when they described a patient with disseminated gastrointestinal carcinoma who developed hyperuricemia, renal failure, and urate crystals in the renal collecting system on autopsy. It has since been described in a variety of clinical situations, either related to therapy (chemotherapy, monoclonal antibody, radiotherapy, corticosteroid therapy) or not related to therapy (spontaneous) for different types of hematologic and solid malignancies.
(Hyperuricemic acute renal failure in disseminated carcinoma, 1977)
The incidence of tumor lysis syndrome is unknown. The prevalence varies among different malignancies; bulky, aggressive, treatment-sensitive tumors are associated with higher frequencies of tumor lysis syndrome. In studies of frequency in patients with intermediate-grade or high-grade non-Hodgkin lymphomas, laboratory evidence of tumor lysis syndrome (42%) occurred much more frequently than the symptomatic clinical syndrome (6%). In children with acute leukemia receiving induction chemotherapy, silent laboratory evidence of tumor lysis syndrome occurred in 70% of cases, but clinically significant tumor lysis syndrome occurred in only 3% of cases.
(Guidelines for the Management of Pediatric and Adult Tumor Lysis Syndrome: An Evidence-Based Review, 2008)
Spontaneous tumor lysis syndrome
This entity is associated with acute renal failure due to uric acid nephropathy prior to the institution of chemotherapy and is largely associated with lymphomas and leukemias. The important distinction between this syndrome and the post-chemotherapy syndrome is that spontaneous TLS is not associated with hyperphosphatemia. One suggestion for the reason of this is that the high cell turnover rate leads to high uric acid levels through nucleobase turnover but the tumor reuses the released phosphate for growth of new tumor cells. In post-chemotherapy TLS, tumor cells are destroyed and no new tumor cells are being synthesized.
(Spontaneous tumour lysis syndrome, 2012)
In 2004, Cairo and Bishop defined a classification system for tumor lysis syndrome.
- abnormality in two or more of the following, occurring within three days before or seven days after chemotherapy.
|uric acid||> 8 mg/dL or 25% increase|
|potassium||> 6 meq/L or 25% increase|
|phosphate||> 4.5 mg/dL or 25% increase|
|calcium||< 7 mg/dL or 25% decrease|
- laboratory tumor lysis syndrome plus one or more of the following:
- increased serum creatinine (1.5 times upper limit of normal)
- cardiac arrhythmia or sudden death
A grading scale (0-5) is used depending on the presence of lab TLS, serum creatinine, arrhythmias, or seizures.
(Tumour lysis syndrome: new therapeutic strategies and classification, 2004)
Chemotherapy is the treatment of cancer with one or more cytotoxic anti-neoplastic drugs, acting by killing cells that divide rapidly and by impairing mitosis. They prevent it by various mechanisms including damaging DNA and inhibition of the cellular machinery involved in cell division, inducing apoptosis.
The electrolyte abnormalities and clinical consequences seen in TLS are associated with rapid cellular breakdown in patients with high tumor burden. Various cancers have different growth rates and responsiveness to chemotherapy. Within similar tumor types, variations in tumor behavior are also present. Cytogenetics plays an important role in the prognosis of many cancers and may help stratify more advanced disease within each cancer type. Certain cytogenetic abnormalities are associated with more aggressive disease. For example, the presence of MYCN gene mutation in neuroblastoma, in L3 type of acute lymphoblastic leukemia is associated with higher tumor burden and higher incidence of TLS after induction chemotherapy.
In TLS, rapid turnover of tumor cells results in a massive release of various intracellular contents (potassium, phosphate, nucleic acids, lactate dehydrogenase, etc.) into the systemic circulation. This results in an ionic imbalance within various organs.
(Incidence and pathogenesis of tumor lysis syndrome, 2005)
Endogenous or exogenous purine nucleotides are catabolized primarily in the liver, but to a lesser extent in the mucosa of the small intestine, and are catalyzed by a protein called xanthine oxidase (XO). The final product of this complex pathway is urate and acid urates(C5H4N4O3).
Urate handling in the renal proximal tubule is composed of a combination of reabsorption, which predominates, and secretion, so it is excrected in urine.
There are a lot of urate transporters, and among these, URAT-1 is the one best studied in humans, located in the apical membrane of proximal tubule cells, critical in urate reabsorption. URAT-1 transports urate across the apical membrane in exchange with anions. Urate then moves across the basolateral membrane into the blood by way of the organic anion transporter. In human blood plasma, the reference range of uric acid is typically 200-430 µmol/L for men and 140-360 µmol/L for women and it's very strong reducing agents (electron donors) and potent antioxidants. In humans, over half the antioxidant capacity of blood plasma comes from uric acid.
Hyperuricemia is defined as serum uric acid 8.0 mg/d or 25% increase from baseline 3 days before or 7 daysafter the initiation of chemotherapy. The major route of urate clearance is through the proximal renal tubule. The kidney is the main organ affected by high urate levels. One of the most dreaded complications related to TLS is acute kidney injury (AKI) from urate nephropathy. Dehydration brought about by nausea, vomiting, diarrhea, and diabetes insipidus are commonly caused by the underlying malignancy and chemotherapy, resulting in low urine flow rates. The low urine flow rates coupled with heavy cell turnover promotes urate precipitation in the distal nephron. which leads to kidney failure by various mechanisms. Kidney failure then limits the clearance of potassium, phosphorus, and uric acid leading to hyperkalemia, hyperphosphatemia, and secondary hypocalcemia, which can be fatal.
K is the main intracellular cation regulated through the Na-K ATPase system. Its normal regulation is critical in maintaining the normal resting membrane potential of various cells: skeletal muscle, neural and cardiac muscle.
Hyperkalemia is defined as serum K level >6.0 mEq/L or 25% increase from baseline 3 days before or 7 days after the initiation of chemotherapy. Hyperkalemia causes cardiac arrhythmia, one of the most serious complications related to TLS. It is usually seen 6 -72 hours post-chemotherapy. Neuromuscular and cardiac tissues are most susceptible to changes in K level.
- muscle cramps
In the cardiac tissue, depending on the degree of hyperkalemia, a variety of electrocardiographic changes can occur and ultimately atrioventricular dissociation, ventricular tachycardia or ventricular fibrillation and death when the serum K level increases above 9 mEq/L.
Coexisting renal failure, metabolic acidosis, and K sparing medications can worsen hyperkalemia.
Hyperphosphatemia is defined as serum phosphate 4.5 mg/dL or 25% increase from baseline, and hypocalcemia is defined as corrected serum calcium level 7.0 mg/dL or 25% decrease from baseline, 3 days before or 7 days after the initiation of chemotherapy.
Both electrolyte abnormalities usually develop 24 to 48 hours after chemotherapy. Several mechanisms contribute to elevation in phosphate levels in TLS, including increased endogenous release as a result of massive tumor breakdown, impaired glomerular filtration secondary to preceding urate nephropathy/nephrocalcinosis-induced renal failure, and decreased ability of malignant cells to use available endogenous phosphate. Symptoms related to hyperphosphatemia are manifested indirectly through its effect on calcium. Calcium phosphate precipitates when the calcium and phosphate solubility product is exceeded in the renal parenchyma, leading to both hypocalcemia and organ damage related to calcium deposition.Treatment of hyperphosphatemia reduces dietary phosphate intake and includes phosphate binders such as aluminum hydroxide and aluminum carbonate. Hypocalcemia can result in both neurologic and cardiac symptoms.
- mental incapacity
- muscle cramps
- depressed cardiac contractility.
Calcium phosphate precipitation can lead to acute nephrocalcinosis.
(Tumor lysis syndrome, 2007)
Risk factors include a large tumor size, tumors with rapid cell division and growth, hematologic cancers such as acute leukemia or high-grade (aggressive) lymphoma, and tumors with a high sensitivity to chemotherapy.
Patients with high levels of lactate dehydrogenase (greater than 1,000 U/L) and impaired renal function are also at risk, as are some patients with mediastinal tumors. Several chemotherapy agents are associated with TLS.
Based on the presence of certain risk factors, patients can be placed into low, intermediate, or high-risk categories:
|High||Burkitt's lymphoma, ALL, AMC|
|Intermediate||Large-cell lymphoma, Rapidly growing cancers|
|Low||Slow-growing lymphoma, Slowly proliferating cancers|
Conventional management of TLS consists of aggressive intravenous hydration, diuretic therapy, urinary alkalization, and inhibition of urate production by high-dose allopurinol. Recent advancements in the treatment options of TLS have drastically changed the way it is managed. Hydration and effective urine flow rates remain a cornerstone of TLS prevention and treatment.
Intravenous fluid generally is administered 48 hours prior to chemotherapy. The volume expansion brought about by hydration helps decrease extracellular phosphate, K and urate levels. Hydration also improves the rate of renal blood flow, producing diuresis of 150 to 300 mL/h and protecting against tubular crystallization. In certain patients, alkalinization (urine pH 6.5 to 7.5) may increase precipitation of calcium phosphate product in the renal tubules and interfere with renal tubular phosphate reabsorption.
Allopurinol, the earliest and the prototype of all XO inhibitors, was first approved in 1966 to treat patients with gout. An isomer of hypoxanthine, it is rapidly metabolized by XO to its metabolite, oxypurinol. Both allopurinol and oxypurinol irreversibly inhibit XO either by competitive or noncompetitive inhibition.The first study looking at its use for TLS was in 1966, in which 33 patients with chronic leukemia, acute leukemia, and lymphoma had a dose-related reduction in uric acid after treatment with allopurinol.
More recently, two new investigational agents, namely febuxostat and Y700 were synthesized and found to be efficacious for patients with hyperuricemia. Y700 is even more potent than allopurinol in reducing urate levels, is similar to febuxostat, and is eliminated primarily through the hepatic system, and thus can be safely used in renal failure.
(Febuxostat compared with allopurinol in patients with hyperuricemia and gout, 2005)
Rasburicase is a 34-kd tetrameric protein; it is a recombinant version of urate oxidase which catalyses the conversion of uric acid to allantoin, an inactive metabolite of purine metabolism. Allantoin is five to ten times more water-soluble than uric acid making it easier for the kidneys to excrete.
In clinical trials, rasburicase is superior to allopurinol. Despite its great potential for TLS, rasburicase and native uricase are highly immunogenic, eliciting formation of antibodies to the enzyme, making it difficult to prescribe on a regular basis except in the most mitigating situations. Hypersensitivity and anaphylactic reactions have also been reported. This limitation has motivated investigators to develop a less antigenic variant of uricase.
(Rasburicase in tumor lysis syndrome of the adult: a systematic review and meta-analysis, 2013)
Early initiation of renal replacement therapy (RRT) has been advocated to control volume status, remove purine by products, and decrease the impact of hyperkalemia, hyperphosphatemia and hypocalcemia.
Patients with significant tumor burden may warrant intermittent hemodialysis alone or in conjunction with continuous renal replacement therapy.