- Rapid Reference 🚀
- Clinically relevant physiology
- Epidemiology & risk factors
- Signs & symptoms
- Questions & discussion
- PDF of this chapter (or create customized PDF)
simplified Cairo definition of tumor lysis syndrome: (more)
- Malignancy plus at least two of the following:
- K >6 mEq/L.
- Phosphate >4.5 mg/dL (>1.45 mM).
- Uric acid >8 mg/dL (>476 uM).
- Calcium <7 mg/dL (<1.75 mM).
treatment of established tumor lysis syndrome:
- Limit intake of K & Phos:
- Change to a renal diet.
- Discontinue PRN potassium orders (hold potassium unless K<3.0 mM).
- Initiate phosphate binder (e.g., sevelamer* 800-1600 mg TID with meals).
- Discontinue nephrotoxins as able.
- Discontinue allopurinol.
- If uric acid >8 mg/dL (>476 uM), give rasburicase.
- If present, treat hyperkalemia 🚀
- Administer fluid (e.g., LR at ~150 ml/hour), but follow fluid balance and stop giving fluid if the patient is retaining it.
- Dialysis, if unresponsive to medical management as above.
clinically relevant physiology
- Lysis of tumor cells releases purine nucleotides, which are metabolized as shown above.
- Uric acid and Xanthine are both potentially nephrotoxic, due to precipitation in the renal tubules. Uric acid has a greater tendency to precipitate and to cause renal damage.
- Allopurinol is a medication which inhibits xanthine oxidase.
- i) This will reduce the production of uric acid (which is potentially beneficial).
- ii) This may cause the accumulation of xanthine (which is potentially dangerous, but not as bad as uric acid).
- Rasburicase is the most effective approach to manage purine nucleotide toxicity. It converts uric acid into allantoin, which is harmless. Treatment with rasburicase has the advantage over allopurinol of not leading to accumulation of Xanthine.
- Only Rasburicase can act on uric acid which has already been generated (allopurinol can prevent generation of additional uric acid, but doesn't affect pre-existing uric acid).
vicious cycle of tumor lysis syndrome
- Tumor lysis may lead to a spiral of progressive renal dysfunction as follows:
- (1) This begins with tumor cells releasing phosphate, potassium, and uric acid.
- (2) Renal failure occurs due to the precipitation of uric acid and calcium phosphate in the kidneys.
- (3) Renal failure then inhibits the excretion of potassium and uric acid, which causes further elevation of potassium and uric acid levels with worsening of tumor lysis syndrome.
- Early dialysis may be needed to break this cycle (more on this below).
the primary problem is now calcium-phosphate
- Tissue damage in tumor lysis syndrome results largely from the precipitation of two substances: uric acid and calcium-phosphate.
- Historically, uric acid was a major concern. This is currently less of an issue because it's relatively easily treated with rasburicase.
- Calcium-phosphate precipitation is becoming the predominant problem:
- The calcium-phosphate product is the calcium concentration (in mg/dL) multiplied by the phosphate concentration (in mg/dL).
- When the calcium-phosphate product rises >60-70, there is a risk of systemic precipitation of calcium phosphate (calciphylaxis).
one minute video to illustrate this better:
epidemiology & risk factors
- TLS generally occurs 1-5 days after chemotherapy initiation.
- It can also occur spontaneously or after radiation therapy.
general risk factors for tumor lysis syndrome
- Baseline LDH >1,500 IU/L.
- Pretreatment hyperuricemia (uric acid >7.5 mg/dL or >446 uM).
- Pretreatment hyperphosphatemia.
- Baseline renal dysfunction.
- Use of novel and more potent therapies (e.g., biological treatments).
- Use of nephrotoxins.(32850076)
malignancies with high risk for tumor lysis syndrome
- Beyond the above risk factors, the tumor type and burden may predict the risk of tumor lysis syndrome (table below).
- Tumor lysis syndrome is rare with most cancers (especially solid tumors). Therefore, don't assume that any renal failure or electrolyte abnormality following chemotherapy is tumor lysis syndrome.
clinical signs & symptoms
symptoms / signs are due to electrolyte abnormalities
- Hyperkalemia (usually first abnormality to emerge)
- Paresthesias, muscle spasms/tetany.
- Uric acid:
- Oliguric renal failure.
- May see uric acid crystals.
simplified Cairo definition of tumor lysis syndrome
- Laboratory definition = Malignancy plus at least two of the following abnormalities (usually following chemotherapy):
- (1) K >6 mEq/L.
- (2) Phosphate >4.5 mg/dL (>1.45 mM).
- (3) Uric acid >8 mg/dL (>476 uM).
- (4) Calcium <7 mg/dL (<1.75 mM).
- Clinical definition
- (1) Laboratory definition plus:
- (2) At least one of the following:
- Acute kidney injury (Cr >1.5 times baseline).
- Cardiac arrhythmia.
- Sudden death.
- Technically, the definition may also be met based on changes in electrolytes over time (e.g. 25% increase in potassium, 25% increase in phosphate). However, in practice such changes are usually not considered (25876990).
differential diagnosis: pseudohyperkalemia
- (1) Pseudohyperkalemia may occur among patients with very high WBC or platelet count.
- Suspect this in patients with elevated potassium, but normal EKG.
- May diagnose this either by:
- (a) Sending STAT potassium to the lab on ice using a heparinized tube.
- (b) Measuring potassium at the bedside with a point-of-care monitor.
- (2) Other sources of tissue necrosis may cause a similar pattern of electrolyte abnormalities
- Acute hepatic necrosis.
- Crush injury.
prevention of tumor lysis syndrome
purine nucleotide metabolism manipulation
- This decision will typically be made by the hematology/oncology team, as part of the chemotherapeutic plan.
- (1) High risk for tumor lysis syndrome:
- Prophylactic rasburicase may be used.(18509186) This is expensive, but it is the most effective medication for protecting against purine metabolites. This makes the most sense in the context of patients whose uric acid level is already elevated.
- (2) Intermediate risk for tumor lysis syndrome:
- (3) Low risk for tumor lysis syndrome:
- Hydration alone (without allopurinol or rasburicase).
- Fluid selection
- Acidic pH may encourage crystallization of uric acid, so historically urinary alkalinization has been used. More recent evidence indicated that urinary alkalinization isn't beneficial, so this has been abandoned.
- For most patients, balanced crystalloid is a reasonable choice (e.g. LR or Plasmalyte). For patients with significant acidosis due to non anion-gap metabolic acidosis or uremia, isotonic bicarbonate could be considered with a goal of bringing the serum bicarbonate level to a normal level (more on pH-guided resuscitation here).
- No clear evidence exists regarding what the ideal fluid and/or rate may be.
- The goal is to render the patient in a euvolemic state with good urine output.
- 🛑 Be careful about placing the patient on a high rate of crystalloid if the patient isn't mobilizing infused fluid. Ideally, patient will mobilize excess fluid in the urine, to achieve a net even fluid balance. However, if the patient is retaining fluid (e.g., due to cardiac or renal dysfunction), then reduce or stop fluid infusion.
- Avoid any nephrotoxic medications (e.g. NSAIDs).
- A complete list of nephrotoxic medications is here.
- Avoid hypotension/malperfusion of kidneys.
- Patients at intermediate-high risk of tumor lysis syndrome may be monitored with serial labs (electrolytes including Ca/Mg/Phos and uric acid).
- The frequency of monitoring depends on the risk of tumor lysis syndrome. For example, q6hr labs may be useful for high-risk patients during induction chemotherapy.
- Enzyme which metabolizes uric acid.
- Effective at reducing uric acid levels within hours. The main drawback is that it's expensive.
- Some retrospective studies suggest that the use of rasburicase may be associated with shorter ICU length of stay (27965022).
- Rasburicase is indicated for patients with tumor lysis syndrome and a uric acid level of >8 mg/dL or >476 uM (especially patients with acute renal failure).
- Contraindications: G6PD deficiency.
- Risks are rare:
- Hemolysis (if patient has G6PD deficiency).
- Conventional dosing: 0.2 mg/kg daily for up to 5 days (this will work great, but it's probably a higher dose than is necessary).
- Reduced dosing strategy: Give 3 mg (fixed dose), repeat if uric acid level remains elevated 12 hours later (29320954).
- The half-life of rasburicase is ~20 hours. Rasburicase may be re-dosed daily, depending on uric acid levels.
- 💡After rasburicase administration, uric acid measurement may be artificially low, due to degradation of uric acid in the blood collection tube. To prevent this, uric acid levels must be obtained on ice and sent directly to the lab. Make sure to order the uric acid level properly:
allopurinol is potentially harmful
- Allopurinol reduces the uric acid level, but increases the level of xanthine production. This is a problem for a few reasons:
- 1) Xanthine can precipitate in the kidneys, causing acute kidney injury (xanthine nephropathy).
- 2) Xanthine levels can't be measured clinically – so we cannot know whether this is happening.
- For most patients, it's better to allow purine nucleotides to be metabolized into uric acid, which can then be treated with rasburicase.
- Allopurinol use may impair the efficacy of rasburicase, so the two drugs shouldn't be used together (25876990).
- Allopurinol might be considered in patients who cannot receive rasburicase (due to allergy or G6PD deficiency).
- Avoid any nephrotoxic medications (e.g. NSAIDs). A complete list of nephrotoxic medications is here.
- Avoid hypotension/malperfusion of kidneys.
avoid potassium or phosphate intake
- Switch to a renal diet (potassium & phosphate restricted).
- Consider short-term use of an oral phosphate binder. Sevelamer (RENAGEL) 800-1600 mg TID with meals may be best choice here (using a higher dose if the phosphate level is already elevated >7.5 mg/dL or >2.4 mM)
- Stop potassium or phosphate supplements (including PRN potassium orders).
- Hyperkalemia is generally the most life-threatening abnormality.
- Management of hyperkalemia is explored in detail within the hyperkalemia chapter. Some minor modifications may be considered within the context of tumor lysis syndrome:
- Avoid acetazolamide (urinary alkalinization could theoretically promote calcium-phosphate precipitation within renal tubules).
- Bicarbonate therapy should be used a bit more cautiously. Excessive bicarbonate and metabolic alkalosis may encourage calcium-phosphate precipitation in kidneys.
- Overall there is a lower threshold for initiation of dialysis (given that dialysis may benefit many abnormalities encountered in tumor lysis syndrome; see below).
ignore hypocalcemia if possible
- Do not treat asymptomatic hypocalcemia (calcium may precipitate with phosphate).
- Symptomatic hypocalcemia may be treated with the lowest dose of calcium possible.
- The ideal treatment for hypocalcemia might be dialysis (with a goal of removing phosphate).
- Hypocalcemia here is really a secondary problem due to hyperphosphatemia, so giving calcium doesn't really fix this.
adequate hydration +/- diuresis
- Fluid selection:
- Alkalinizing the urine may reduce the risk of uric acid precipitation, but an alkaline urine will promote precipitation of calcium-phosphate and xanthine. The uric acid level can generally be controlled with rasburicase, so it's best to avoid urine alkalinization.
- For most patients, a balanced crystalloid is optimal (lactated Ringers or Plasmalyte). In patients with marked acidosis (due to NAGMA or uremic acidosis), isotonic bicarbonate is probably preferable – but it should be used cautiously with a goal of elevating the bicarbonate to the low-normal range (e.g., ~20-24 mM).
- (#1) The first and most important step is to establish euvolemia. If the patient is clinically hypovolemic, administer crystalloid to achieve euvolemia.
- (#2) Once the patient is euvolemic, provide a generous amount of IV fluid (e.g., ~150-200 ml/hr lactated Ringers).
- (#3) If patient doesn't excrete most of the fluid you're administering, consider judicious administration of diuretic (furosemide and/or thiazide diuretic).
- Both furosemide & thiazide diuretics will help excrete potassium and phosphate.
- Forced diuresis is reasonable, yet not proven to be beneficial. If this is done, be careful to replace urinary losses and avoid inducing hypovolemia.
- (#4) Carefully monitor fluid status (inputs/outputs):
- The goal is for patient to have a high urine output while being euvolemic. If the patient has poor urine output despite diuretic use, then stop fluid administration.
- Follow electrolytes and replete potassium and magnesium PRN.
- In general, there is a low threshold for dialysis, because this will resolve numerous problems encountered in tumor lysis syndrome.
- Consider early consultation with nephrology.
- Indications for dialysis may include:
- Volume overload.
- Uric acid severely elevated despite rasburicase (e.g. >10 mg/dL).
- Marked hyperphosphatemia, elevated Calcium-Phosphate product (e.g. >70 mg2/dL2), symptomatic hypocalcemia.
- Uncontrolled hyperkalemia.
- Uremia, acidosis.
- Tumor lysis syndrome plus oliguria.
Follow us on iTunes
The Podcast Episode
Want to Download the Episode?
Right Click Here and Choose Save-As
questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- Don't “correct” hypocalcemia unless mandatory, as this may cause calcium-phosphate precipitation.
- Consult nephrology and consider dialysis early.
- Consider the possibility of tumor lysis syndrome in any cancer patient with hyperkalemia or renal failure.
- Don't forget to discontinue allopurinol in patients with established tumor lysis syndrome who are being treated with rasburicase.
- Tumor Lysis Syndrome (WikEM)
- 18509186 Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008 Jun 1;26(16):2767-78. doi: 10.1200/JCO.2007.15.0177 [PubMed]
- 25876990 Jones GL, Will A, Jackson GH, Webb NJ, Rule S; British Committee for Standards in Haematology. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2015 Jun;169(5):661-71. doi: 10.1111/bjh.13403 [PubMed]
- 27965022 Cairo MS, Thompson S, Tangirala K, Eaddy MT. A Clinical and Economic Comparison of Rasburicase and Allopurinol in the Treatment of Patients With Clinical or Laboratory Tumor Lysis Syndrome. Clin Lymphoma Myeloma Leuk. 2017 Mar;17(3):173-178. doi: 10.1016/j.clml.2016.11.003 [PubMed]
- 29320954 Boutin A, Blackman A, O'Sullivan DM, Forcello N. The value of fixed rasburicase dosing versus weight-based dosing in the treatment and prevention of tumor lysis syndrome. J Oncol Pharm Pract. 2019 Apr;25(3):577-583. doi: 10.1177/1078155217752075 [PubMed]
- 31774551 Durani U, Hogan WJ. Emergencies in haematology: tumour lysis syndrome. Br J Haematol. 2020 Feb;188(4):494-500. doi: 10.1111/bjh.16278 [PubMed]
- 32850076 Puri I, Sharma D, Gunturu KS, Ahmed AA. Diagnosis and management of tumor lysis syndrome. J Community Hosp Intern Med Perspect. 2020 Jun 14;10(3):269-272. doi: 10.1080/20009666.2020.1761185 [PubMed]