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Treatment is first targeted at the specific metabolic disorder.
Treatment is first targeted at the specific metabolic disorder.


In general, [[rasburicase]] and hydration are the mainstays of treatment in patients with clinical evidence of tumor lysis syndrome.<ref name=":6">{{Cite journal |last=Tosi |first=P. |last2=Barosi |first2=G. |last3=Lazzaro |first3=C. |last4=Liso |first4=V. |last5=Marchetti |first5=M. |last6=Morra |first6=E. |last7=Pession |first7=A. |last8=Rosti |first8=G. |last9=Santoro |first9=A. |last10=Zinzani |first10=P. L. |last11=Tura |first11=S. |date=2008-12-01 |title=Consensus conference on the management of tumor lysis syndrome |url=http://www.haematologica.org/cgi/doi/10.3324/haematol.13290 |journal=Haematologica |language=en |volume=93 |issue=12 |pages=1877–1885 |doi=10.3324/haematol.13290 |issn=0390-6078}}</ref> A [[loop diuretic]] may also be indicated to maintain appropriate urine output.<ref name=":6" /> Further treatment is targeted towards the specific metabolic abnormalities present in patients with TLS (see "main articles" linked above). Mild [[hyperkalemia]] without symptoms can be treated with a [[loop diuretic]] and sodium polystirene, while a temporizing agent such as rapid acting [[insulin]] (in conjunction with glucose) and an agent to stabilize cardiac membranes such as [[calcium carbonate]] may be given in cases of severe hyperkalemia.<ref name=":6" /> Concerning symptoms related to hypocalcemia (e.g. seizures) in TLS patients can be treated with [[calcium gluconate]].<ref name=":6" /> Tumor lysis patients patients may ultimately also require [[renal replacement therapy]] such as through hemodialysis if indicated.<ref name=":6" />
In general, [[rasburicase]] and hydration are the mainstays of treatment in patients with clinical evidence of tumor lysis syndrome.<ref name=":6">{{Cite journal |last=Tosi |first=P. |last2=Barosi |first2=G. |last3=Lazzaro |first3=C. |last4=Liso |first4=V. |last5=Marchetti |first5=M. |last6=Morra |first6=E. |last7=Pession |first7=A. |last8=Rosti |first8=G. |last9=Santoro |first9=A. |last10=Zinzani |first10=P. L. |last11=Tura |first11=S. |date=2008-12-01 |title=Consensus conference on the management of tumor lysis syndrome |url=http://www.haematologica.org/cgi/doi/10.3324/haematol.13290 |journal=Haematologica |language=en |volume=93 |issue=12 |pages=1877–1885 |doi=10.3324/haematol.13290 |issn=0390-6078}}</ref> A [[loop diuretic]] may also be indicated to maintain appropriate production of urine by the kidneys.<ref name=":6" /> Further treatment is targeted towards the specific metabolic abnormalities present in patients with TLS (see "main articles" linked above). Mild [[hyperkalemia]] without symptoms can be treated with a [[loop diuretic]] and sodium polystirene, while a temporizing agent such as rapid acting [[insulin]] (in conjunction with glucose) and an agent to stabilize cardiac membranes such as [[calcium carbonate]] may be given in cases of severe hyperkalemia.<ref name=":6" /> Concerning symptoms related to hypocalcemia (e.g. seizures) in TLS patients can be treated with [[calcium gluconate]].<ref name=":6" /> Tumor lysis patients patients may ultimately also require [[renal replacement therapy]] such as through hemodialysis if indicated.<ref name=":6" />


==Prognosis==
==Prognosis==

Revision as of 16:47, 25 March 2022

Tumor lysis syndrome
Other namesTLS
SpecialtyOncology, hematology Edit this on Wikidata

Tumor lysis syndrome is a group of metabolic abnormalities that can occur as a complication from the treatment of cancer,[1] where large amounts of tumor cells are killed off (lysed) from the treatment, releasing their contents into the bloodstream. This occurs most commonly after the treatment of lymphomas and leukemias and in particular when treating non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL).[2][3] This is a potentially fatal complication[3] and patients at increased risk for TLS should be closely monitored while receiving chemotherapy and should receive preventive measures and treatments as necessary.[4] TLS can also occur on its own (while not being treated with chemotherapy) although this is less common.[4][5]

Tumor lysis syndrome is characterized by high blood potassium (hyperkalemia), high blood phosphate (hyperphosphatemia), low blood calcium (hypocalcemia), high blood uric acid (hyperuricemia), and higher than normal levels of blood urea nitrogen (BUN).[4] These changes in blood electrolytes and metabolites are a result of the release of cellular contents of dying cells into the bloodstream.[4] In this respect, TLS is analogous to rhabdomyolysis, with comparable mechanism and blood chemistry effects but with different cause. In TLS, the breakdown occurs after cytotoxic therapy or from cancers with high cell turnover and tumor proliferation rates.[4] The metabolic abnormalities seen in tumor lysis syndrome can ultimately result in serious complications such as acute uric acid nephropathy, acute kidney failure, seizures, cardiac arrhythmias, and death.[6][7]

Signs and symptoms

  • Hyperkalemia. Potassium is mainly an intracellular ion. High turnover of tumor cells leads to spill of potassium into the blood. Symptoms usually do not manifest until levels are high (> 6.5 mmol/L) [normal 3.5–5.0 mmol/L] and they include[8]
    • palpitations, cardiac conduction abnormalities, and arrhythmias (can be fatal)
    • muscle weakness or paralysis
  • Hyperphosphatemia. Like potassium, phosphates are also predominantly intracellular. Hyperphosphatemia causes acute kidney injury in tumor lysis syndrome, because of deposition of calcium phosphate crystals in the kidney parenchyma.[2]
  • Hypocalcemia. Because of the hyperphosphatemia, calcium is precipitated to form calcium phosphate, leading to hypocalcemia.[2] Symptoms of hypocalcemia include (but are not limited to):[9]
  • Hyperuricemia[10] and hyperuricosuria. Massive cell death and nuclear breakdown generates large quantities of nucleic acids. Of these, the purines (adenine and guanine) are converted to uric acid via the purine degradation pathway and excreted in the urine. However, at the high concentrations of uric acid generated by tumor lysis, uric acid is apt to precipitate as monosodium urate crystals.

Acute uric acid nephropathy (AUAN) due to hyperuricosuria has been a dominant cause of acute kidney failure but with the advent of effective treatments for hyperuricosuria, AUAN has become a less common cause than hyperphosphatemia. Two common conditions related to excess uric acid, gout and uric acid nephrolithiasis, are not features of tumor lysis syndrome.

  • Lactic acidosis.[11][12]
  • Pretreatment spontaneous tumor lysis syndrome. This entity is associated with acute kidney failure due to uric acid nephropathy prior to the institution of chemotherapy and is largely associated with lymphoma and leukemia. 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.[citation needed] TLS is most common during cytotoxic treatment of hematologic neoplasms.[13]

Risk factors

Risk factors for tumor lysis syndrome depend on several different characteristics of the patient, the type of cancer, and the type of chemotherapy used.[14]

Tumor Characteristics: Tumors with a high cell turnover rate, rapid growth rate, and high tumor bulk tend to be more associated with the development of tumor lysis syndrome. The most common tumors associated with this syndrome are poorly differentiated lymphomas (such as Burkitt's lymphoma), other Non-Hodgkin Lymphomas (NHL), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML).[3] Other cancers (such as melanoma) have also been associated with TLS but are less common.

Patient Characteristics: Certain patient-related factors can affect the development of clinical tumor lysis syndrome. These factors include elevated baseline serum creatinine, kidney failure, dehydration, and other issues affecting urinary flow or the acidity of urine.[14]

Chemotherapy Characteristics: Chemo-sensitive tumors, such as lymphomas, carry a higher risk for the development of tumor lysis syndrome. Those tumors that are more responsive to a chemotherapy agent carry a higher TLS risk.[7] Usually, the precipitating medication regimen includes combination chemotherapy, but TLS can be triggered in cancer patients by steroid treatment alone, and sometimes without any treatment—in this case the condition is referred to as "spontaneous tumor lysis syndrome".[13]

Diagnosis

TLS should be suspected in patients with large tumor burden who develop acute kidney failure along with hyperuricemia (> 15 mg/dL) or hyperphosphatemia (> 8 mg/dL). (Most other acute kidney failure occurs with uric acid < 12 mg/dL and phosphate < 6 mg/dL). Acute uric acid nephropathy is associated with little or no urine output. The urinalysis may show uric acid crystals or amorphous urates. The hypersecretion of uric acid can be detected with a high urine uric acid - creatinine ratio > 1.0, compared to a value of 0.6–0.7 for most other causes of acute kidney failure.[citation needed]

Cairo-Bishop definition

In 2004, Cairo and Bishop defined a classification system for tumor lysis syndrome.[15]

  • Laboratory 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
  • Clinical tumor lysis syndrome: 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
    • seizure

A grading scale (0–5) is used depending on the presence of lab TLS, serum creatinine, arrhythmias, or seizures.

Howard definition

In 2011, Howard proposed a refinement of the standard Cairo-Bishop definition of TLS accounting for 2 limitations:[2]

  • Two or more electrolyte laboratory abnormalities must be present simultaneously to be considered related to TLS. In fact, some patients may present with one abnormality, but later another one may develop that is unrelated to the TLS (e.g., hypocalcemia associated with sepsis).
  • A 25% change from baseline should not be considered a criterion since such increases are rarely clinically important unless the value is already outside the normal range.

Moreover, any symptomatic hypocalcemia should constitute clinical TLS.

Prevention

It is important to prevent life threatening manifestations associated with TLS which include acute kidney injury, hyperkalemia (which may cause cardiac arrhythmias), and or hypocalcemia (which may cause cardiac arrhythmias and neuromuscular irritability).[2]

Acute Kidney Injury: Patients at risk for developing TLS (e.g. patients about to receive chemotherapy for a cancer with a high cell turnover rate, especially lymphomas and leukemias) should receive appropriate intravenous hydration in order to improve blood flow to the kidneys, maximize urine output, and ultimately prevent precipitation of uric acid crystals that can led to acute kidney injury.[2][4] A diuretic may also be indicated to further increase urine output in addition to intravenous hydration.[2][4] Another approach to prevent damage to the kidneys is to prevent the build up of uric acid during TLS, and this can be accomplished with use of allopurinol or rasburicase.[2] Allopurinol (a xanthine oxidase inhibitor, which inhibits uric acid production) works by preventing the formation of uric acid following tumor cell lysis.[4][13] Rasburicase is a synthetic urate oxidase enzyme and acts by degrading uric acid.[16][17] It is not recommended to alkalinize urine in the management of TLS.[2][4]

Hyperkalemia: Monitoring potassium levels in the blood frequently and cardiac monitoring (given the risk of cardiac arrhythmias) are important components in the prevention of adverse consequences in TLS.[2] Other strategies include limiting oral intake of potassium and excreting potassium through the gastrointestinal tract using agents such as oral sodium polystyrene sulfonate can be beneficial.[2][4] Insulin therapy (in conjunction with glucose administration) as well as beta-receptor agonists (such as albuterol) can also be used but are temporary interventions[2] and potassium is not excreted from the body. Hemodialysis and hemofiltration can also be used as options to remove potassium from the bloodstream when hyperkalemia is present.[2]

Hypocalcemia: Hyperphosphatemia is a common finding in TLS and high phosphorus levels can itself contribute to hypocalcemia and therefore phosphate binders may be beneficial in preventing this form of hypocalcemia.[2]

Treatment

Main articles: hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia

Treatment is first targeted at the specific metabolic disorder.

In general, rasburicase and hydration are the mainstays of treatment in patients with clinical evidence of tumor lysis syndrome.[18] A loop diuretic may also be indicated to maintain appropriate production of urine by the kidneys.[18] Further treatment is targeted towards the specific metabolic abnormalities present in patients with TLS (see "main articles" linked above). Mild hyperkalemia without symptoms can be treated with a loop diuretic and sodium polystirene, while a temporizing agent such as rapid acting insulin (in conjunction with glucose) and an agent to stabilize cardiac membranes such as calcium carbonate may be given in cases of severe hyperkalemia.[18] Concerning symptoms related to hypocalcemia (e.g. seizures) in TLS patients can be treated with calcium gluconate.[18] Tumor lysis patients patients may ultimately also require renal replacement therapy such as through hemodialysis if indicated.[18]

Prognosis

The rate of mortality from tumor lysis syndrome may vary widely depending on the type of underlying malignancy.[19] However, the occurrence of acute kidney injury is concerning given the high mortality that is generally associated with it.[2]

References

  1. ^ Davidson MB, Thakkar S, Hix JK, Bhandarkar MD, Wong A, Schreiber MJ (April 2004). "Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome". Am. J. Med. 116 (8): 546–54. doi:10.1016/j.amjmed.2003.09.045. PMID 15063817.
  2. ^ a b c d e f g h i j k l m n o Howard, SC; Jones, DP; Pui, CH (12 May 2011). "The tumor lysis syndrome". The New England Journal of Medicine. 364 (19): 1844–54. doi:10.1056/NEJMra0904569. PMC 3437249. PMID 21561350.
  3. ^ a b c Cairo, Mitchell S.; Coiffier, Bertrand; Reiter, Alfred; Younes, Anas; on behalf of the TLS Expert Panel (2010-03-16). "Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus: TLS Risk Classification in Adults/Children with Malignancies". British Journal of Haematology. 149 (4): 578–586. doi:10.1111/j.1365-2141.2010.08143.x.
  4. ^ a b c d e f g h i j Coiffier, Bertrand; Altman, Arnold; Pui, Ching-Hon; Younes, Anas; Cairo, Mitchell S. (2008-06-01). "Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review". Journal of Clinical Oncology. 26 (16): 2767–2778. doi:10.1200/JCO.2007.15.0177. ISSN 1527-7755. PMID 18509186.
  5. ^ Belay, Yohannes; Yirdaw, Ketsela; Enawgaw, Bamlaku (2017). "Tumor Lysis Syndrome in Patients with Hematological Malignancies". Journal of Oncology. 2017: 9684909. doi:10.1155/2017/9684909. ISSN 1687-8450. PMC 5688348. PMID 29230244.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ Cheuk, Daniel Kl; Chiang, Alan Ks; Chan, Godfrey Cf; Ha, Shau Yin (8 March 2017). "Urate oxidase for the prevention and treatment of tumour lysis syndrome in children with cancer". The Cochrane Database of Systematic Reviews. 2017 (3): CD006945. doi:10.1002/14651858.CD006945.pub4. ISSN 1469-493X. PMC 6464610. PMID 28272834.
  7. ^ a b Niederhuber, John E.; Armitage, James O.; Doroshow, James H.; Kastan, Michael B.; Tepper, Joel E. (2014). Aebeloff's Clinical Oncology, Fifth Edition. Philadelphia: Elsevier Saunders. ISBN 978-1-4557-2865-7.
  8. ^ Viera, Anthony J.; Wouk, Noah (2015-09-15). "Potassium Disorders: Hypokalemia and Hyperkalemia". American Family Physician. 92 (6): 487–495. ISSN 1532-0650. PMID 26371733.
  9. ^ Schafer, Anne L.; Shoback, Dolores M. (2000), Feingold, Kenneth R.; Anawalt, Bradley; Boyce, Alison; Chrousos, George (eds.), "Hypocalcemia: Diagnosis and Treatment", Endotext, South Dartmouth (MA): MDText.com, Inc., PMID 25905251, retrieved 2022-03-11
  10. ^ Rampello E, Fricia T, Malaguarnera M (August 2006). "The management of tumor lysis syndrome". Nat Clin Pract Oncol. 3 (8): 438–47. doi:10.1038/ncponc0581. PMID 16894389. S2CID 23245352.
  11. ^ A. R. Moossa; Stephen C. Schimpff; Martin C. Robson (1991). Comprehensive textbook of oncology, Volume 2. Lippincott Williams & Wilkins. ISBN 9780683061475. Retrieved 2 May 2012. ... result in severe metabolic derangements (e.g., hyperuricemia, hypocalcemia, lactic aci- dosis, and the acute tumor lysis syndrome) which require expeditious management. Hyperuricemia Uric acid is the end product of purine catabolism.
  12. ^ Darmon, Michael; Malak, Sandra; Guichard, Isabelle; Schlemmer, Benoit (July–September 2008). "Acute tumor lysis syndrome: a comprehensive review". Revista Brasileira de Terapia Intensiva. 20 (3): 278–285. doi:10.1590/S0103-507X2008000300011. ISSN 0103-507X. PMID 25307096.
  13. ^ a b c Weeks, A. C.; Kimple, M. E. (26 August 2015). "Spontaneous Tumor Lysis Syndrome: A Case Report and Critical Evaluation of Current Diagnostic Criteria and Optimal Treatment Regimens". Journal of Investigative Medicine High Impact Case Reports. 3 (3): 232470961560319. doi:10.1177/2324709615603199. PMC 4748506. PMID 26904699.
  14. ^ a b Coiffier, Bertrand; Riouffol, Catherine (2007-02-01). "Management of tumor lysis syndrome in adults". Expert Review of Anticancer Therapy. 7 (2): 233–239. doi:10.1586/14737140.7.2.233. ISSN 1473-7140. PMID 17288532. S2CID 41115749.
  15. ^ Cairo MS, Bishop M (October 2004). "Tumour lysis syndrome: new therapeutic strategies and classification". Br. J. Haematol. 127 (1): 3–11. doi:10.1111/j.1365-2141.2004.05094.x. PMID 15384972. S2CID 35738745.
  16. ^ Jones, Gail L; Will, Andrew; Jackson, Graham H; Webb, Nicholas J A; Rule, Simon (2015-04-15). "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". British Journal of Haematology. 169 (5): 661–671. doi:10.1111/bjh.13403. ISSN 0007-1048.
  17. ^ Cammalleri L, Malaguarnera M (2007). "Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout". Int J Med Sci. 4 (2): 83–93. doi:10.7150/ijms.4.83. PMC 1838823. PMID 17396159.
  18. ^ a b c d e Tosi, P.; Barosi, G.; Lazzaro, C.; Liso, V.; Marchetti, M.; Morra, E.; Pession, A.; Rosti, G.; Santoro, A.; Zinzani, P. L.; Tura, S. (2008-12-01). "Consensus conference on the management of tumor lysis syndrome". Haematologica. 93 (12): 1877–1885. doi:10.3324/haematol.13290. ISSN 0390-6078.
  19. ^ Durani, Urshila; Shah, Nilay D.; Go, Ronald S. (December 2017). "In-Hospital Outcomes of Tumor Lysis Syndrome: A Population-Based Study Using the National Inpatient Sample". The Oncologist. 22 (12): 1506–1509. doi:10.1634/theoncologist.2017-0147. ISSN 1549-490X. PMC 5728022. PMID 28904174.
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