Tumor Lysis Syndrome2


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Tumor Lysis Syndrome2

  1. 1. 主講者 : 黃馨瑩 指導者 : 李偉政 96-09-27
  2. 2. Introduction <ul><li>Tumor lysis syndrome (TLS) is the metabolic complication of either rapid tumor cell turnover or chemotherapy-induced tumor necrosis. </li></ul><ul><li>It is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia with secondary hypocalcemia and acute renal failure. </li></ul><ul><li>Key points: </li></ul><ul><ul><ul><li>Identification of high-risk patients </li></ul></ul></ul><ul><ul><ul><li>Initiation of preventive therapy </li></ul></ul></ul><ul><ul><ul><li>Early recognition and intervention of TLS. </li></ul></ul></ul>96-09-27
  3. 3. Outline <ul><li>Definition </li></ul><ul><li>Frequency </li></ul><ul><li>Etiology and risk factors </li></ul><ul><li>Pathophysiology </li></ul><ul><li>Prevention </li></ul><ul><li>Diagnostic evaluation and Management </li></ul><ul><li>Conclusion </li></ul>96-09-27
  4. 4. Definition <ul><li>A potentially fatal metabolic abnormalities resulting from spontaneous or treatment-related tumor necrosis or apoptosis . </li></ul><ul><li>Characteristic: 4 “H” </li></ul><ul><ul><li>Hyperuricemia - deoxyribonucleic acid (DNA) breakdown </li></ul></ul><ul><ul><li>Hyperkalemia - cytosol breakdown </li></ul></ul><ul><ul><li>Hyperphosphatemia - protein breakdown </li></ul></ul><ul><ul><li>Hypocalcemia - secondary to hyperphosphatemia . </li></ul></ul><ul><li>These derangements can result in acute renal failure , cardiac dysrhythmias, muscle cramps and sudden death . </li></ul>96-09-27
  5. 5. Outline <ul><li>Definition </li></ul><ul><li>Frequency </li></ul><ul><li>Etiology and risk factors </li></ul><ul><li>Pathophysiology </li></ul><ul><li>Prevention </li></ul><ul><li>Diagnostic evaluation and Management </li></ul><ul><li>Conclusion </li></ul>96-09-27
  6. 6. Frequency <ul><li>Incidence: unknown. </li></ul><ul><li>Prevalence: varies, but Lab > Clinical TLS </li></ul><ul><ul><li>bulky, aggressive, and treatment-sensitive tumors </li></ul></ul><ul><ul><li>intermediate-grade or high-grade non-Hodgkin lymphomas: </li></ul></ul><ul><ul><ul><li>Laboratory TLS: 42% </li></ul></ul></ul><ul><ul><ul><li>Clinical TLS: 6% </li></ul></ul></ul><ul><ul><li>Acute leukemia: </li></ul></ul><ul><ul><ul><li>Laboratory TLS:70% </li></ul></ul></ul><ul><ul><ul><li>Clinical TLS: 3% </li></ul></ul></ul><ul><li>Future: incidence of TLS  </li></ul><ul><li>Advance / aggressive regimen  broader spectrum of malignancies. </li></ul>96-09-27
  7. 7. Outline <ul><li>Definition </li></ul><ul><li>Frequency </li></ul><ul><li>Etiology and risk factors </li></ul><ul><li>Pathophysiology </li></ul><ul><li>Prevention </li></ul><ul><li>Diagnostic evaluation and Management </li></ul><ul><li>Conclusion </li></ul>96-09-27
  8. 8. Etiology <ul><li>Mostly associated with: 2 “L” </li></ul><ul><ul><li>High grade lymphomas , eg. Burkitt lymphoma </li></ul></ul><ul><ul><li>Leukemias , eg.acute lymphoblastic leukemia (ALL) </li></ul></ul><ul><li>Other malignancies: eg. Multiple myeloma, Breast cancer, ovarian cancer, Small cell lung cancer, etc. </li></ul>96-09-27
  9. 9. Spontaneous vs. Chemotherapy-induced TLS <ul><li>Spontaneous: </li></ul><ul><ul><li>Prior to chemotherapy </li></ul></ul><ul><ul><li>Rapid cell turnover rate </li></ul></ul><ul><ul><li>Lack of hyperphosphatemia (reutilize released phosphorus for resynthesis of new tumor cells) </li></ul></ul><ul><li>Chemotherapy-induced: </li></ul><ul><ul><li>Post chemotherapy: </li></ul></ul><ul><ul><li>< 3 days </li></ul></ul><ul><ul><li>Tumors that have a high growth fraction and high sensitivity to chemotherapy. </li></ul></ul>96-09-27
  10. 10. Risk Factors <ul><li>Tumor </li></ul><ul><ul><li>high proliferative rate </li></ul></ul><ul><ul><li>high sensitivity to cytotoxic therapy </li></ul></ul><ul><ul><li>Large tumor masses </li></ul></ul><ul><li>Pre-existing renal insufficiency </li></ul><ul><li>Hyperuricemia </li></ul><ul><li>Hypovolemia </li></ul><ul><li>High serum LDH: highest risk for TLS </li></ul>96-09-27
  11. 11. Outline <ul><li>Definition </li></ul><ul><li>Frequency </li></ul><ul><li>Etiology and risk factors </li></ul><ul><li>Pathophysiology </li></ul><ul><li>Prevention </li></ul><ul><li>Diagnostic evaluation and Management </li></ul><ul><li>Conclusion </li></ul>96-09-27
  12. 12. Pathophysiology 96-09-27
  13. 13. Pathophysiology <ul><li>ARF : </li></ul><ul><li>Renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine  obstructive nephropathy. </li></ul><ul><ul><li>Oliguric (<400 ml/d)  volume overload  hypertension, pulmonary edema. </li></ul></ul><ul><ul><li>High BUN levels (increased protein catabolism)  pericarditis, platelet dysfunction, defective cellular immunity. </li></ul></ul><ul><ul><li>Severe enough to require dialysis, but with prompt supportive measures it usually is reversible. </li></ul></ul><ul><li>Two forms of ARF: </li></ul><ul><ul><li>Prior to chemotherapy: Uric acid nephropathy </li></ul></ul><ul><ul><ul><li>Intratubular precipitation of UA  obstructive nephropathy </li></ul></ul></ul><ul><ul><ul><li>Direct toxicity to epithelial and endothelial cells  activate immune system </li></ul></ul></ul><ul><ul><li>Post chemotherapy: Hyperphosphatemia-associated </li></ul></ul><ul><ul><ul><li>Intrarenal Calcium phosphate precipitation </li></ul></ul></ul><ul><ul><ul><li>Direct tubular toxicity of phosphate </li></ul></ul></ul><ul><li>Purine metabolism </li></ul>96-09-27
  14. 14. Pathophysiology <ul><li>Other Problems to be Considered: </li></ul><ul><ul><li>Prerenal: </li></ul></ul><ul><ul><li>volume depletion from anorexia, vomiting, diarrhea, and bleeding. </li></ul></ul><ul><ul><li>Renal parenchymal: </li></ul></ul><ul><ul><li>tumor infiltration, myeloma kidney, drug nephrotoxicity from chemotherapeutic agents or antibiotics, radiocontrast nephropathy, vasculitis, and cryoglobulinemic glomerulonephritis. </li></ul></ul><ul><ul><li>Postrenal: </li></ul></ul><ul><ul><li>Pelvic or retroperitoneal masses. </li></ul></ul>96-09-27
  15. 15. Pathophysiology <ul><li>Cardiac arrhythmia : </li></ul><ul><li>Electrolyte imbalance </li></ul><ul><ul><li>Hyperkalemia </li></ul></ul><ul><ul><li> ECG changes (peaked T waves, flattened P waves, prolonged PR interval, widened QRS complexes, deep S wave, and sine waves)  asystole. </li></ul></ul><ul><ul><li>Hypocalcemia </li></ul></ul><ul><ul><li> QT interval lengthening  ventricular arrhythmia. </li></ul></ul><ul><li>Metabolic acidosis : </li></ul><ul><li>ARF and liberation of large amounts of endogenous intracellular acids  HCO3 ↓, high anion gap acidosis  worsen electrolyte imbalances </li></ul><ul><ul><li>K: intracellular uptake↓ </li></ul></ul><ul><ul><li>UA: solubility ↓ </li></ul></ul><ul><ul><li>P: extracellular shift ↑ </li></ul></ul><ul><ul><li>Ca: solubility ↑ </li></ul></ul><ul><ul><li> Proper fluid management, alkalinization of the urine, correction of acidosis, and attention to infections. </li></ul></ul>96-09-27 96-09-27
  16. 16. Outline <ul><li>Definition </li></ul><ul><li>Frequency </li></ul><ul><li>Etiology and risk factors </li></ul><ul><li>Pathophysiology </li></ul><ul><li>Prevention </li></ul><ul><li>Diagnostic evaluation and Management </li></ul><ul><li>Conclusion </li></ul>96-09-27
  17. 17. Prevention – High-risk patients <ul><li>Prophylactic measures: </li></ul><ul><ul><li>Hydration (maintain U/O > 2.5 L/day) </li></ul></ul><ul><ul><li>Xanthine oxidase inhibitors: Allopurinol </li></ul></ul><ul><ul><li>Urine alkalinization </li></ul></ul><ul><ul><li>Reversible forms of renal insufficiency (eg, volume contraction, hypercalcemia, urinary tract obstruction) </li></ul></ul><ul><li>Timeframe: 24~48hours prior to initiation of cytotoic therapy until 48~72 hours after chemotherapy. </li></ul>96-09-27
  18. 18. Allopurinol vs. Rasburicase <ul><li>Low risk patients: Allopurinol </li></ul><ul><ul><li>UA: normal </li></ul></ul><ul><ul><li>certain tumors (namely non-hematologic malignancies, Hodgkin's lymphoma, chronic myeloid leukemia), </li></ul></ul><ul><ul><li>Tumor burden: lower </li></ul></ul><ul><ul><li>(WBC < 50 x 10(9)/L and LDH < 2x normal), </li></ul></ul><ul><ul><li>Intensity of cytoreductive therapy: Low </li></ul></ul><ul><ul><li>Intravascular volume: adequate </li></ul></ul><ul><ul><li>Tumor infiltration of the kidney: absent </li></ul></ul><ul><li>High risk patients: Rasburicase </li></ul><ul><ul><li>UA: increased </li></ul></ul><ul><ul><li>certain tumors (eg, Burkitt's lymphoma, lymphoblastic lymphoma, acute lymphoblastic leukemia, and acute myeloid leukemia), </li></ul></ul><ul><ul><li>Tumor burden: High </li></ul></ul><ul><ul><li>(WBC > 50 x 10(9)/L and LDH >2x normal), </li></ul></ul><ul><ul><li>Intensity of cytoreductive therapy: aggressive </li></ul></ul><ul><ul><li>Intravascular volume: decrease </li></ul></ul><ul><ul><li>Tumor infiltration of the kidney: present </li></ul></ul>96-09-27 Goal: prevention and/or treatment of uric acid nephropathy
  19. 19. Mechanisms of action 96-09-27
  20. 20. Urine alkalinization <ul><li>Controversial. </li></ul><ul><li>Medication: acetazolamide and sodium bicarbonate . </li></ul><ul><li>Alkalinization to a pH in the range of 6.5 to 7.0 </li></ul><ul><li>Discourage: </li></ul><ul><ul><li>Hydration alone is effective. </li></ul></ul><ul><ul><li>Application of rasburicase. </li></ul></ul><ul><ul><li>Disadvantage: </li></ul></ul><ul><ul><ul><li>fluid overload </li></ul></ul></ul><ul><ul><ul><li>Metabolic alkalosis </li></ul></ul></ul><ul><ul><ul><li>Requires a pH >7.4 in order to prevent xanthine precipitation </li></ul></ul></ul><ul><ul><ul><li>Promoting calcium phosphate deposition in the kidney . </li></ul></ul></ul>96-09-27
  21. 21. Rampello E et al. (2006) The management of tumor lysis syndrome Nat Clin Pract Oncol 3 : 438 – 447 doi:10.1038/ncponc0581 Table 2 Solubility of purine analogs and calcium phosphate at pH 5.0 and 7.0 96-09-27
  22. 22. Outline <ul><li>Definition </li></ul><ul><li>Frequency </li></ul><ul><li>Etiology and risk factors </li></ul><ul><li>Pathophysiology </li></ul><ul><li>Prevention </li></ul><ul><li>Diagnostic evaluation and Management </li></ul><ul><li>Conclusion </li></ul>96-09-27
  23. 23. Diagnostic evaluation 96-09-27 History of malignancy Symptom and sign of metabolic abnormality and complications prior to or after chemotherapy Management: Hydration and diuretics Correct electrolyte imbalance Hemodialysis if needed Urine alkalization: controversial. TLS?? 4 “H” Presence of risk factor Work up: Laboratory: electrolyte, LDH, RFT, urine pH, EKG Image studies Others: Monitor I/O, fluid status, histologic findings
  24. 24. Classification – Cairo-Bishop definition <ul><li>Laboratory TLS: </li></ul><ul><ul><li>3days < chemotherapy + adequate hydration (plus/minus alkalinization) and a hypouricemic agent(s). < 7 days, </li></ul></ul><ul><ul><li>≧ 2 of the following </li></ul></ul><ul><ul><ul><li>Uric acid </li></ul></ul></ul><ul><ul><ul><ul><li>> 8 mg/dl (476 micromol/L), or </li></ul></ul></ul></ul><ul><ul><ul><ul><li>> 25% from baseline </li></ul></ul></ul></ul><ul><ul><ul><li>Potassium </li></ul></ul></ul><ul><ul><ul><ul><li>> 6.0 meq/L, or </li></ul></ul></ul></ul><ul><ul><ul><ul><li>> 25% from baseline </li></ul></ul></ul></ul><ul><ul><ul><li>Phosphate </li></ul></ul></ul><ul><ul><ul><ul><li>> 4.5 mg/dl (1.45 mmol/L), or </li></ul></ul></ul></ul><ul><ul><ul><ul><li>> 25% from baseline </li></ul></ul></ul></ul><ul><ul><ul><li>Calcium </li></ul></ul></ul><ul><ul><ul><ul><li>< 7 mg/dl (1.75 mmol/L), or </li></ul></ul></ul></ul><ul><ul><ul><ul><li>< 25% from baseline). </li></ul></ul></ul></ul><ul><li>Clinical TLS: </li></ul><ul><ul><li>Laboratory TLS + ≧ 1 of the following: </li></ul></ul><ul><ul><ul><li>Cr >1.5x upper limit of normal </li></ul></ul></ul><ul><ul><ul><li>cardiac arrhythmia/sudden death </li></ul></ul></ul><ul><ul><ul><li>seizure. </li></ul></ul></ul>The grading system (zero to five) is based upon the presence or absence of the laboratory syndrome, degree of elevation in the serum creatinine concentration, presence and type of cardiac arrhythmia, and presence and severity of seizure. 96-09-27
  25. 25. Management <ul><li>Hydration and diuretics </li></ul><ul><li>Correct electrolyte imbalance </li></ul><ul><ul><li>Hemodialysis if needed </li></ul></ul><ul><li>Urine alkalization: controversial. </li></ul><ul><li>Monitor sodium, calcium, potassium, phosphate, creatinine, uric acid, urine pH and LDH levels </li></ul>96-09-27
  26. 26. Rampello E et al. (2006) The management of tumor lysis syndrome Nat Clin Pract Oncol 3 : 438 – 447 doi:10.1038/ncponc0581 Table 3 Tumor lysis syndrome management 96-09-27
  27. 27. Outline <ul><li>Definition </li></ul><ul><li>Frequency </li></ul><ul><li>Etiology and risk factors </li></ul><ul><li>Pathophysiology </li></ul><ul><li>Prevention </li></ul><ul><li>Diagnostic evaluation and Management </li></ul><ul><li>Conclusion </li></ul>96-09-27
  28. 28. Conclusion <ul><li>Tumor lysis syndrome (TLS): spontaneous or chemotherapy-induced tumor necrosis. </li></ul><ul><li>It is characterized by 4 “H”and acute renal failure. </li></ul><ul><li>Identify high-risk patients: tumor, pre-existing conditions. </li></ul><ul><li>Initiation of preventive therapy: hydration, allopurinol vs. rasburicase, urine alkalinization (controversial). </li></ul><ul><li>Dialysis if needed: refractory electrolyte imbalance, hyperuricemia and ARF. </li></ul><ul><li>Future: incidence of TLS may increase. </li></ul>96-09-27 96-09-27
  29. 29. Reference <ul><li>1. Kjellstrand, CM, Campbell, DC, von Hartitzsch, B, Buselmeier, TJ. Hyperuricemic acute renal failure. Arch Intern Med 1974; 133:349. </li></ul><ul><li>2. Tsokos, GC, Balow, JE, Spiegel, RJ, Magrath, IT. Renal and metabolic complications of undifferentiated and lymphoblastic lymphomas. Medicine 1981; 60:218. </li></ul><ul><li>3. Hande, KR, Garrow, GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin's lymphoma. Am J Med 1993; 94:133. </li></ul><ul><li>4. Fassas, AB, Desikan, KR, Siegel, D, et al. Tumour lysis syndrome complicating high-dose treatment in patients with multiple myeloma. Br J Haematol 1999; 105:938. </li></ul><ul><li>5. Drakos, P, Bar-Ziv, J, Catane, R. Tumor lysis syndrome in nonhematologic malignancies. Report of a case and review of the literature. Am J Clin Oncol 1994; 17:502. </li></ul><ul><li>6. Gold, JE, Malamud, SC, LaRosa, F, Osband, ME. Adoptive chemoimmunotherapy using ex vivo activated memory T-cells and cyclophosphamide: Tumor lysis syndrome of a metastatic soft tissue sarcoma. Am J Hematol 1993; 44:42. </li></ul><ul><li>7. Bilgrami, SF, Fallon, BG. Tumor lysis syndrome after combination chemotherapy for ovarian cancer. Med Pediatr Oncol 1993; 21:521. </li></ul><ul><li>8. Chan, JK. Tumor lysis syndrome associated with chemotherapy in ovarian cancer. J Clin Oncol 2005; 23:6794,. </li></ul><ul><li>9. Shamseddine, AI, Khalil, AM, Wehbeh, MH. Acute tumor lysis syndrome with squamous cell carcinoma of the vulva. Gynecol Oncol 1993; 51:258. </li></ul><ul><li>10. Kalemkerian, GP, Darwish, B, Varterasian, ML. Tumor lysis syndrome in small cell carcinoma and other solid tumors. Am J Med 1997; 103:363. </li></ul><ul><li>11. Pentheroudakis, G, O'Neill, VJ, Vasey, P, Kaye, SB. Spontaneous acute tumour lysis syndrome in patients with metastatic germ cell tumours. Report of two cases. Support Care Cancer 2001; 9:554. </li></ul><ul><li>12. Malik, IA, Abubakar, S, Alam, F, Khan, A. Dexamethasone-induced tumor lysis syndrome in high-grade non- Hodgkin's lymphoma. South Med J 1994; 87:409. </li></ul><ul><li>13. Tiley, C, Grimwade, D, Findlay, M, et al. Tumour lysis following hydrocortisone prior to a blood product transfusion in T-cell acute lymphoblastic leukaemia. Leuk Lymphoma 1992; 8:143. </li></ul><ul><li>14. Cairo, MS, Bishop, M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004; 127:3. </li></ul><ul><li>15. Frei, E, 3rd, Bentzel, CJ, Rieselbach, R, Block, JB. Renal complications of neoplastic disease. J Chronic Dis 1963; 16:757. </li></ul><ul><li>16. Razis, E, Arlin, ZA, Ahmed, T, et al. Incidence and treatment of tumor lysis syndrome in patients with acute leukemia. Acta Haematol 1994; 91:171. </li></ul><ul><li>17. Band, PR, Silverberg, DS, Henderson, JF, et al. Xanthine nephropathy in a patient with lymphosarcoma treated with allopurinol. N Engl J Med 1970; 283:354. </li></ul><ul><li>18. Veenstra, J, Krediet, RT, Somers, R, Arisz, L. Tumour lysis syndrome and acute renal failure in Burkitt's lymphoma. Description of 2 cases and a review of the literature on prevention and management. Neth J Med 1994; 45:211. </li></ul><ul><li>19. Jasek, AM, Day, HJ. Acute spontaneous tumor lysis syndrome. Am J Hematol 1994; 47:129. </li></ul><ul><li>20. Sklarin, N, Markham, M. Spontaneous recurrent tumor lysis syndrome in breast cancer. Am J Clin Oncol 1995; 18:71. </li></ul><ul><li>21. Stapleton, FB, Strother, DR, Roy, S, et al. Acute renal failure at onset of therapy for advanced stage Burkitt lymphoma and B cell acute lymphoblastic lymphoma. Pediatrics 1988; 82:863. </li></ul><ul><li>22. Kelton, J, Kelley, WN, Holmes, EW. A rapid method for the detection of acute uric acid nephropathy. Arch Intern Med 1978; 138:612. </li></ul><ul><li>23. Smalley, RV, Guaspari, A, Haase-Statz, S, et al. Allopurinol: intravenous use for prevention and treatment of hyperuricemia. J Clin Oncol 2000; 18:1758. </li></ul><ul><li>24. Feusner, J, Farber, MS. Role of intravenous allopurinol in the management of acute tumor lysis syndrome. Semin Oncol 2001; 28:13. </li></ul><ul><li>25. Sanofi Elitek for uric acid management will launch by mid-August. &quot;The Pink Sheet&quot;, July 22, 2002. F-D-C Reports 2002; 64:16. </li></ul><ul><li>26. Rasburicase (Elitek) for Hyperuricemia. Med Lett Drugs Ther 2002; 44:96. </li></ul><ul><li>27. Navolanic, PM, Pui, CH, Larson, RA, et al. Elitek-rasburicase: an effective means to prevent and treat hyperuricemia associated with tumor lysis syndrome, a Meeting Report, Dallas, Texas, January 2002. Leukemia 2003; 17:499. </li></ul><ul><li>28. Conger, JD, Falk, SA. Intrarenal dynamics in the pathogenesis and prevention of acute urate nephropathy. J Clin Invest 1977; 59:786. </li></ul><ul><li>29. Pichette, V, Leblanc, M, Bonnardeaux, A, et al. High dialysate flow rate continuous arteriovenous hemodialysis: A new approach for the treatment of acute renal failure and tumor lysis syndrome. Am J Kidney Dis 1994; 23:591. </li></ul><ul><li>30. Sakarcan, A, Quigley, R. Hyperphosphatemia in tumor lysis syndrome: The role of hemodialysis and continuous veno-venous hemofiltration. Pediatr Nephrol 1994; </li></ul><ul><li>31. PURINE METABOLISM; Georges VAN DEN BERGHE, Françoise BONTEMPS, Marie-Françoise VINCENT. </li></ul>96-09-27
  30. 31. Mechanism of Action Recommended dosing: 0.15 or 0.20 mg/kg/d for 5 d 96-09-27
  31. 32. Management 25~50gm Q6h Kayexalate Exchange resins Insulin + dextrose 1meq/kg IV 50~100meq/L IVF Sodium bicarbonate Intracellular potassium transporters Hyperkalemia 10ml Q2h for 12x/day Aluminum hydroxide Phosphate-binding agents Hyperphosphatemia 10% calcium chloride: K + ↑: 2~4mg/kg Q6~8h prn K + ↓: 0.5~1gm Q1~3d Calcium gluconate; Calcium chloride Mineral Hypocalcemia 0.15~0.2mg/kg/d for 5~7 d Rasburicase Uric acid oxidizers Prophylaxis: 200~600mg/dl Tx: 600~900mg/dl Allopurinol Xanthine oxidase inhibitors Hyperuricemia Dose Drug name Drug category Metabolic abnormality