N-ACETYLCYSTEINE RESCUE PROTOCOL FOR NEPHROTOXICITY IN CHILDREN CAUSED BY IFOSFAMIDE
Main Article Content
Keywords
Ifosfamide, nephrotoxicity, n-acetylcysteine, rescue protocol
Abstract
Nephrotoxicity is a serious side effect associated with ifosfamide use. It can affect up to 30% of children who are treated with this chemotherapeutic drug, and treatment may necessitate lifelong supplementations, renal dialysis, renal transplant, and in severe cases may result in death. The antioxidant n-acetylcysteine is a promising strategy for mitigating this renal toxicity. It is currently used in children for acetaminophen overdose in the 21-hour IV protocol, a dose which has also been suggested to provide renal protection against ifosfamide. Of significance, both in vitro and in vivo studies suggest n-acetylcysteine does not interfere with the antitumor actions of ifosfamide. Most importantly, n-acetylcysteine has successfully protected against ifosfamide-induced nephrotoxicity in both cell and rodent models, as well as in several paediatric cases, suggesting it should be evaluated as a treatment option for children on ifosfamide who present with renal dysfunction. The purpose of this paper is to outline strategies and recommendations for treating patients at risk or suffering from nephrotoxicity during ifosfamide therapy. These recommendations may be used when deciding who to treat, how and when to treat, as well as several considerations when exact recommendations cannot be met. They have been created to increase both the quality of care and quality of life of paediatric oncology patients.
References
1. Howlander NNA, Krapcho M, Neyman N, et al. Seer cancer statistics review, 1975-2009. (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, April 2012.
2. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006;355:1572-1582.
3. Loebstein R, Koren G. Ifosfamide-induced nephrotoxicity in children: Critical review of predictive risk factors. Pediatrics 1998;101:E8.
4. Jurgens H, Treuner J, Winkler K and Gobel U. Ifosfamide in pediatric malignancies. Semin Oncol 1989;16:46-50.
5. de Kraker J. Ifosfamide in pediatric oncology. Anticancer Drugs 1991;2:339-341.
6. Pratt CB, Douglass EC, Etcubanas EL, et al. Ifosfamide in pediatric malignant solid tumors. Cancer Chemother Pharmacol 1989;24 Suppl 1:S24-27.
7. Bramwell VH, Mouridsen HT, Santoro A, et al. Cyclophosphamide versus ifosfamide: Final report of a randomized phase ii trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 1987; 23: 311-321.
8. Skinner R. Chronic ifosfamide nephrotoxicity in children. Med Pediatr Oncol 2003;41:190-197.
9. Huang Z, Roy P, Waxman DJ. Role of human liver microsomal cyp3a4 and cyp2b6 in catalyzing n-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol 2000;59:961-972.
10. Norpoth K. Studies on the metabolism of isopnosphamide (nsc-109724) in man. Cancer Treat Rep 1976;60:437-443.
11. Woodland C, Ito S, Granvil C P, et al. Evidence of renal metabolism of ifosfamide to nephrotoxic metabolites. Life Sci 2000;68:109-117.
12. Smeitink J, Verreussel M, Schroder C, Lippens R. Nephrotoxicity associated with ifosfamide. Eur J Pediatr 1988;148:164-166.
13. De Schepper J, Stevens G, Verboven M, Baeta C, Otten J. Ifosfamide-induced fanconi's syndrome with growth failure in a 2-year-old child. Am J Pediatr Hematol Oncol 1991;13:39-41.
14. Springate J, Chan K, Lu H, Davies S, Taub M. Toxicity of ifosfamide and its metabolite chloroacetaldehyde in cultured renal tubule cells. In Vitro Cell Dev Biol Anim 1999;35:314-317.
15. Boddy AV, English M, Pearson AD, Idle J R, Skinner R. Ifosfamide nephrotoxicity: Limited influence of metabolism and mode of administration during repeated therapy in paediatrics. Eur J Cancer 1996;32A:1179-1184.
16. Aleksa K, Ito S, Koren G. Renal-tubule metabolism of ifosfamide to the nephrotoxic chloroacetaldehyde: Pharmacokinetic modeling for estimation of intracellular levels. J Lab Clin Med 2004; 143: 159-162.
17. Chen N, Aleksa K, Woodland C, Rieder M, Koren G. N-acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats. Br J Pharmacol 2008;153:1364-1372.
18. Benesic A, Schwerdt G, Mildenberger S, et al. Disturbed ca2+-signaling by chloroacetaldehyde: A possible cause for chronic ifosfamide nephrotoxicity. Kidney Int 2005;68:2029-2041.
19. Sener G, Sehirli O, Yegen BC, et al. Melatonin attenuates ifosfamide-induced fanconi syndrome in rats. J Pineal Res 2004;37:17-25.
20. Berry C, Rector FC, Jr. Renal transport of glucose, amino acid, sodium, chloride, and water. In: The Kidney, Chapter 7, 4th edn. Brenner BM, Rector FC, Jr eds., WB Saunders Co, Philadelphia, PA, 1991; pp. 245-257.
21. Harman AW, Maxwell MJ. An evaluation of the role of calcium in cell injury. Annu Rev Pharmacol Toxicol 1995;35:129-144.
22. Dubourg L, Taniere P, Cochat P, Baverel G, Michoudet C. Toxicity of chloroacetaldehyde is similar in adult and pediatric kidney tubules. Pediatr Nephrol 2002;17:97-103.
23. Takahashi K, Sakurai K, Tanaka H, Fujimoto Y. Necrotic pathway in human osteosarcoma saos-2 cell death induced by chloroacetaldehyde. Anticancer Drugs 2007;18:543-553.
24. Sehirli O, Sakarcan A, Velioglu-Ogunc A, et al. Resveratrol improves ifosfamide-induced fanconi syndrome in rats. Toxicol Appl Pharmacol 2007;222:33-41.
25. Chen N, Aleksa K, Woodland C, Rieder M, Koren G. The effect of n-acetylcysteine on ifosfamide-induced nephrotoxicity: In vitro studies in renal tubular cells. Transl Res 2007;150:51-57.
26. Tylicki L, Rutkowski B, Horl WH. Antioxidants: A possible role in kidney protection. Kidney Blood Press Res 2003;26:303-314.
27. Badary OA. Taurine attenuates fanconi syndrome induced by ifosfamide without compromising its antitumor activity. Oncol Res 1998;10:355-360.
28. Badary OA. Thymoquinone attenuates ifosfamide-induced fanconi syndrome in rats and enhances its antitumor activity in mice. J Ethnopharmacol 1999;67:135-142.
29. Badary OA. L-histidinol attenuates fanconi syndrome induced by ifosfamide in rats. Exp Nephrol 1999;7:323-327.
30. Nissim I, Weinberg JM. Glycine attenuates fanconi syndrome induced by maleate or ifosfamide in rats. Kidney Int 1996;49:684-695.
31. De Vries E, De Flora S. N-acetyl-l-cysteine. J Cell Biochem 1993;17F:S270-S277.
32. Marzullo L. An update of n-acetylcysteine treatment for acute acetaminophen toxicity in children. Curr Opin Pediatr 2005;17:239-245.
33. Prescott LF, Illingworth RN, Critchley JA, Proudfoot AT. Intravenous n-acetylcysteine: Still the treatment of choice for paracetamol poisoning. Br Med J 1980;280:46-47.
34. Williamson K, Wahl MS, Mycyk MB. Direct comparison of 20-hour iv, 36-hour oral, and 72-hour oral acetylcysteine for treatment of acute acetaminophen poisoning. Am J Ther 20:37-40.
35. Smilkstein MJ, Bronstein AC, Linden C, et al. Acetaminophen overdose: A 48-hour intravenous n-acetylcysteine treatment protocol. Ann Emerg Med 1991;20:1058-1063.
36. Yarema MC, Johnson DW, Berlin RJ, et al. Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning. Ann Emerg Med 2009;54:606-614.
37. Mullins ME, Schmidt RU, Jr., Jang TB. What is the rate of adverse events with intravenous versus oral n-acetylcysteine in pediatric patients? Ann Emerg Med 2004;44:547-548; author reply 548-549.
38. Algren A. Review of n-acetylcysteine for the treatment of acetaminophen (paracetamol) toxicity in paediatrics. Second Meeting of the Subcommittee of the Expert Committee on the Selection and Use of Essential Medicines. Geneva, 29 September to 3 October 2008.
39. Mant TG, Tempowski JH, Volans GN and Talbot JC. Adverse reactions to acetylcysteine and effects of overdose. Br Med J (Clin Res Ed) 1984;289:217-219.
40. Zyoud SH, Awang R, Syed Sulaiman SA, Sweileh WM, Al-Jabi SW. Incidence of adverse drug reactions induced by n-acetylcysteine in patients with acetaminophen overdose. Hum Exp Toxicol 29:153-160.
41. Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous n-acetylcysteine. Ann Emerg Med 1998;31:710-715.
42. Stey C, Steurer J, Bachmann S, Medici TC, Tramer MR. The effect of oral n-acetylcysteine in chronic bronchitis: A quantitative systematic review. Eur Respir J 2000;16:253-262.
43. Hanly L, Chen N, Aleksa K, et al. N-acetylcysteine as a novel prophylactic treatment for ifosfamide-induced nephrotoxicity in children: Translational pharmacokinetics. J Clin Pharmacol 2012; 52(1):55-64.
44. Chen N, Hanly L, Rieder M, Yeger H, Koren G. The effect of n-acetylcysteine on the antitumor activity of ifosfamide. Can J Physiol Pharmacol 89:335-343.
45. Hanly L, Figueredo R, Rieder MJ, Koropatnick J, Koren G. The effects of n-acetylcysteine on ifosfamide efficacy in a mouse xenograft model. Anticancer Res 32:3791-3798.
46. Benvenuto JA, Ayele W, Legha SS, et al. Clinical pharmacokinetics of ifosfamide in combination with n-acetylcysteine. Anticancer Drugs 1992;3:19-23.
47. Loebstein R, Atanackovic G, Bishai R, et al. Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children. J Clin Pharmacol 1999;39:454-461.
48. Akcan-Arikan A, Zappitelli M, Loftis LL, et al. Modified rifle criteria in critically ill children with acute kidney injury. Kidney Int 2007;71:1028-1035.
49. Borgstrom L, Kagedal B, Paulsen O. Pharmacokinetics of n-acetylcysteine in man. Eur J Clin Pharmacol 1986;31:217-222.
50. Brade WP, Herdrich K, Kachel-Fischer U,d Araujo CE. Dosing and side-effects of ifosfamide plus mesna. J Cancer Res Clin Oncol 1991;117 Suppl 4:S164-186.
51. Temple A, Baggish J. Guidelines for management of acetaminophen overdose. McNeil Consumer and Specialty; Fort Washington, Pennsylvania; 2005.
52. Sung L, Simons JA, Dayneka NL. Dilution of intravenous n-acetylcysteine as a cause of hponatremia. Pediatrics 1997;100:389-391.
53. Neuwelt EA, Pagel MA, Kraemer DF, Peterson DR, Muldoon LL. Bone marrow chemoprotectionacy in a rat brain tumor model. J Pharmacol Exp Ther 2004;309:594-599.
2. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006;355:1572-1582.
3. Loebstein R, Koren G. Ifosfamide-induced nephrotoxicity in children: Critical review of predictive risk factors. Pediatrics 1998;101:E8.
4. Jurgens H, Treuner J, Winkler K and Gobel U. Ifosfamide in pediatric malignancies. Semin Oncol 1989;16:46-50.
5. de Kraker J. Ifosfamide in pediatric oncology. Anticancer Drugs 1991;2:339-341.
6. Pratt CB, Douglass EC, Etcubanas EL, et al. Ifosfamide in pediatric malignant solid tumors. Cancer Chemother Pharmacol 1989;24 Suppl 1:S24-27.
7. Bramwell VH, Mouridsen HT, Santoro A, et al. Cyclophosphamide versus ifosfamide: Final report of a randomized phase ii trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 1987; 23: 311-321.
8. Skinner R. Chronic ifosfamide nephrotoxicity in children. Med Pediatr Oncol 2003;41:190-197.
9. Huang Z, Roy P, Waxman DJ. Role of human liver microsomal cyp3a4 and cyp2b6 in catalyzing n-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol 2000;59:961-972.
10. Norpoth K. Studies on the metabolism of isopnosphamide (nsc-109724) in man. Cancer Treat Rep 1976;60:437-443.
11. Woodland C, Ito S, Granvil C P, et al. Evidence of renal metabolism of ifosfamide to nephrotoxic metabolites. Life Sci 2000;68:109-117.
12. Smeitink J, Verreussel M, Schroder C, Lippens R. Nephrotoxicity associated with ifosfamide. Eur J Pediatr 1988;148:164-166.
13. De Schepper J, Stevens G, Verboven M, Baeta C, Otten J. Ifosfamide-induced fanconi's syndrome with growth failure in a 2-year-old child. Am J Pediatr Hematol Oncol 1991;13:39-41.
14. Springate J, Chan K, Lu H, Davies S, Taub M. Toxicity of ifosfamide and its metabolite chloroacetaldehyde in cultured renal tubule cells. In Vitro Cell Dev Biol Anim 1999;35:314-317.
15. Boddy AV, English M, Pearson AD, Idle J R, Skinner R. Ifosfamide nephrotoxicity: Limited influence of metabolism and mode of administration during repeated therapy in paediatrics. Eur J Cancer 1996;32A:1179-1184.
16. Aleksa K, Ito S, Koren G. Renal-tubule metabolism of ifosfamide to the nephrotoxic chloroacetaldehyde: Pharmacokinetic modeling for estimation of intracellular levels. J Lab Clin Med 2004; 143: 159-162.
17. Chen N, Aleksa K, Woodland C, Rieder M, Koren G. N-acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats. Br J Pharmacol 2008;153:1364-1372.
18. Benesic A, Schwerdt G, Mildenberger S, et al. Disturbed ca2+-signaling by chloroacetaldehyde: A possible cause for chronic ifosfamide nephrotoxicity. Kidney Int 2005;68:2029-2041.
19. Sener G, Sehirli O, Yegen BC, et al. Melatonin attenuates ifosfamide-induced fanconi syndrome in rats. J Pineal Res 2004;37:17-25.
20. Berry C, Rector FC, Jr. Renal transport of glucose, amino acid, sodium, chloride, and water. In: The Kidney, Chapter 7, 4th edn. Brenner BM, Rector FC, Jr eds., WB Saunders Co, Philadelphia, PA, 1991; pp. 245-257.
21. Harman AW, Maxwell MJ. An evaluation of the role of calcium in cell injury. Annu Rev Pharmacol Toxicol 1995;35:129-144.
22. Dubourg L, Taniere P, Cochat P, Baverel G, Michoudet C. Toxicity of chloroacetaldehyde is similar in adult and pediatric kidney tubules. Pediatr Nephrol 2002;17:97-103.
23. Takahashi K, Sakurai K, Tanaka H, Fujimoto Y. Necrotic pathway in human osteosarcoma saos-2 cell death induced by chloroacetaldehyde. Anticancer Drugs 2007;18:543-553.
24. Sehirli O, Sakarcan A, Velioglu-Ogunc A, et al. Resveratrol improves ifosfamide-induced fanconi syndrome in rats. Toxicol Appl Pharmacol 2007;222:33-41.
25. Chen N, Aleksa K, Woodland C, Rieder M, Koren G. The effect of n-acetylcysteine on ifosfamide-induced nephrotoxicity: In vitro studies in renal tubular cells. Transl Res 2007;150:51-57.
26. Tylicki L, Rutkowski B, Horl WH. Antioxidants: A possible role in kidney protection. Kidney Blood Press Res 2003;26:303-314.
27. Badary OA. Taurine attenuates fanconi syndrome induced by ifosfamide without compromising its antitumor activity. Oncol Res 1998;10:355-360.
28. Badary OA. Thymoquinone attenuates ifosfamide-induced fanconi syndrome in rats and enhances its antitumor activity in mice. J Ethnopharmacol 1999;67:135-142.
29. Badary OA. L-histidinol attenuates fanconi syndrome induced by ifosfamide in rats. Exp Nephrol 1999;7:323-327.
30. Nissim I, Weinberg JM. Glycine attenuates fanconi syndrome induced by maleate or ifosfamide in rats. Kidney Int 1996;49:684-695.
31. De Vries E, De Flora S. N-acetyl-l-cysteine. J Cell Biochem 1993;17F:S270-S277.
32. Marzullo L. An update of n-acetylcysteine treatment for acute acetaminophen toxicity in children. Curr Opin Pediatr 2005;17:239-245.
33. Prescott LF, Illingworth RN, Critchley JA, Proudfoot AT. Intravenous n-acetylcysteine: Still the treatment of choice for paracetamol poisoning. Br Med J 1980;280:46-47.
34. Williamson K, Wahl MS, Mycyk MB. Direct comparison of 20-hour iv, 36-hour oral, and 72-hour oral acetylcysteine for treatment of acute acetaminophen poisoning. Am J Ther 20:37-40.
35. Smilkstein MJ, Bronstein AC, Linden C, et al. Acetaminophen overdose: A 48-hour intravenous n-acetylcysteine treatment protocol. Ann Emerg Med 1991;20:1058-1063.
36. Yarema MC, Johnson DW, Berlin RJ, et al. Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning. Ann Emerg Med 2009;54:606-614.
37. Mullins ME, Schmidt RU, Jr., Jang TB. What is the rate of adverse events with intravenous versus oral n-acetylcysteine in pediatric patients? Ann Emerg Med 2004;44:547-548; author reply 548-549.
38. Algren A. Review of n-acetylcysteine for the treatment of acetaminophen (paracetamol) toxicity in paediatrics. Second Meeting of the Subcommittee of the Expert Committee on the Selection and Use of Essential Medicines. Geneva, 29 September to 3 October 2008.
39. Mant TG, Tempowski JH, Volans GN and Talbot JC. Adverse reactions to acetylcysteine and effects of overdose. Br Med J (Clin Res Ed) 1984;289:217-219.
40. Zyoud SH, Awang R, Syed Sulaiman SA, Sweileh WM, Al-Jabi SW. Incidence of adverse drug reactions induced by n-acetylcysteine in patients with acetaminophen overdose. Hum Exp Toxicol 29:153-160.
41. Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous n-acetylcysteine. Ann Emerg Med 1998;31:710-715.
42. Stey C, Steurer J, Bachmann S, Medici TC, Tramer MR. The effect of oral n-acetylcysteine in chronic bronchitis: A quantitative systematic review. Eur Respir J 2000;16:253-262.
43. Hanly L, Chen N, Aleksa K, et al. N-acetylcysteine as a novel prophylactic treatment for ifosfamide-induced nephrotoxicity in children: Translational pharmacokinetics. J Clin Pharmacol 2012; 52(1):55-64.
44. Chen N, Hanly L, Rieder M, Yeger H, Koren G. The effect of n-acetylcysteine on the antitumor activity of ifosfamide. Can J Physiol Pharmacol 89:335-343.
45. Hanly L, Figueredo R, Rieder MJ, Koropatnick J, Koren G. The effects of n-acetylcysteine on ifosfamide efficacy in a mouse xenograft model. Anticancer Res 32:3791-3798.
46. Benvenuto JA, Ayele W, Legha SS, et al. Clinical pharmacokinetics of ifosfamide in combination with n-acetylcysteine. Anticancer Drugs 1992;3:19-23.
47. Loebstein R, Atanackovic G, Bishai R, et al. Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children. J Clin Pharmacol 1999;39:454-461.
48. Akcan-Arikan A, Zappitelli M, Loftis LL, et al. Modified rifle criteria in critically ill children with acute kidney injury. Kidney Int 2007;71:1028-1035.
49. Borgstrom L, Kagedal B, Paulsen O. Pharmacokinetics of n-acetylcysteine in man. Eur J Clin Pharmacol 1986;31:217-222.
50. Brade WP, Herdrich K, Kachel-Fischer U,d Araujo CE. Dosing and side-effects of ifosfamide plus mesna. J Cancer Res Clin Oncol 1991;117 Suppl 4:S164-186.
51. Temple A, Baggish J. Guidelines for management of acetaminophen overdose. McNeil Consumer and Specialty; Fort Washington, Pennsylvania; 2005.
52. Sung L, Simons JA, Dayneka NL. Dilution of intravenous n-acetylcysteine as a cause of hponatremia. Pediatrics 1997;100:389-391.
53. Neuwelt EA, Pagel MA, Kraemer DF, Peterson DR, Muldoon LL. Bone marrow chemoprotectionacy in a rat brain tumor model. J Pharmacol Exp Ther 2004;309:594-599.