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Ifosfamide-Related Encephalopathy in Elderly Patients

Report of Five Cases and Review of the Literature

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Abstract

Encephalopathy is a serious adverse reaction occurring in 15–30% of patients treated with the alkylating agent ifosfamide. Patients with this adverse effect may experience seizures, drowsiness, confusion and hallucinations of different grades of severity. In this article, we describe five cases of acute CNS toxicity in patients aged ≥65 years of age treated with ifosfamide and we review data on the management and outcome of this serious complication in elderly patients.

All five patients experienced symptoms of encephalopathy soon after receiving combination chemotherapy including ifosfamide for different tumours. All of the patients had been assessed by means of a Comprehensive Geriatric Assessment for the presence of associated diseases, disability, cognitive status and depression, and scores were satisfactory in all patients, although case 5 was deemed frail because of cancer-related limitation in movement. In four patients, the antidote methylene blue (methylthioninium chloride) was administered intravenously, with successful recovery in three patients and a fatal outcome in the fourth patient. The fifth patient rapidly recovered after discontinuation of ifosfamide and did not receive methylene blue.

The roles of older age, peak ifosfamide concentration, low albumin levels, increased serum creatinine and bulky abdominal disease as predisposing factors for ifosfamide-related encephalopathy in retrospective series are controversial.

Although methylene blue has been frequently administered in patients with ifosfamide-related encephalopathy, its efficacy in this context has not been assessed objectively. Thus, careful baseline evaluation of elderly patients and constant clinical observation during infusion, especially during the first course of therapy, are recommended to reduce the risk of severe CNS toxicity from ifosfamide.

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References

  1. Kaijser GP, Beijnen JH, Bult A. Ifosfamide metabolism and pharmacokinetics. Anticancer Res 1994 Mar-Apr; 14(2A): 517–32

    PubMed  CAS  Google Scholar 

  2. Klastersky J. Side effects of ifosfamide. Oncology 2003; 65Suppl. 2: 7–10

    Article  PubMed  CAS  Google Scholar 

  3. Cerny T, Lind M, Thatcher N, et al. A simple outpatient treatment with oral ifosfamide and oral etoposide for patients with small cell lung cancer (SCLC). Br J Cancer 1989 Aug; 60(2): 258–61

    Article  PubMed  CAS  Google Scholar 

  4. Kupfer A, Aeschlimann C, Cerny T. Methylene blue and the neurotoxic mechanisms of ifosfamide and encephalopathy. Eur J Clin Pharmacol 1996; 50: 249–52

    Article  PubMed  CAS  Google Scholar 

  5. Visarius TM, Bahler H, Kupfer A, et al. Thiodiglycolic acid is excreted by humans receiving ifosfamide and inhibits mitochondrial function in rats. Drug Metab Dispos 1998 Mar; 26(3): 193–6

    PubMed  CAS  Google Scholar 

  6. Chatten JY, Idle JR, Vagbo CB, et al. Insights into the mechanisms of ifosfamide encephalopathy: drug metabolites have agonistic effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and induce cellular acidification in mouse cortical neurons. J Pharmacol Exp Ther 2001 Dec; 299(3): 1161–8

    Google Scholar 

  7. Kupfer A, Aeschlimann C, Wermuth B, et al. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet 1994 Mar 26; 343(8900): 763–4

    Article  PubMed  CAS  Google Scholar 

  8. Patel PN. Methylene blue for management of ifosfamide-induced encephalopathy. Ann Pharmacother 2006 Feb; 40(2): 299–303

    Article  PubMed  CAS  Google Scholar 

  9. Pelgrims J, De Vos F, Van den Brande J, et al. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Br J Cancer 2000 Jan; 82(2): 291–4

    Article  PubMed  CAS  Google Scholar 

  10. Buesa JM, Garcia-Teijido P, Losa R, et al. Treatment of ifosfamide encephalopathy with intravenous thiamin. Clin Cancer Res 2003 Oct 1; 9(12): 4636–7

    PubMed  CAS  Google Scholar 

  11. Hamadani M, Awan F. Role of thiamine in managing ifosfamide-induced encephalopathy. J Oncol Pharm Pract 2006 Dec; 12(4): 237–9

    Article  PubMed  CAS  Google Scholar 

  12. Basso U, Monfardini S. Multidimensional geriatric evaluation in elderly cancer patients: a practical approach. Eur J Cancer Care (Engl) 2004 Dec; 13(5): 424–33

    Article  CAS  Google Scholar 

  13. Balducci L, Yates J. General guidelines for the management of older patients with cancer. Oncology (Williston Park) 2000; 14: 221–7

    CAS  Google Scholar 

  14. Rieger C, Fiegl M, Tischer J, et al. Incidence and severity of ifosfamide-induced encephalopathy. Anticancer Drugs 2004 Apr; 15(4): 347–50

    Article  PubMed  CAS  Google Scholar 

  15. David KA, Picus J. Evaluating risk factors for the development of ifosfamide encephalopathy. Am J Clin Oncol 2005 Jun; 28(3): 277–80

    Article  PubMed  CAS  Google Scholar 

  16. Meanwell CA, Blake AE, Kelly KA, et al. Prediction of ifosfamide/mesna associated encephalopathy. Eur J Cancer Clin Oncol 1986 Jul; 22(7): 815–9

    Article  PubMed  CAS  Google Scholar 

  17. Danesh MM, De Giorgio CM, Beydoun SR. Ifosfamide encephalopathy. J Toxicol Clin Toxicol 1989; 27(4–5): 293–8

    Article  PubMed  CAS  Google Scholar 

  18. Zulian GB, Tullen E, Maton B. Methylene blue for ifosfamide-associated encephalopathy. N Engl J Med 1995 May 4; 332(18): 1239–40

    Article  PubMed  CAS  Google Scholar 

  19. Park IS, Lee HJ, Lee YS, et al. Ifosfamide-induced encephalopathy with or without using methylene blue. Int J Gynecol Cancer 2005 Sep-Oct; 15(5): 807–10

    Article  PubMed  CAS  Google Scholar 

  20. Sarosy G. Ifosfamide: pharmacologic overview. Semin Oncol 1989 Feb; 16 (1 Suppl. 3): 2–8

    PubMed  CAS  Google Scholar 

  21. Lewis LD, Fitzgerald DL, Mohan P. The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients. Br J Clin Pharmacol 1991 Jan; 31(1): 77–8

    Article  PubMed  CAS  Google Scholar 

  22. Aeschlimann C, Cerny T, Küpfer A. Inhibition of mono(amine) oxidase activity and prevention of ifosfamide encephalopathy by methylene blue. Drug Metab Dispos 1996; 24: 1336–9

    PubMed  CAS  Google Scholar 

  23. Kaijser GP, Keize HJ, Beijnen JH, et al. Pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide in plasma and urine of cancer patients treated with a 10-day continuous infusion of ifosfamide. Anticancer Res 1996 Sep-Oct; 16(5B): 3247–57

    PubMed  CAS  Google Scholar 

  24. Cerny T, Castiglione M, Brunner K, et al. Ifosfamide by continuous infusion to prevent encephalopathy [letter]. Lancet 1990 Jan 20; 335(8682): 175

    Article  PubMed  CAS  Google Scholar 

  25. Cain JW, Bender CM. Ifosfamide-induced neurotoxicity: associated symptoms and nursing implications. Oncol Nurs Forum 1995 May; 22(4): 659–66

    PubMed  CAS  Google Scholar 

  26. Gonzalez-Angulo AM, Orzano JA, Davila E. Ifosfamide-induced encephalopathy. South Med J 2002 Oct; 95(10): 1215–7

    PubMed  Google Scholar 

  27. Katz S, Ford AB, Moskowitz RW, et al. Studies of illness in the age: the index of ADL. A standardised measure of biological and psychological function. JAMA 1963 Sep 21; 185: 914–9

    Article  PubMed  CAS  Google Scholar 

  28. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Geron-tologist 1969 Autumn; 9(3): 179–86

    CAS  Google Scholar 

  29. Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975 Apr; 12(1): 189–98

    Article  PubMed  CAS  Google Scholar 

  30. Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression rating scale: a preliminary report. J Psychiatr Res 1982–3; 17(1): 37–49

    Article  PubMed  Google Scholar 

  31. Hickie C, Snowdon J. Depression scales for the elderly: GDS. Clin Gerontol 1987; 6: 51–3

    Google Scholar 

  32. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987; 40(5): 373–83

    Article  PubMed  CAS  Google Scholar 

  33. Linn BS, Linn MW, Gurel L. Cumulative Illness Rating Scale. J Am Geriatr Soc 1968 May; 16(5): 622–6

    PubMed  CAS  Google Scholar 

  34. Miller MD, Paradis CF, Houck PR, et al. Rating chronic medical illness burden in gero-psychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 1992 Mar; 41(3): 237–48

    Article  PubMed  CAS  Google Scholar 

  35. De Pas T, Curigliano G, Catania C, et al. Ifosfamide in the elderly: clinical considerations for a better drug management. Crit Rev Oncol Hematol 2000 Feb; 33(2): 129–35

    Article  PubMed  Google Scholar 

  36. Marx GM, Blake GM, Galani E, et al. Evaluation of the Cockroft-Gault, Jelliffe and Wright formulae in estimating renal function in elderly cancer patients. Ann Oncol 2004 Feb; 15(2): 291–5

    Article  PubMed  CAS  Google Scholar 

  37. Ifosfamide; drug index, BC Cancer Agency cancer drug manual [online]. Available from URL: http://www.bccancer.bc.ca [Accessed 2007 Sep 13]

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Acknowledgements

No sources of funding were used to assist in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this article.

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Authors and Affiliations

  1. Department of Medical Oncology 2, Istituto Oncologico Veneto I.O.V.-I.R.C.C.S., Padova, Italy

    Antonella Brunello, Umberto Basso, Elena Rossi, Micaela Stefani, Cristina Ghiotto, Dario Marino, Gino Crivellari & Silvio Monfardini

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  1. Antonella Brunello
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  2. Umberto Basso
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  3. Elena Rossi
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  4. Micaela Stefani
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  8. Silvio Monfardini
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Correspondence to Antonella Brunello.

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Brunello, A., Basso, U., Rossi, E. et al. Ifosfamide-Related Encephalopathy in Elderly Patients. Drugs Aging 24, 967–973 (2007). https://doi.org/10.2165/00002512-200724110-00008

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