Ifosfamide-Induced Encephalopathy in Children and Young Adults: The MD Anderson Cancer Center Experience
Simple Summary
Abstract
1. Introduction
2. Patients and Methods
3. Results
3.1. Patients
3.2. Neurological Symptoms
3.3. Investigations and Potential Risk Factors
3.4. Management of Encephalopathy
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Dechant, K.L.; Brogden, R.N.; Pilkington, T.; Faulds, D. Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs 1991, 42, 428–467. [Google Scholar] [CrossRef] [PubMed]
- Abu-Ghosh, A.M.; Krailo, M.D.; Goldman, S.C.; Slack, R.S.; Davenport, V.; Morris, E.; Laver, J.H.; Reaman, G.H.; Cairo, M.S. Ifosfamide, carboplatin and etoposide in children with poor-risk relapsed Wilms’ tumor: A Children’s Cancer Group report. Ann. Oncol. 2002, 13, 460–469. [Google Scholar] [CrossRef]
- Kushner, B.H.; Modak, S.; Kramer, K.; Basu, E.M.; Roberts, S.S.; Cheung, N.-K.V. Ifosfamide, carboplatin, and etoposide for neuroblastoma. Cancer 2013, 119, 665–671. [Google Scholar] [CrossRef]
- Murillo, L.C.; Sutachan, J.J.; Albarracín, S.L. An update on neurobiological mechanisms involved in the development of chemotherapy-induced cognitive impairment (CICI). Toxicol. Rep. 2023, 10, 544–553. [Google Scholar] [CrossRef] [PubMed]
- Ide, Y.; Yanagisawa, R.; Kubota, N.; Sakashita, K.; Tozuka, M.; Nakamura, T.; Honda, T. Analysis of the clinical characteristics of pediatric patients who experience ifosfamide-induced encephalopathy. Pediatr. Blood Cancer 2019, 66, e27996. [Google Scholar] [CrossRef]
- Ajithkumar, T.; Parkinson, C.; Shamshad, F.; Murray, P. Ifosfamide encephalopathy. Clin. Oncol. (R. Coll. Radiol.) 2007, 19, 108–114. [Google Scholar] [CrossRef] [PubMed]
- David, K.A.; Picus, J. Evaluating risk factors for the development of ifosfamide encephalopathy. Am. J. Clin. Oncol. 2005, 28, 277–280. [Google Scholar] [CrossRef] [PubMed]
- Kupfer, A.; Aeschlimann, C.; Wermuth, B.; Cerny, T. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet 1994, 343, 763–764. [Google Scholar] [CrossRef]
- Richards, A.; Marshall, H.; McQuary, A. Evaluation of methylene blue, thiamine, and/or albumin in the prevention of ifosfamide-related neurotoxicity. J. Oncol. Pharm. Pract. 2011, 17, 372–380. [Google Scholar] [CrossRef]
- Kataria, P.S.; Kendre, P.P.; Patel, A.A. Ifosfamide-induced Encephalopathy Precipitated by Aprepitant: A Rarely Manifested Side Effect of Drug Interaction. J. Pharmacol. Pharmacother. 2017, 8, 38–40. [Google Scholar] [CrossRef]
- Salloum, E.; Flamant, F.; Ghosn, M.; Taleb, N.; Akatchereian, C. Irreversible encephalopathy with ifosfamide/mesna. J. Clin. Oncol. 1987, 5, 1303–1304. [Google Scholar] [CrossRef] [PubMed]
- Nicolao, P.; Giometto, B. Neurological toxicity of ifosfamide. Oncology 2003, 65, 11–16. [Google Scholar] [CrossRef] [PubMed]
- Hamadani, M.; Awan, F. Role of thiamine in managing ifosfamide-induced encephalopathy. J. Oncol. Pharm. Pract. 2006, 12, 237–239. [Google Scholar] [CrossRef]
- Park, I.S.; Lee, H.J.; Lee, Y.S.; Hwang, J.S.; Lee, M.S. Ifosfamide-induced encephalopathy with or without using methylene blue. Int. J. Gynecol. Cancer 2005, 15, 807–810. [Google Scholar] [CrossRef] [PubMed]
- Di Cataldo, A.; Astuto, M.; Rizzo, G.; Bertuna, G.; Russo, G.; Incorpora, G. Neurotoxicity during ifosfamide treatment in children. Med. Sci. Monit. 2009, 15, CS22–CS25. [Google Scholar]
- Pelgrims, J.; De Vos, F.; Van den Brande, J.; Schrijvers, D.; Prove, A.; Vermorken, J.B. 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, 82, 291–294. [Google Scholar] [CrossRef]
- Aeschlimann, C.; Kupfer, A.; Schefer, H.; Cerny, T. Comparative pharmacokinetics of oral and intravenous ifosfamide/mesna/methylene blue therapy. Drug Metab. Dispos. 1998, 26, 883–890. [Google Scholar]
- Cerny, T.; Castiglione, M.; Brunner, K.; Kupfer, A.; Martinelli, G.; Lind, M. Ifosfamide by continuous infusion to prevent encephalopathy. Lancet 1990, 335, 175. [Google Scholar] [CrossRef]
- Verstappen, C.C.; Heimans, J.J.; Hoekman, K.; Postma, T.J. Neurotoxic complications of chemotherapy in patients with cancer: Clinical signs and optimal management. Drugs 2003, 63, 1549–1563. [Google Scholar] [CrossRef]
- Howell, J.E.; Szabatura, A.H.; Hatfield Seung, A.; Nesbit, S.A. Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant. J. Oncol. Pharm. Pract. 2008, 14, 157–162. [Google Scholar] [CrossRef]
- Tajino, T.; Kikuchi, S.; Yamada, H.; Takeda, A.; Konno, S. Ifosfamide encephalopathy associated with chemotherapy for musculoskeletal sarcomas: Incidence, severity, and risk factors. J. Orthop. Sci. 2010, 15, 104–111. [Google Scholar] [CrossRef] [PubMed]
- Sweiss, K.I.; Beri, R.; Shord, S.S. Encephalopathy after high-dose Ifosfamide: A retrospective cohort study and review of the literature. Drug Saf. 2008, 31, 989–996. [Google Scholar] [CrossRef]
- Torchia, A.; Vari, S.; Onesti, C.E.; Ceddia, S.; Maschio, M.; Maggi, G.; Riva, F.; Faltyn, W.; Russillo, M.; Ferraresi, V. A narrative review on diagnosis and treatment of ifosfamide-induced encephalopathy, the perspective of a EURACAN reference center for sarcomas. Front. Pharmacol. 2025, 16, 1512966. [Google Scholar] [CrossRef]
- Szabatura, A.H.; Cirrone, F.; Harris, C.; McDonnell, A.M.; Feng, Y.; Voit, D.; Neuberg, D.; Butrynski, J.; Fisher, D.C. An assessment of risk factors associated with ifosfamide-induced encephalopathy in a large academic cancer center. J. Oncol. Pharm. Pract. 2015, 21, 188–193. [Google Scholar] [CrossRef]
- Jarkowski, A., III; Miller, A.; Hecke, T.A.; Blustein, L.; Wong, M.K.K. The Risk of Neurotoxicity with Concomitant Use of Aprepitant and Ifosfamide. J. Hematol. Oncol. Pharm. 2011, 1, 16–21. Available online: https://jhoponline.com/issue-archive/2011-issues/june-vol-1-no-2/top-14265 (accessed on 1 June 2025).
- Ho, H.; Yuen, C. Aprepitant-associated ifosfamide neurotoxicity. J. Oncol. Pharm. Pract. 2009, 16, 137–138. [Google Scholar]
- Kettle, J.K.; Grauer, D.; Folker, T.L.; O’Neal, N.; Henry, D.W.; Williams, C.B. Effectiveness of exogenous albumin administration for the prevention of ifosfamide-induced encephalopathy. Pharmacotherapy 2010, 30, 812–817. [Google Scholar] [CrossRef]
- Gharaibeh, E.Z.; Telfah, M.; Powers, B.C.; Salacz, M.E. Hydration, methylene blue, and thiamine as a prevention regimen for ifosfamide-induced encephalopathy. J. Oncol. Pharm. Pract. 2019, 25, 1784–1786. [Google Scholar] [CrossRef] [PubMed]
- Vazirian, F.; Samadi, S.; Rahimi, H.; Sadeghi, M.; Mohammadpour, A.H. Aprepitant, fosaprepitant and risk of ifosfamide-induced neurotoxicity: A systematic review. Cancer Chemother. Pharmacol. 2022, 90, 1–6. [Google Scholar] [CrossRef]
- Pratt, C.B.; Goren, M.P.; Meyer, W.H.; Singh, B.; Dodge, R.K. Ifosfamide neurotoxicity is related to previous cisplatin treatment for pediatric solid tumors. J. Clin. Oncol. 1990, 8, 1399–1401. [Google Scholar] [CrossRef]
- Primavera, A.; Audenino, D.; Cocito, L. Ifosfamide encephalopathy and nonconvulsive status epilepticus. Can. J. Neurol. Sci. 2002, 29, 180–183. [Google Scholar] [CrossRef] [PubMed]
- Bruggers, C.S.; Friedman, H.S.; Tien, R.; Delong, R. Cerebral Atrophy in an Infant Following Treatment with Ifosfamide. Med. Pediatr. Oncol. 1994, 23, 380–383. [Google Scholar] [CrossRef] [PubMed]
- Ames, B.; Lewis, L.D.; Chaffee, S.; Kim, J.; Morse, R. Ifosfamide-induced encephalopathy and movement disorder. Pediatr. Blood Cancer 2010, 54, 624–626. [Google Scholar] [CrossRef] [PubMed]
- Feyissa, A.M.; Tummala, S. Ifosfamide related encephalopathy: The need for a timely EEG evaluation. J. Neurol. Sci. 2014, 336, 109–112. [Google Scholar] [CrossRef]
- Merimsky, O.; Reidergroswasser, I.; Wigler, N.; Chaitchik, S. Encephalopathy in Ifosfamide-Treated Patients. Acta Neurol. Scand. 1992, 86, 521–525. [Google Scholar] [CrossRef]
Characteristic | No. of Patients (%) |
---|---|
Age in years | |
Median | 17.6 |
Range | 4–30 |
Gender | |
Male | 13 (54) |
Female | 11 (46) |
Race/ethnicity | |
Non-Hispanic White | 11 (46) |
White Hispanic | 8 (33) |
Other (African American, Arabic) | 5 (21) |
BMI | |
<18.5 | 8 (33) |
18.5–24.9 (Normal) | 10 (42) |
25–29.9 (Overweight) | 2 (8) |
≥30 (Obese) | 4 (17) |
Diagnosis | |
Osteosarcoma | 5 (21) |
Ewing sarcoma | 6 (25) |
Soft-tissue sarcoma | 6 (25) |
Hodgkin’s lymphoma | 3 (13) |
Other | 10 (42) |
Tumor Location | |
Extremity | 3 (13) |
Pelvis | 4 (17) |
Other bones | 4 (17) |
Lymph nodes | 3 (13) |
Other | 10 (42) |
Performance Status (ECOG) | |
0 | 6 (25) |
1 | 6 (25) |
2 | 6 (25) |
3 | 6 (25) |
Disease status | |
Localized | 6 (25) |
Metastatic | 9 (38) |
Recurrent metastatic/progressive | 9 (38) |
Cumulative ifosfamide dose prior to event (grams/m2) | |
Median | 18 |
Range | 0–80 |
Neurologic Symptoms/Findings | No. of Patients (%) |
---|---|
Drowsiness | 8 (33) |
Confusion | 6 (25) |
Lethargy | 4 (17) |
Disorientation | 3 (13) |
Agitation | 3 (13) |
Sensory deficits | 2 (8) |
Motor deficits | 2 (8) |
Seizures | 3 (13) |
Dizziness | 3 (13) |
Tremors | 1 (4) |
Slurred speech | 1 (4) |
Headache | 1 (4) |
NCI Toxicity Grading * | |
0 | 1 (4%) |
1 | 4 (17) |
2 | 2 (8) |
3 | 12 (50) |
4 | 5 (21) |
Time to onset | |
Within 24 h | 10 (42) |
Within 48 h | 6 (25) |
Between 48 and 96 h | 8 (33) |
Time to resolution | |
Within 24 h | 12 (50) |
24–48 h | 4 (17) |
>48 h | 6 (25) |
Not resolved | 1 (4) |
Not specified | 1 (4) |
Factor | No. of Patients (%) |
---|---|
History of IIE | 3 (13) |
Brain irradiation | 4 (17) |
Short intermittent ifosfamide infusion (1–3 h) | 12 (50) |
Continuous ifosfamide infusion (12–24 h) | 12 (50) |
Concomitant medications | |
Aprepitant | 7 (29) |
5-HT3 antagonist | 15 (63) |
Antihistamine | 11 (46) |
Benzodiazepine | 9 (38) |
Narcotics | 10 (42) |
Dexamethasone | 4 (17) |
Antipsychotic | 3 (13) |
Laboratory evaluations | |
Anemia | 22 (92) |
Hypocalcemia | 12 (50) |
Hypoalbuminemia | 10 (42) |
Elevated creatinine | 1 (4) |
Prior therapy with cisplatin | 8 (33) |
Obesity | 4 (17) |
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Alqahtani, S.; Bitar, S.D.; Mireles, M.E.; Corrales-Medina, F.F.; Herzog, C.E.; Slopis, J.; Daw, N.C. Ifosfamide-Induced Encephalopathy in Children and Young Adults: The MD Anderson Cancer Center Experience. Cancers 2025, 17, 2192. https://doi.org/10.3390/cancers17132192
Alqahtani S, Bitar SD, Mireles ME, Corrales-Medina FF, Herzog CE, Slopis J, Daw NC. Ifosfamide-Induced Encephalopathy in Children and Young Adults: The MD Anderson Cancer Center Experience. Cancers. 2025; 17(13):2192. https://doi.org/10.3390/cancers17132192
Chicago/Turabian StyleAlqahtani, Shaikha, Sabrina D. Bitar, Maria Estela Mireles, Fernando F. Corrales-Medina, Cynthia E. Herzog, John Slopis, and Najat C. Daw. 2025. "Ifosfamide-Induced Encephalopathy in Children and Young Adults: The MD Anderson Cancer Center Experience" Cancers 17, no. 13: 2192. https://doi.org/10.3390/cancers17132192
APA StyleAlqahtani, S., Bitar, S. D., Mireles, M. E., Corrales-Medina, F. F., Herzog, C. E., Slopis, J., & Daw, N. C. (2025). Ifosfamide-Induced Encephalopathy in Children and Young Adults: The MD Anderson Cancer Center Experience. Cancers, 17(13), 2192. https://doi.org/10.3390/cancers17132192