Ifosfamide is a chemotherapeutic agent frequently used in the treatment of sarcomas and hematologic malignancies. Ifosfamide is associated with unique neurotoxicity that may include confusion, seizures, hallucinations, incontinence, and cranial nerve abnormalities. Currently, ifosfamide is available commercially as either a lyophilized powder or a liquid formulation. Since the release of aqueous ifosfamide in 2002, several institutions have transitioned to utilizing this formulation as a costsaving measure, but ifosfamide dosing strategies have essentially remained the same. Previous pharmacologic studies have not identified any distinct differences in metabolism between these 2 formulations.1 The mechanisms related to ifosfamide-induced neurotoxicity remain unclear; however, reports suggest an association with accumulation of neurotoxic metabolites such as chloroacetaldehyde (CAA), concurrent use of aprepitant, cisplatin exposure, reduced thiamine bioavailability, hypoalbuminemia, low hemoglobin level, low total bilirubin level, and renal dysfunction.2-6
This retrospective chart review of patients diagnosed with ifosfamide-induced neurotoxicity was conducted at 5 pediatric oncology centers—Children’s Hospital of Alabama, Birmingham; Wolfson Children’s Hospital, Jacksonville, FL; Sacred Heart Children’s Hospital, Pensacola, FL; Florida Hospital, Orlando; and University of Kansas Hospital, Kansas City. Pertinent data reviewed for this study included patient age, diagnosis, treatment regimen, ifosfamide dose and formulation, description of neurotoxicity symptoms, concurrent use of aprepitant, cisplatin exposure, serum albumin levels, serum creatinine, and the use of methylene blue, an electron acceptor.
We reviewed 13 cases of ifosfamide-induced neurotoxicity in children and teens aged 4 to 19 years who were diagnosed between 2002 and 2010 (Table). The predominant diagnosis was sarcoma (N = 11), although 2 other patients received ifosfamide as therapy for pre–B-cell acute lymphocytic leukemia (ALL) and primitive neuroectodermal tumor. All patients initially received the aqueous formulation of ifosfamide.
Daily dosages of ifosfamide ranged from 1.8 g/m2 per dose to 3.5 g/m2 per dose. Only 1 patient received concurrent therapy with aprepitant.
All patients exhibited multiple symptoms of neurotoxicity: confusion (N = 7), lethargy (N = 5), aphasia (N = 4), and incontinence (N = 4). One patient experienced auditory hallucinations. Data were analyzed for possible organic predisposing factors for neurotoxicity. Of the 13 patients, 9 received intravenous methylene blue as treatment, and all patients experienced abatement of symptoms within 5 days. After the resolution of neurotoxicity, 5 patients who had previously received the aqueous compound received subsequent dosing with the powder formulation of ifosfamide, without further recurrence of neuropsychiatric symptoms.
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Incidence of Ifosfamide-Induced Neurotoxicity
Approximately 10% to 40% of pediatric and adult patients who receive ifosfamide experience en cephalopathy.2-4,6 Although widely reported in adult medical oncology literature, this phenomenon is less frequent in the pediatric population.7 Ifosfamide neurotoxicity in the pediatric patient varies in presentation but most often consists of confusion, hallucinations, and incontinence.8
Risk factors for ifosfamide neurotoxicity, such as hypoalbuminemia, renal dysfunction, concurrent use of aprepitant, and a history of cisplatin exposure, were identified in our patient population (Table). Other less reported risk factors, such as low hemoglobin and low total bilirubin levels, were not evaluated in our study.
Currently, the greatest risk factor for neurotoxicity is hypoalbuminemia, predominantly a serum albumin level <3.3 g/dL.2,3 Recent reports show that prophylaxis with an albumin infusion has no apparent effect on the development of ifosfamide-related neurotoxicity, suggesting that hepatic dysfunction rather than albumin depletion may account for such a predisposition.
Of the often implicated risk factors, hypoalbuminemia was the most frequently identified risk factor in our study. A total of 7 patients had hypoalbuminemia with albumin levels of ≤3.3 g/dL at the time of ifosfamide administration. In addition, 3 of the 5 patients who were rechallenged with the powder remained hypoalbuminemic but did not experience recurrent symptoms of neurotoxicity when the powder formulation was used.
Renal dysfunction was not identified as a risk factor in our patient population, because only 1 patient experienced elevated creatinine level (1.3 mg/dL) throughout the course of therapy. Only 1 patient had concurrent use of aprepitant, suggesting that this is also difficult to identify as a predisposing factor in the pediatric population.
Although 3 patients had a history of previous cisplatin exposure, they had normal renal function at the time of ifosfamide administration. Of these patients, 2 did not experience encephalopathy when rechallenged with a powder formulation. Therefore, in our population it is difficult to determine if cisplatin exposure is related to ifosfamide neurotoxicity, particularly in the setting of normal renal function.
Mechanism of Neurotoxicity
The metabolism of ifosfamide by the hepatic cytochrome (CY) P450 system results in inactive metabolites, toxic metabolites, and the active form of the drug, isophosphoramide, a nitrogen mustard. Neurotoxic effects are thought to be associated with disruption of the mitochondrial respiratory chain and the accumulation of nicotinamide adenine dinucleotide hydride, which prevents dehydrogenation of the neurotoxic metabolite CAA.9,10 Therefore, factors that may account for predisposition to neurotoxicity include markers of hepatic function, such as albumin, or concurrent administration of substances that affect the CYP450 enzymes, including aprepitant.
Recent reports show that prophylaxis with an albumin infusion has no apparent effect on the development of ifosfamide-related neurotoxicity, further suggesting that hepatic dysfunction rather than albumin depletion may account for this predisposition.11 The treatment of ifosfamide-induced neurotoxicity is focused on the reduction of excess electrons and restoration of the mitochondrial respiratory chain, resulting in increased metabolism of CAA (Figure). Methylene blue has traditionally been used to accomplish this.9,10,12
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Methylene blue may also reduce the formation of CAA by blocking activity of monoamine oxidases. Although not as well described, intravenous thiamine administration has been reported in the literature as an intervention for ifosfamide-induced neurotoxicity. The proposed mechanism of action has been postulated to be related to ifosfamide-induced thiamine dysfunction or reduced thiamine availability.13-15 Alternatively, attempts have been made to prevent neurotoxicity by modifying the ifosfamide molecule, altering metabolism so that CAA production is hindered.16
Characteristics of rechallenged patients are also shown in the Table. For several years, anecdotal observations suggesting a higher incidence of encephalopathy with the aqueous formulation of ifosfamide have been discussed among oncologists and oncologic pharmacists. In this case series, we report 5 cases in which patients who developed encephalopathy with an aqueous ifosfamide formulation did not experience recurrence of such symptoms when rechallenged with the powder formulation.
A 19-year-old male with undifferentiated sarcoma and an 11-year-old female with osteosarcoma experienced neurotoxicity with the liquid formulation and later during therapy received the powder formulation without adverse effects. Neither had hypoalbuminemia or renal dysfunction when encephalopathy occurred. The 11-year-old female did have a history of cisplatin exposure. Both patients had normal serum albumin levels at the time of infusion with powder formulation.
Two additional patients, a 14-year-old female with rhabdomyosarcoma and a 15-year-old female with osteosarcoma, both of whom had also had hypoalbuminemia, developed encephalopathy with the liquid formulation. Both patients were rechallenged at a later date with the powder formulation, which did not result in any adverse effect. The patients remained hypoalbuminemic at the time of infusion with the powder formulation (serum albumin levels, 3.3 g/dL and 3.1 g/dL, respectively). It is interesting to note that the 15-year-old female who was rechallenged had 3 known risk factors for ifosfamideassociated neurotoxicity—hypoalbuminemia, previous cisplatin exposure, and concurrent use of aprepitant. However, she did not experience recurrent encephalopathy with the powder formulation.
A 7-year-old male with pre–B-cell ALL experienced lethargy, confusion, and incontinence after 4 doses of the liquid formulation of ifosfamide. He was persistently hypoalbuminemic throughout his hospital course and had no history of cisplatin exposure or renal dysfunction. He was not administered methylene blue. Rather, the patient’s next dose of ifosfamide was held, and his symptoms resolved within 24 hours. He was then administered the fifth dose of ifosfamide, using the powder formulation, and did not experience neurotoxicity.
Ifosfamide-induced neurotoxicity has been frequently reported in the literature. Our case series raises some interesting questions regarding this phenomenon. Serum albumin has been reported as a risk factor, and this was identified in patients in this pediatric case series. However, low serum albumin levels were not consistently associated with neurotoxicity. Other risk factors, such as renal dysfunction or previous cisplatin exposure, could not be identified in our small population. In addition, the lack of neurotoxicity in patients rechallenged with the powder formulation of ifosfamide suggests a possible increased incidence of ifosfamide neurotoxicity with the liquid formulation of the drug.
The current aqueous formulation of ifosfamide could be a contributing factor to neurotoxicity, and further studies are warranted to evaluate this trend. Investigation utilizing high-performance light chromatography or nuclear magnetic resonance spectroscopy to analyze possible differences in toxic metabolite formation between formulations may be helpful.
Author Disclosure Statement
Dr Parsons is on the Speaker’s Bureau of Sigma Tau Pharmaceuticals. Drs Lee, Ng, Poon, Schwartz, Smith, and Assanasen, and Mr Henry have reported no actual or potential conflicts of interest.
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- Kettle JK, Grauer D, Folker TL, et al. Effectiveness of exogenous albumin administration for the prevention of ifosfamide-induced encephalopathy. Pharmacotherapy. 2010;30:812-817.
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Dr Lee is a Pediatric Resident, Florida State University, Sacred Heart Women and Children’s Hospital, Pensacola; Mr Henry is Associate Professor, Pharmacy Practice, University of Kansas Medical Center, Kansas City; Dr Ng is Pediatric Clinical Pharmacist, Department of Pharmacy, Wolfson Children’s Hospital, and College of Pharmacy, University of Florida, Jacksonville; Dr Parsons is Pediatric Oncology Pharmacist, Children’s Hospital of Alabama, Birmingham; Dr Poon is Hematology/Oncology Clinical Pharmacist, Florida Hospital for Children, Orlando; Dr Schwartz is Chief, Pediatric Hematology/Oncology, Nemours Children’s Clinic, Pensacola, FL; Dr Smith is Clinical Pharmacy Manager, Pediatrics, Sacred Heart Women and Children’s Hospital, Pensacola, FL; and Dr Assanasen is Assistant Professor, Pediatric Hematology-Oncology, University of Texas Health Science Center at San Antonio, CHRISTUS Santa Rosa Children’s Hospital.