Chemotherapeutic Toxicities

Neurotoxicity

Ifosfamide

Ifosfamide is a nitrogen mustard derivative that acts as a DNA alkylation agent. It is commonly used in solid and hematologic malignancies. Neurotoxicity with ifosfamide is common, occurring in 5-40% of patients, especially with higher doses.

Neurotoxicity frequently occurs during the course of treatment and presents as:

• encephalopathy
• coma
• seizure
• delirium
• hallucinations

The onset of symptoms is acute, presenting within hours to days after administration, typically with the first or second dose of chemotherapy. Symptoms are usually transient and can resolve spontaneously within 48-72 hours; however, fatal cases and prolonged symptoms have been reported. The exact mechanism for neurotoxicity with ifosfamide is uncertain, but numerous theories exist including neurotoxic metabolites.

Once metabolite, chloroethylamine disturbs mitochondrial electron transfer chain and leads to accumulation of chloroacetaldehyde (CAA). CAA, which is similar in structure to chloral hydrate and acetaldehyde, leads to depletion of glutathione, which in turn leads to decreased detoxification of neurotoxic substances. Additionally, defective electron transfer leads to impaired hepatic gluconeogenesis which may also contribute to neurotoxicity.

Proposed risk factors for neurotoxicity with ifosfamide include:

• low albumin
• female gender
• previous or current neurologic disease
• renal insufficiency
• hepatic disorders
• concomitant treatment with CYP P450 3A4 inducers
• poor performance status
• bulky pelvic disease
• previous cisplatin administration or high dose therapy (greater than 1.5 gm/m²/day)
• in some studies infusion times of less than 6 hours have also been associated with increased risk of encephalopathy.

Diagnosis is based on clinical findings as CT scan of the head is normal. Also, EEG abnormalities such as triphasic waves, and spike and wave abnormalities have been reported in patients receiving ifosfamide. Treatment of ifosfamide neurotoxicity primarily involves discontinuation of ifosfamide and supportive care including treatment of dehydration and electrolyte disturbances. Infusion of dextrose or glucose should also be utilized to combat possible impairment of gluconeogenesis.

Methylene blue has also been studied in severe cases or in patients with prolonged symptoms of ifosfamide toxicity. Methylene blue acts to restore mitochondrial electron transfer by serving as an alternative electron acceptor. It also acts to restore hepatic gluconeogenesis and prevent the transformation of chloroethylamine into chloroacetaldehyde. Doses of methylene blue for ifosfamide toxicity range from 50-60 mg administered 4-6 times daily.

Adverse events of methylene blue are mild and include headache, confusion, dizziness, gastrointestinal disturbances and hypo- or hypertension. Serious adverse events such as arrhythmias, hemolytic anemia and methemoglobinemia are rare.

Patients in whom continued ifosfamide is necessary may receive prophylaxis with a dextrose or glucose infusion and methylene blue at a dose of 50 mg administered every 6-8 hours during ifosfamide treatment. In some cases, this has decreased or lessened the duration of neurotoxicity.

Additionally, there are case reports of ifosfamide re-challenge without prophylaxis and no subsequent development of neurotoxicity. If patients experience ifosfamide neurotoxicity, further courses of ifosfamide are not absolutely contraindicated.

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