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Ifosfamide neurotoxicity and potential treatment with methylene blue
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Ifosfamide is an antineoplastic agent useful in the treatment of a wide range of cancers including sarcomas, gynecologic cancers, lymphoma and testicular cancers. It is given in a variety of dosing regimens ranging from 1.2 g/m2 per day to 2 g/m2 per day for three to five days up to a single, high dose of 5 g/m2. Because of the risk for hemorrhagic cystitis, ifosfamide is always given with mesna, in a dose of 60% to 100% of the ifosfamide dose. Other frequent side effects include central nervous system toxicity, nausea and vomiting, myelosuppression and metabolic acidosis.
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The severity of central nervous system (CNS) toxicity can range from mild confusion and somnolence to seizure, coma and potentially death. Reported CNS toxicities include delirium, confusion, lethargy, drowsiness, disorientation, hallucinations, stupor, personality changes, mutism, encephalopathy, muscle twitching and incontinence. The reported incidence of CNS toxicity ranges widely from 5% to 60%, but most estimates center around 10% to 20% of patients treated with ifosfamide. The symptoms can occur within 12 hours and up to six days after the start of treatment, but usually occur during or shortly after drug administration. In the majority of cases, the symptoms spontaneously resolve, usually within two to three days after stopping the ifosfamide therapy. These toxicities can be graded from 0 to 4 according to the National Cancer Institute Common Terminology Criteria for Adverse Events scale for encephalopathy or other scales. Grade 3 symptoms include severe hallucinations, confusion or somnolence that significantly interferes with activities of daily living. Grade 4 symptoms include seizures and coma. When neurotoxicity is recognized, low serum levels of sodium or potassium may occur in addition to a rise in serum creatinine.
If confusion, somnolence or other neurotoxicities occur in a patient receiving ifosfamide, the ifosfamide should be stopped immediately. In addition, adequate hydration should be provided and electrolyte abnormalities should be corrected. Other medications with CNS effects should be avoided, but supportive care measures for agitation, delirium or seizures should be provided. Future chemotherapy treatments with ifosfamide are controversial, as neurologic symptoms usually but not always recur in future cycles.
Risk factors and etiology
Some patients are at higher risk for developing ifosfamide-related neurotoxicity. The best-documented risk factor is low serum albumin. This may reflect poor hepatic functioning or a change in plasma protein binding of potential neurotoxins. Other risk factors include age, poor renal function or tumor in the lower abdomen or pelvis. Researchers have not found a clear dose-toxicity relationship, although neurotoxicity may be seen more frequently with faster infusions compared to continuous IV infusions. Other reported risk factors include prior CNS disease, prior treatment with cisplatin, poor performance status, sex (female) and hepatic insufficiency.
Several mechanisms for the etiology of ifosfamide-induced neurotoxicity have been described and most center on a metabolite of ifosfamide, chloroacetaldehyde. Ifosfamide is metabolized in the liver by the cytochrome P-450 enzyme CYP3A4 to the active moiety ifosforamide mustard. Ifosforamide mustard has antineoplastic activity by acting as an alkylating agent. Several other metabolites are formed in this multistep process. One of these is acrolein, which is responsible for causing hemorrhagic cystitis. Chloroacetaldehyde is another potentially toxic metabolite formed, and it can cross the blood-brain barrier. Chloroacetaldehyde is structurally similar to neurotoxic metabolites of ethanol and chloral hydrate and may exert direct neurotoxic effects on the CNS. Other proposed mechanisms include depletion of glutathione in the CNS, inhibition of fatty acid metabolism and induction of glutaricaciduria.
Methylene blue
Methylene blue has been described as a potential therapy for ifosfamide-induced neurotoxicity. Methylene blue is a treatment for methemoglobinemia and cyanide poisoning — it is unclear how it might help reverse neurotoxicity caused by ifosfamide metabolites. Some potential mechanisms include inhibition of monoamine oxidase (reducing further chloroacetaldehyde formation), rescuing impaired hepatic metabolic pathways by acting as an electron acceptor, decreasing the effects of neurotoxic ifosfamide metabolites or by treating possible glutaric aciduria.
Treatment with methylene blue has been proposed as 50-mg dose given intravenously every four hours until the patient’s neurologic state has returned to baseline. It may be administered undiluted as a slow IV push for at least five minutes, or diluted in 50 mg of normal saline or 5% dextrose in water for at least five minutes, or diluted in 250 mL 5% dextrose in water infused during 30 minutes. Oral administration has been described, using the same dosage, diluted in fruit juice. The potential adverse effects of methylene blue include dizziness, hypertension, headache, nausea and vomiting and hemolytic anemia. Blue-green discoloration of the skin, urine and stool may occur. Methylene blue is contraindicated in individuals with glucose-6-phosphate dehydrogenase deficiency.
Researchers have not conducted randomized controlled trials investigating the use of methylene blue in ifosfamide neurotoxicity, but a series of case reports describing its use has been published. Some reports describe a rapid recovery of patients with significant neurologic symptoms in as little as 10 minutes, but recovery time ranges up to a few days. Spontaneous recovery after neurotoxicity often occurs in the same range of one to three days. The researchers attribute the improvement in the patients’ conditions to the treatment with methylene blue therapy. Successful secondary prophylaxis has been described, but ifosfamide neurotoxicity does not always recur.
There is insufficient evidence to recommend methylene blue as a treatment for ifosfamide-induced neurotoxicity in all cases, although case reports suggest some usefulness. Methylene blue may reduce symptoms and hasten recovery, although spontaneous recovery may occur in the same period. Methylene blue therapy is relatively safe for short-term use. If a patient experiences substantial and serious ifosfamide-induced encephalopathy (grade 3 or 4), methylene blue therapy may be considered, along with supportive care measures.
Lisa K. Lohr, PharmD, is Clinical Pharmacist in Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center and is a HemOnc Today Editorial Board member.
For more information:
- Ajithkumar T, Parkinson C, Shamshad F, et al. Ifosfamide encephalopathy. Clin Oncol. 2007;19:108.
- Patel P. Methylene blue for management of ifosfamide-induced encephalopathy. Ann Pharmacother. 2006;40:299.
- Pelgrims J, DeVos F, VandenBrande 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;82:291.