PS-033 Ifosfamide induced encephalopathy: prophylaxis and therapy with methylene blue

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Abstract

Background

Ifosfamide is an alkylating agent effective in young patients affected by sarcoma. Its use is limited due to severe side effects: haemorrhagic cystitis, prevented with mesna; neurotoxicity is currently its worse adverse effect. Hepatic conversion of ifosfamide to chloracetaldehyde seems to be the main pathophysiologic mechanism responsible for development of ifosfamide induced encephalopathy (IIE). There are sporadic case reports suggesting the use of methylene blue as effective treatment for this dose limiting side effect.

Purpose

The aim of the study was to evaluate the benefit derived from use of methylene blue for treatment and prophylaxis of IIE in paediatric and young adult patients. These subjects are more sensible to neurologic damage, irreversible in some cases.

Material and methods

We conducted a retrospective analysis of 74 patients (range 1–25 years of age), most of whom were affected by rhabdomyosarcoma. They were divided into 3 groups based on methylene blue administration; all were treated between 2010 and 2015, with regimens including ifosfamide at an average dose of 9.1 g/cycle. 75% of patients were at high risk of developing IIE due to specific comorbidities. The control group did not have the same risk factors as other two groups, and this was the reason why MB was not used.

Results

23% (17/74) of patients developed neurotoxicity grade 1 or more (NCI-CTC). Comparing the prophylaxis and non-prophylaxis groups, homogenous for risk factors, there was a difference of 5.4% in the incidence of IIE. 14/17 (82.35%) were treated with MB at a dose of 3×50 mg/day intravenously, and all recovered. 3/17 (17.65%) patients spontaneously recovered. 13/17 (76.47%) patients continued ifosfamide cycles with MB as secondary prophylaxis and did not manifest other neurologic symptoms. Patients at high risk, prophylactically treated with MB before the beginning of chemotherapy, manifested neurotoxicity of lower grade, compared with patients with the same risks but without prophylaxis.

Conclusion

Methylene blue is an effective and low cost antidote to treat and prevent IIE in patients at major risk of developing it. MB has potential use in the primary prophylaxis of patients with risk factors for neurotoxicity; it can also be used in secondary prophylaxis and acute treatment. Another important result is that MB enabled our patients to continue further ifosfamide chemotherapy.

References and/or acknowledgements

Kupfer, et al. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet1994;343:763–4.

References and/or acknowledgements

No conflict of interest

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