A

mechlorethamine B

cyclophosphamide C D

figure 2.1

into phosphoramide mustard and acrolein. Ifosfamide undergoes similar metabolic activation by hepatic P450 mixed-function oxidases. Cyclophosphamide has shown activity as salvage treatment against recurrent PBT in adults and children, used as a single agent or in combination regimens [8,21,75-78]. In adult patients, the typical doses have ranged from 500 to 1000 mg/m2; in children doses have been between 80 and 165 mg/kg. Dose-intensified regimens using cyclophosphamide (2000 mg/m2) have failed to improve response rates or survival and have significant toxicity [79]. When administered to adults with recurrent gliomas at a dose of 2500 mg/m2 per day, ifosfamide failed to demonstrate significant activity [80]. Ifosfamide appears to be more active against recurrent pediatric PBT when used in combination regimens. The primary toxicities of cyclophosphamide and ifosfamide are myelosuppression and hemorrhagic cystitis. The risk of hemorrhagic cystitis can be minimized by concomitant hydration and administration of mesna. Mesna binds to the metabolic breakdown product, acrolein, inhibiting its irritation of the bladder mucosa. Those patients treated with high-dose cyclophosphamide, and all patients receiving ifosfamide, require mesna (500-600 mg/ m2 IV x 3 doses at 0, 4, and 8 h after chemotherapy) in addition to hydration [79-81]. Recent research also suggests that oral mesna may have a similar uropro-tective effect, when used alone or in combination with intravenous mesna [82]. Ifosfamide is associated with significant neurotoxicity (e.g., encephalopathy, seizures, hallucinations, and coma) in 5-30 per cent of the patients [83].

Nitrosoureas. Nitrosoureas are the most commonly used chemotherapeutic agents used in the

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