Toxicity of high-dose ifosfamide in children

Ifosfamide has been shown to be an active agent in the treatment of several childhood cancers. However, the optimal dose and method of administration remains to be established. The dose/response relationship of ifosfamide suggests that a maximum tolerable, fractionated dose be given, and to reduce hospitalisation this dose should be given in the shortest possible time. A total of 20 patients aged 1-23 years received 124 courses (mean, 6 courses/patient; range, 1-16); 9 subjects had either relapsed or resistant disease, and all of these had previously received cyclophosphamide. A dose of 3 g/m2 ifosfamide was given for 2 (five patients) or 3 (15 patients) successive days. In all, 9 patients received the drug twice daily as a bolus and 11 were given a continuous infusion. All patients received 3 g/m2 mesna per day with ifosfamide and for 12 h there after, and hydration was maintained with 3 l/m2 fluid daily. Myelosuppression occurred in all patients but was mild and reversible, with no toxic deaths. On four occasions in three patients treatment had to be delayed due to myelosuppression. Seven episodes of fever and neutropaenia were successfully treated with antibiotics. The mean glomerular filtration rate in 13 patients at the start of treatment was 104 ml/min per 1.73 m2 and at the end was 92 ml/min per 1.73 m2. In all, 19 patients had microscopic and 1 macroscopic haematuria, with no clinical sequelae. Two patients with grossly impaired renal function following previous cisplatin therapy may have been precipitated into terminal renal failure by the ifosfamide therapy. Only one person developed neurotoxicity, which recurred on further treatment with ifosfamide but was fully reversible. All patients had moderate to severe vomiting, which was controlled with anti-emetics. No abnormalities of liver or cardiac function were detected. We conclude that ifosfamide given by this schedule is safe in patients with normal renal function.