Ifosfamide — Dosing and Scheduling

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Abstract
SummaryNo significant toxicity was found [26] for single i.v. doses of up to 2.9 g/m2 ifosfamide (IFO), while urotoxicity and CNS symptoms became dose-limiting with higher doses.In order to reduce urotoxicity and because of the experimentally-proven higher cumulative efficacy and lower toxicity of dose fractionation [10], IFO doses between 1.6 and 2.5 g/m2 mostly given over 3–5 days were common in recent years.By giving the uroprotector mesna concomitantly and following the application of IFO, the former dose-limiting urotoxicity can be controlled and single IFO doses have been escalated up to 5 g/m2 given by i.v. infusion over 30 min or up to 8 g IFO/m2 given as 24-h continuous intravenous infusion (ci.-i.v.).Under mesna uroprotection and by ci.-i.v. the maximum tolerated dose of IFO could be increased to 17 g/m2/120 h [63]. The application of higher IFO doses under uroprotection by mesna and by ci.-i.v. might increase efficacy but might also produce more secondary toxicities such as myelosuppression, nephrotoxicity and CNS symptoms.The most common IFO schedule today is a daily short-term infusion over about 1 h on 5 consecutive days concomitantly with i.v. injections of mesna as 20% of the IFO dose at 0, 4, and 8 h and accompanied by a moderate hydration of about 2 1 fluid/day.When IFO is given as ci.-i.v. over 1 day or several days, mesna has empirically been added on 0.5:1 or 1:1 ratio with an additional infusion of mesna as 50% of the daily IFO dose over at least 8–12 h after the end of IFO infusion. This raises the question of the optimal mesna dose and a possible systemic interaction of mesna with the high-dose IFO.A systemic interaction of mesna with IFO for the presently-applied IFO/mesna schedules can be ruled out by the missing effect of mesna on leukotoxic, immunosuppressive and lethal dose-response curves and cure rates of IFO or other cytostatics including DDP1, ADR, and ETO, etc. in tumor-bearing animals, by the special human pharmacokinetics of mesna and by the innumerable CRs and increased MDS values obtained in clinical trials with IFO plus mesna since 1979, when mesna was introduced into clinical trials. 1 Abbreviations see p. 44.

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