Oral ifosfamide-mesna: A clinical investigation in advanced non-small-cell lung cancer

Abstract

The purpose of this study was to evaluate the toxicity and response efficacy of fixed-dose oral ifosfamide (OI)-mesna (M) in advanced, non-small-cell lung cancer (NSCLC). OI was given in four different fractionated-dose treatment schedules with a total dose per cycle of either 3.0 g/m2, 6.0 g/m2, 7.5 g/m2 or 10 g/m2 (equivalent to a daily dose of either 750 mg, 1000 mg or 1250 mg.) M was given p.o. by drinking ampules. In the 64 patients (pts) included, a total of 305 treatment cycles were administered with no evidence of severe neurotoxicity. Twenty-two pts (37%) developed mild to moderate CNS toxicity. Neither myelosuppression, alopecia, gastrointestinal toxicity nor urotoxicity were clinical problems. On schedule 2 (6 g/m2), 3 of 14 evaluable pts (21%) had partial remissions (PR), and on schedule 3 (7.5 g/m2) 4 pts (25%) showed PRs. The median duration of response was 9 months (mts) for pts on schedule 2, and 8 mts for pts on schedule 3. We conclude that OIM can easily be tolerated in the same dose usually given intravenously (7.5 g/m2/mts), when patients at high risk for developing CNS toxicity have been previously excluded from therapy. In order to reduce CNS toxicity, it is suggested that the total dose per cycle should not exceed 7.5 g/m2 (1000 mg daily) within a fractionated-dose, 14-day treatment schedule. We further conclude that the tumor response efficacy of OIM in NSCLC is comparable to the one achieved by intravenously-administered IM, whereby the total monthly OI dose should not be less than 6.0 g/m2 (750 mg daily).

Gender difference in ifosfamide metabolism by human liver microsomes

“…Because of the much more severe neurotoxicity after oral than after i. v .-administration, the oral application form was stopped [27,28].…”

Neurological Toxicity of Ifosfamide

“…The neurotoxic effects of IFOS are more common and severe when oral regimens are used [2, 5]. Cyclophosphamide does not exhibit neurotoxicity.…”

“…Acute encephalopathy represents the dose-limiting adverse effect of ifosfamide (IFOS) chemotherapy, affecting up to 50% of patients treated orally and a smaller percentage of patients treated with intravenous regimens [1, 2, 3, 4, 5]. CNS toxicity of IFOS was reported during phase I testing and has been consistently reported in subsequent studies [6].…”

Reversal of Resistance to Oxazaphosphorines

“…At high doses (0.7 g/m 2 ), CPA has an 87.7% oral bioavailability [146]. Similarly, oral IFO is easily absorbed through gastrointestinal tract with an oral bioavailability of almost 100% [147][148][149][150][151][152][153], but oral administered IFO resulted in unacceptable incidence of neurotoxicity [147,154]. The maximum concentration is reached within 1 to 2 hours after oral administration of IFO [147,155,156].…”