Dosing and side-effects of ifosfamide plus mesna

Abstract

In clinical practice and in most ongoing studies in adult and pediatric tumours, daily short-time infusions of ifosfamide (IFO) on 2-5 consecutive days with cycle doses between 6 g/m2 and 12 g/m2 are used at present. The continuous i.v. infusion of IFO/mesna over 1-5 days is still experimental. Since mesna prevents IFO-induced urotoxicity, the IFO dose could be increased to 16 g/m2 per cycle. As the dose and schedules of IFO/mesna were increased and varied, CNS and renal toxicity became more evident. CNS toxicity seems not to be dependent on i.v., but on oral dosing of IFO. Renal dysfunction and previous administration of cisplatinum predispose for CNS toxicity. The incidence or severity of CNS toxicity does not increase with subsequent courses of IFO i.v. The nephrotoxicity of IFO is dependent on IFO dose, diuresis, mesna dose and whether there has been previous cisplatinum and seems to involve preferentially the tubulus system, leading to 25 cases of Fanconi renal syndrome as published in 1988-1990. Fanconi's syndrome depends on the cumulative IFO dose, the previous administration of nephrotoxic drugs such as cisplatinum and the age of the children. Studies are continuing to determine the least nephrotoxic dose and schedule of IFO plus mesna. Leucopenia and thrombopenia are well-known dose-dependent side-effects of IFO, with similar incidence after i.v. short-time and continuous infusion.

Ifosfamide nephrotoxicity in paediatric cancer patients

“…Nine patients (1,2,8,9,10,11,14,16,19) could not acidify urine to pH of less than 6 in the same samples although the venous blood gas analysis was normal in all but one patient (8). Details of five patients in this study who had evidence of generalised nephrotoxicity are documented in Table 5.…”

“…Seven patients (1,5,8,10,12,14,16) showed glycosufia with the fractional excretion of glucose greater than 1%; all of these patients had a normal blood glucose. Nine children (1,2,6,8,9,10,14,15,16) had hypercalciuria with a urinary calcium/creatinine ratio greater than 0.74. Urinary excretion of magnesium was normal in all patients.…”

“…A major side-effect of ifosfamide is nephrotoxicity [2]; studies in children who have been treated with ifosfamide have shown clinical, subclinical and progressive renal damage [7,15,19].…”

“…The aims of this study were: (1) to assess renal function in a group of paediatric oncology patients who had been treated with, or were currently receiving, ifosfamide, (2) to compare the degree of dysfunction between patients on treatment and those off and (3) to identify those patients for whom prospective monitoring, whether on or off treatment, was indicated.…”

A dose escalation study for salvage chemotherapy in patients with refractory lymphoma prior to high-dose myeloablative therapy with stem cell transplantation

“…Dose escalation of ifosfamide and mitoxantrone was based on the linear dose-response curve in the therapeutic range and nonoverlapping toxicity. 8,9 Peripheral blood stem cells (PBSC) harvested immediately before the second cycle were used to support two subsequent cycles of treatment to reduce the extent of hematologic toxicity, thereby allowing timely administration of therapy without delay, and later for transplantation. [10][11][12] In the present report, we describe toxicities and preliminary response data of the 15 patients.…”