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.

Stepping stones to improve cardio-oncological care

“…In the smallest of these studies (n=12) [4], patients received higher doses of doxorubicin, providing a plausible explanation for the higher incidence. However, for the other two studies [5][6] we did not find any differences in patient characteristics, definitions of cardiac dysfunction, or handled cardiac imaging techniques that could explain the observed differences. A sensitivity analysis excluding these studies separately, one at a time, did not change the pooled proportion of patients with treatment-related overall heart failure considerably (8•1-10•6%), nor did it change the statistical significance.…”

Stepping stones to improve cardio-oncological care

“…In the smallest of these studies (n=12) [4], patients received higher doses of doxorubicin, providing a plausible explanation for the higher incidence. However, for the other two studies [5][6] we did not find any differences in patient characteristics, definitions of cardiac dysfunction, or handled cardiac imaging techniques that could explain the observed differences. A sensitivity analysis excluding these studies separately, one at a time, did not change the pooled proportion of patients with treatment-related overall heart failure considerably (8•1-10•6%), nor did it change the statistical significance.…”

Efficacy and tolerability of the ifosfamide-epirubicin combination in relapsed ovarian cancer

“…Nonhematologic toxicity was infrequent, but we observed some severe CNS toxicity among heavily pretreated patients. Encephalopathy has been reported previously (10,17,31) . CNS toxicity is usually mild and reversible.…”

Ifosfamide nephrotoxicity in paediatric cancer patients

“…In this study, the addition of mesna at 150% of ifosfamide dose did not prevent toxicity. In view of this and also the fact that mesna has been shown to interfere with the therapeutic efficacy of activated oxazophosphorines in animals [20], a reduction of mesna to 60% or 75% of ifosfamide dose, as has been recommended by Brade et al [2] and Goren et al [6] respectively, might therefore be considered for chemotherapy schedules incorporating ifosfamide.…”

“…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.…”

Stepping stones to improve cardio-oncological care

“…In the smallest of these studies (n=12) [4], patients received higher doses of doxorubicin, providing a plausible explanation for the higher incidence. However, for the other two studies [5][6] we did not find any differences in patient characteristics, definitions of cardiac dysfunction, or handled cardiac imaging techniques that could explain the observed differences. A sensitivity analysis excluding these studies separately, one at a time, did not change the pooled proportion of patients with treatment-related overall heart failure considerably (8•1-10•6%), nor did it change the statistical significance.…”

Efficacy and tolerability of the ifosfamide-epirubicin combination in relapsed ovarian cancer

“…Nonhematologic toxicity was infrequent, but we observed some severe CNS toxicity among heavily pretreated patients. Encephalopathy has been reported previously (10,17,31) . CNS toxicity is usually mild and reversible.…”

Ifosfamide nephrotoxicity in paediatric cancer patients

“…In this study, the addition of mesna at 150% of ifosfamide dose did not prevent toxicity. In view of this and also the fact that mesna has been shown to interfere with the therapeutic efficacy of activated oxazophosphorines in animals [20], a reduction of mesna to 60% or 75% of ifosfamide dose, as has been recommended by Brade et al [2] and Goren et al [6] respectively, might therefore be considered for chemotherapy schedules incorporating ifosfamide.…”

“…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.…”

Stepping stones to improve cardio-oncological care

“…In the smallest of these studies (n=12) [4], patients received higher doses of doxorubicin, providing a plausible explanation for the higher incidence. However, for the other two studies [5][6] we did not find any differences in patient characteristics, definitions of cardiac dysfunction, or handled cardiac imaging techniques that could explain the observed differences. A sensitivity analysis excluding these studies separately, one at a time, did not change the pooled proportion of patients with treatment-related overall heart failure considerably (8•1-10•6%), nor did it change the statistical significance.…”

Efficacy and tolerability of the ifosfamide-epirubicin combination in relapsed ovarian cancer

“…Nonhematologic toxicity was infrequent, but we observed some severe CNS toxicity among heavily pretreated patients. Encephalopathy has been reported previously (10,17,31) . CNS toxicity is usually mild and reversible.…”

Ifosfamide nephrotoxicity in paediatric cancer patients

“…In this study, the addition of mesna at 150% of ifosfamide dose did not prevent toxicity. In view of this and also the fact that mesna has been shown to interfere with the therapeutic efficacy of activated oxazophosphorines in animals [20], a reduction of mesna to 60% or 75% of ifosfamide dose, as has been recommended by Brade et al [2] and Goren et al [6] respectively, might therefore be considered for chemotherapy schedules incorporating ifosfamide.…”

“…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.…”