Renal toxicity of ifosfamide in pilot regimens of the intergroup rhabdomyosarcoma study for patients with gross residual tumor.

Purpose: The purpose of this review is to characterize the nephrotoxicity noted in newly diagnosed patients under 21 years of age after treatment with ifosfamide-containing chemotherapy regimens and local irradiation for localized gross residual rhabdomyosarcoma or undifferentiated sarcoma.

Patients and methods: From 1987 to 1991, 194 previously untreated patients received vincristine and ifosfamide plus dactinomycin or etoposide for 1-2 years. Ifosfamide was given at 1.8 g/m2/day for 5 days with sodium mercaptoethane sulfonate, or 9 g/m2 of ifosfamide per course. The three-drug regimen was repeated every 3-4 weeks.

Results: Twenty-eight patients (14%) developed renal toxicity: 19 had renal tubular dysfunction (RTD) characterized by low serum phosphate (< or = 3 mg/dl) or bicarbonate (< 20 or = mEq/L) levels, five had decreased glomerular function (DGF), and four had both RTD and DGF. When nine or more courses of ifosfamide (> 72 g/m2) were given, children < 3 years of age had a higher incidence of RTD than did children > or = 3 years of age (34% versus 6%; p < 0.001). A similar age difference was observed even when eight or fewer courses (< or = 72 g/m2) were given (p = 0.03). A matched case-control comparison showed that renal abnormalities at diagnosis, chiefly hydronephrosis, also increased the risk of renal tubular injury by ifosfamide by a factor of 13 (p < 0.001). Patients with DGF tended to be older than those with RTD, and all but one received > 72 g/m2 of ifosfamide.

Conclusions: Patients who are < 3 years of age who receive more than eight courses (> 72 g/m2) of ifosfamide and who have a preexisting renal abnormality have an increased risk of RTD and DGF. The renal function of patients being considered for ifosfamide treatment must be carefully monitored. Ifosfamide should be avoided in patients with renal abnormalities at diagnosis unless the potential benefit clearly exceeds the risk of further renal impairment.