Ifosfamide nephrotoxicity in paediatric cancer patients

Abstract

Ifosfamide is an alkylating agent which has been incorporated into frontline therapy for a number of malignant paediatric tumours. Recent data appears to suggest that tubular dysfunction may result from incorporation of this drug into chemotherapy schedules and that toxicity may be dose related. A detailed investigation of renal function was performed in a group of patients, ranging in age from 8 months to 15.9 years (median 8.6 years) with rhabdomyosarcoma (n = 11) and Ewing's sarcoma (n = 9) who were currently receiving (n = 4) or had completed ifosfamide (n = 16) therapy a mean of 16 months at the time of study. All but one patient demonstrated some degree of renal dysfunction and toxicity did not necessarily appear to be dose related. Implications for incorporation of this agent into future schedules for childhood sarcomas, which can expect to cure more than 60% of such children, must be addressed. The importance of ongoing monitoring is emphasised.

Ifosfamide nephrotoxicity in children: a mechanistic base for pharmacological prevention

“…A diagnosis of Fanconi's syndrome was documented as far as 3 years following cessation of treatment [63]. This has been supported by previous studies which found that most patients received a diagnosis of Fanconi's syndrome in 2 years after treatment [49,64].…”

“…More severe proximal tubule toxicity can result in Fanconi's syndrome with clinically-relevant hypophosphatemic rickets, proximal renal tubule acidosis and hypokalemia [19,[49][50][51]. Chronic glomerular dysfunction, evident by reduced glomerular filtration rate (GRF) and elevated serum creatinine, may coexist [19,42,49]. Although relatively uncommon [43], severe distal toxicity, when present, can lead to diabetes insipidus and distal renal tubular acidosis [51,52].…”

“…Subclinical features may include glycosuria, aminoaciduria and increased excretion of low molecular mass proteins [44][45][46][47][48]. More severe proximal tubule toxicity can result in Fanconi's syndrome with clinically-relevant hypophosphatemic rickets, proximal renal tubule acidosis and hypokalemia [19,[49][50][51]. Chronic glomerular dysfunction, evident by reduced glomerular filtration rate (GRF) and elevated serum creatinine, may coexist [19,42,49].…”

Osteomalacia as a Late Metabolic Complication of Ifosfamide Chemotherapy in Young Adults: Illustrative Cases and Review of the Literature

“…While subclinical glycosuria was detected in 88% of patients in a large study [14], clinically significant abnormalities including Fanconi syndrome occur in between 1.3 and 27% of treated patients [11, 17, 23, 24]. Risk is increased by prior or concurrent platinum chemotherapy [11, 13, 15, 25, 26], increasing cumulative ifosfamide dose [12–14, 17, 25, 27], and reduced functioning nephron mass [13, 23, 25, 28], but not scheduling of ifosfamide dose [29, 30]. Whether aminoglycoside use increases risk is unclear [14, 31] although aminoglycosides per se may cause Fanconi syndrome [32].…”

True

“…Although early studies failed to reveal any evidence of nephrotoxicity in children receiving ifosfamide (de Kraker and Voute, 1984;Gasparini, 1986;Biron et al, 1987;Kellie et al, 1988;Demeocq et al, 1989), subsequent reports described a characteristic pattern of proximal renal tubular damage, often accompanied by glomerular and sometimes by distal tubular impairment (Smeitink et al, 1988;Burk et al, 1990;Skinner et al, 1990;Pratt et al, 1991;Suarez et al, 1991;Caron et al, 1992;Shore et al, 1992;De Schepper et al, 1993;Arndt et al, 1994;Ashraf et al, 1994). Such toxicity persisted long after discontinuation of ifosfamide treatment in many patients, often presenting with clinical manifestations due to the Fanconi syndrome (Skinner et al, 1993).…”