Dose-related nephrotoxicity of carboplatin in children

Abstract

Summary This study investigated changes and the time course of these changes in renal function in children following treatment with carboplatin, and identified risk factors for nephrotoxicity. Glomerular and proximal renal tubular function were investigated before and up to 2 years after treatment in 23 children who received carboplatin. The main findings were reduced glomerular filtration rate (GFR), and increased renal tubular loss of magnesium, manifested by a low serum magnesium (S Mg). The mean fall in GFR was 22 ml min -1 1.73 m -2 (P = 0.012), and in S Mg it was 0.17 mmol l -1 (P = 0.0077). No patient had a clinically important reduction in GFR, and only one patient had symptomatic hypomagnesaemia. GFR and S Mg did not change over time after completion of treatment. Cumulative dose (CD) of carboplatin was inversely related to mean S Mg at the end of treatment (P = 0.031), and directly related to the fall in S Mg (P < 0.001). Calculated cumulative area under the plasma concentration versus time curve (AUC) of carboplatin was inversely related to S Mg after treatment (P = 0.004). Dose intensity (DI) of carboplatin was not shown to be related to S Mg following treatment. CD, AUC and DI of carboplatin were not related to GFR, nor change in GFR, after treatment. High CDs of carboplatin may be associated with evidence of renal damage qualitatively similar to but less severe than that caused by cisplatin. GFR and SMg should be carefully monitored when high CDs of carboplatin are used, or if carboplatin is combined with other nephrotoxic chemotherapy.

Dose Response of Carboplatin‐Induced Nephrotoxicity in Rats

“…These doses are equivalent to the clinical therapeutic doses of carboplatin in cancer patients (Bishop 1992;Bohm et al 1999;Wandt et al 1999;Maldoon et al 2000). However, administration of high and/or cumulative doses of carboplatin produced renal toxicity in humans (Agraharkar et al 1998;English et al 1999) and experimental animals (Ueda et al 1991;Martinez et al 1993). The data show that carboplatin in single high doses (192 and 256 mg/ kg) caused renal dysfunction in rats as evidenced by elevation of plasma creatinine and blood urea nitrogen levels.…”

“…dysfunction (Agraharkar et al 1998;English et al 1999). Clinically, treatment with carboplatin significantly reduced glomerular filtration rate and serum magnesium in children (English et al 1999).…”

“…Carboplatin is more stable than its analogue cisplatin, and has equivalent antitumour activity (Alberts 1995;Mckeage 1995;Meyer et al 2001). Since carboplatin has a less toxic adverse effect profile than cisplatin, it is being tried as a replacement for cisplatin in many cancer therapy regimens (Mckeage 1995;English et al 1999). In order to achieve optimal antitumour effects, administration of increased doses of carboplatin is required in the clinic (Bohm et al 1999;Wandt et al 1999).…”

“…The predominant dose-limiting toxicities of carboplatin are bone marrow suppression and ototoxicity (Mckeage 1995;Cavaletti et al 1998;Husain et al 2001). However, carboplatin-induced renal side effects, especially with higher dosage regimens or in the presence of other risk factors have also been reported (Yasumasu et al 1992;English et al 1999). Further, carboplatin is primarily excreted by the kidneys via tubular filtration and secretion, hence its dosage needs to be reduced in patients with renal Author for correspondence: Kazim Husain, Department of Surgery, Southern Illinois University School of Medicine, 800 N Rutledge St., Springfield, IL 62794-9638, USA (fax π1 217 545 1793, e-mail khusain/siumed.edu).…”

“…Clinically, treatment with carboplatin significantly reduced glomerular filtration rate and serum magnesium in children (English et al 1999). In addition there is a high degree of platinum-DNA adduct persistence in kidneys subsequent to carboplatin administration in cancer patients (Poirier et al 1992;Blommaert et al 1996).…”