NEPHROTOXICITY OF CONTINUOUS INFUSION IFOSFAMIDE. A STUDY OF THE SPANISH GROUP FOR RESEARCH ON SARCOMAS (GEIS)

Buesa JM^*, Teijido PG, Galbe M, López-Pousa A, García del Muro J, Martín J, Antón A, Montalar J, de las Peñas R, Cruz J, Escudero P, Fra J, Menéndez D and Poveda A for the G.E.I.S. ^*Oncología Médica, Hospital Central de Asturias, 33006 Oviedo, Spain.

The nephrotoxicity of ifosfamide (IFOS) delivered by c.i. at doses > 10 g/m², combined or not with doxorubicin, was analyzed in adult patients (pts) with advanced soft-tissue sarcoma included in different phase II studies, in order to characterize this side-effect, evaluate its reversibility and identify parameters of early renal damage. Pts previously exposed to nephrotoxic drugs, nephrectomized or with obstructive uropathy were excluded. All pts received sodium bicarbonate, without special hydration or electrolyte supplements. Serum and urine parameters (24 hr collection) were routinely monitored at least twice per cycle, and glomerular (serum creatinine and creatinine clearance [Clcr]) and proximal tubular functions (fractional excretion of phosphate [FEp], calcium [FEca] or magnesium [FEmg] and renal threshold for phosphate [Tm_p/GFR], and serum bicarbonate) were determined. Aminoaciduria or differential proteinuria were not measured. The reversibility of observed changes was evaluated at day 28 to 40 post-cycle. Changes were graded according to NCI-CTC scales when applicable. Forty-three pts, median age 51 yr (21-69), received 187 cycles (median 4, range 1-11) every 4 wks, with a median cumulative dose of IFOS (CD) of 84 g (22-338).

Results (% of cycles): Glomerular function: serum creatinine G 1 7, and ClCr < 50 ml/min 5, with no episodes of acute renal failure; proteinuria G 1 65, G 2 12. Proximal tubular function: serum Na, K, Ca and Mg were normal in 80% of cycles; serum phosphate G 2 11, G 3 8, G 4 2, serum bicarbonate (mmol/l) 20-22 17, 18-20 4, <18 9; FEca, FEmg or FEp ³ x 2 N occurred, respectively, in 46%, 20% and 50%, and after one cycle only 21% of FEp values were within basal values ± 1 s.d.; Tm_p/GFR was £ 0,36 ± 0,13 mmol/l in 28% (baseline value 0,64 ± 0,06 mmol/l). Clcr changes correlated with CD (p = 0,042) and with proteinuria (g/l) (p = 0,0012). Decrease in serum phosphate correlated with an increase in FEp and a decrease in Tm_p/GFR, traducing renal damage. CD was correlated with FEp (p = 0,002) and Tm_p/GFR (p = 0,038). Altered Clcr returned to baseline values in all but 1 pt, and proteinuria disappeared in 90% of positive cycles; Tm_p/GFR had lower normal values with increased CD, and FEp did not recover by day 28 to 40. These data suggest that IFOS administered by continuous infusion at doses ³ 10 g/m² induces a subclinical and reversible renal damage in up to 90% of cycles. FEp appears a sensitive parameter for early detection and follow-up of some of the renal changes induced by IFOS. Long-term evolution of the renal function in these pts should allow us to know the relevance of these alterations.