Reappraisal of treatment-induced renal dysfunction in patients receiving antiangiogenic agents in phase I trials

Abstract

Background: Several phase I trials are currently evaluating new antiangiogenic compounds. While hypertension and proteinuria have been largely reported as a class side effect of these agents, data on renal function [i.e. the glomerular filtration rate (GFR)] in patients (pts) treated with new antiangiogenic compounds in phase I trials are much scarcer.

Patients and methods: Between November 2005 and March 2008, we identified 72 pts with solid tumors who had been included in four Phase I trials testing antiangiogenic or related compounds. Thirty-two pts had received a pan-HER/VEGFR inhibitor (A), 29 had received a vascular-disrupting agent (B) and 11 had received a pan-VEGFR inhibitor in combination with CPT11 (C). For each patient, we retrospectively analyzed the serum creatinine level (SCr), Cr clearance (CrCl) calculated by both the Cockcroft and Gault and aMDRD equations at baseline, during treatment and at the end of treatment. Acute renal failure (ARF) was defined as a decrease of >25% in CrCl, and severe renal failure (SRF) as a decrease of >50% in CrCl. Chronic renal failure (CRF) was defined according to the KDOQI-KDIGO classification. Renal dysfunction was defined as Cl <60 ml/min with a normal Cr level (<125 μmol/l).

Results: Each pt had received an average of 4 cycles of treatment (1 to 12). During treatment, the incidence of ARF ranged from 40.2% to 44.4% (A = 11/32, B = 19/29, C = 2/11). Seven to 9.7% of these cases were severe (A = 1/32, B = 6/29, C = 0/11). Moreover, 26.4 to 27.7% of the pts had exhibited persistent renal insufficiency at the end of the study (A = 5/32, B = 15/29, C = 0/11). From the start till the end of treatment, ARF had been documented in 20.8% to 22.2% of the pts. The average reduction in clearance was 9.8 to 11.6 ml/min/1.73 m2 between baseline and the end of treatment.

Conclusion: The incidence of renal toxicity in phase I pts treated with antiangiogenic compounds was much higher than expected. Simple screening of Cr levels appears to be insufficient and careful nephrologic monitoring at baseline and during treatment should be implemented in early clinical trials assessing the risk/benefit ratio of new antiangiogenic compounds.