Effect of Renal Dysfunction on Toxicity in Three Decades of Cancer Therapy Evaluation Program-Sponsored Single-Agent Phase I Studies.

PURPOSE: Alterations in renal clearance of anticancer drugs can affect the occurrence of toxicities related to drug exposure. The National Cancer Institute and the US Food and Drug Administration (FDA) use different criteria to classify renal dysfunction. We examined those discrepancies and their potential association with the incidence of toxicities in patients enrolled onto Cancer Therapy Evaluation Program-sponsored single-agent phase I studies over three decades (1979 to 2010).
METHODS: Data to estimate creatinine clearance according to the Cockcroft-Gault and Jelliffe formulas were available from 10,236 patients, and data to estimate creatinine clearance according to the six- and four-variable Modification of Diet in Renal Disease formulas were available from a subset (n = 4,084). Patients were classified according to National Cancer Institute and FDA criteria, and the rates of clinically relevant toxicities were evaluated within groups and compared among groups.
RESULTS: Cockcroft-Gault estimated renal function improved over time, which may be attributed to an increase in weight of patients in the same time frame. Approximately 36% of patients enrolled onto phase I trials had mild renal dysfunction by FDA criteria. Relative to normal function, mild renal dysfunction was associated with a statistically significant but small increase in grade 3 or 4 nonhematologic toxicity and any relevant toxicities.
CONCLUSION: Patients with mild renal dysfunction by FDA criteria have routinely been enrolled onto phase I studies of antineoplastics without clinically meaningful increase in the risk of toxicity. In future oncology renal dysfunction trials based on the FDA classification, the FDA mild group may only need to be activated when the moderate and normal groups differ substantially in tolerability or pharmacokinetics.