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Published on: February 6, 2015
Effect of Renal Dysfunction on Toxicity in Three Decades of Cancer Therapy Evaluation Program-Sponsored Single-Agent
Jan H Beumer1, Fei Ding2, Hussein Tawbi2
1Jan H. Beumer, Fei Ding, Hussein Tawbi, Yan Lin, and Selina L. Chow, University of Pittsburgh Cancer Institute; Jan H. Beumer, University of Pittsburgh School of Pharmacy; Jan H. Beumer and Hussein Tawbi, University of Pittsburgh School of Medicine; Yan Lin, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; Diana Viluh, Indrani Chatterjee, and Matthew Rinker, Theradex, Princeton, NJ; and S. Percy Ivy, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD. beumerj@gmail.com.
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.
Insights
Patients with mild renal dysfunction enrolled in phase I cancer trials show a small increase in toxicity. The US Food and Drug Administration (FDA) criteria for renal dysfunction are used to guide patient selection in oncology studies.
Area of Science:
- Oncology
- Pharmacology
- Nephrology
Background:
- Renal clearance significantly impacts anticancer drug toxicity.
- Discrepancies exist between National Cancer Institute (NCI) and US Food and Drug Administration (FDA) criteria for classifying renal dysfunction.
- Understanding these differences is crucial for patient safety in clinical trials.
Purpose of the Study:
- To examine discrepancies in renal dysfunction classification between NCI and FDA criteria.
- To assess the association between these classifications and toxicity incidence in phase I cancer trials.
- To evaluate patient enrollment trends over three decades (1979-2010).
Main Methods:
- Utilized creatinine clearance data from 10,236 patients using Cockcroft-Gault and Jelliffe formulas.
- Applied Modification of Diet in Renal Disease (MDRD) formulas to a subset of 4,084 patients.
- Classified patients per NCI and FDA criteria, comparing toxicity rates.
Main Results:
- Estimated renal function improved over time, potentially due to increased patient weight.
- Approximately 36% of phase I trial patients exhibited mild renal dysfunction by FDA criteria.
- Mild renal dysfunction was linked to a statistically significant, albeit small, increase in severe nonhematologic toxicity and overall toxicities.
Conclusions:
- Patients with FDA-defined mild renal dysfunction are routinely included in phase I antineoplastic trials without a clinically significant rise in toxicity risk.
- Future oncology trials using FDA classification may only need to activate the mild renal dysfunction group if significant differences in tolerability or pharmacokinetics are observed between groups.
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