title: Effect of Renal Dysfunction on Toxicity in Three Decades of Cancer Therapy Evaluation Program-Sponsored Single-Agent Phase I Studies.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Jan 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.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: Jan 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.
authors.forename: Fei
authors.initials: F
authors.lastname: Ding
authors.affiliation: Jan 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.
authors.forename: Hussein
authors.initials: H
authors.lastname: Tawbi
authors.affiliation: Jan 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Jan 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.
authors.forename: Diana
authors.initials: D
authors.lastname: Viluh
authors.affiliation: Jan 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.
authors.forename: Indrani
authors.initials: I
authors.lastname: Chatterjee
authors.affiliation: Jan 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.
authors.forename: Matthew
authors.initials: M
authors.lastname: Rinker
authors.affiliation: Jan 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.
authors.forename: Selina L
authors.initials: SL
authors.lastname: Chow
authors.affiliation: Jan 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.
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D003404:Creatinine / Q000378:metabolism*; D016208:Databases, Factual; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D012720:Severity of Illness Index; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D003404:Creatinine