title: The role of age on dose-limiting toxicities in phase I dose-escalation trials.
abstract: OBJECTIVE
  Elderly oncology patients are not enrolled in early-phase trials in proportion to the numbers of geriatric patients with cancer. There may be concern that elderly patients will not tolerate investigational agents as well as younger patients, resulting in a disproportionate number of dose-limiting toxicities (DLT). Recent single-institution studies provide conflicting data on the relationship between age and DLT.
  
  
  METHODS
  We retrospectively reviewed data about patients treated on single-agent, dose-escalation, phase I clinical trials sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute. Patients' dose levels were described as a percentage of maximum tolerated dose, the highest dose level at which <33% of patients had a DLT, or recommended phase II dose (RP2D). Mixed-effect logistic regression models were used to analyze relationships between the probability of a DLT and age and other explanatory variables.
  
  
  RESULTS
  Increasing dose, increasing age, and worsening performance status (PS) were significantly related to an increased probability of a DLT in this model (P < 0.05). There was no association between dose level administered and age (P = 0.57).
  
  
  CONCLUSIONS
  This analysis of phase I dose-escalation trials, involving more than 500 patients older than 70 years of age, is the largest reported. As age and dose level increased and PS worsened, the probability of a DLT increased. Although increasing age was associated with occurrence of DLT, this risk remained within accepted thresholds of risk for phase I trials. There was no evidence of age bias on enrollment of patients on low or high dose levels.
authors.affiliation: Case Western Reserve School of Medicine, Cleveland, Ohio.
authors.forename: A
authors.initials: A
authors.lastname: Schwandt
authors.affiliation: National Cancer Institute, Bethesda, Maryland.
authors.forename: P J
authors.initials: PJ
authors.lastname: Harris
authors.affiliation: National Cancer Institute, Bethesda, Maryland.
authors.forename: S
authors.initials: S
authors.lastname: Hunsberger
authors.affiliation: Institut Jules Bordet, Brussels, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Deleporte
authors.affiliation: National Cancer Institute, Bethesda, Maryland.
authors.forename: G L
authors.initials: GL
authors.lastname: Smith
authors.affiliation: Theradex Systems, Inc, Princeton, New Jersey.
authors.forename: D
authors.initials: D
authors.lastname: Vulih
authors.affiliation: Theradex Systems, Inc, Princeton, New Jersey.
authors.forename: B D
authors.initials: BD
authors.lastname: Anderson
authors.affiliation: National Cancer Institute, Bethesda, Maryland. ivyp@ctep.nci.nih.gov.
authors.forename: S P
authors.initials: SP
authors.lastname: Ivy
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents