title: A statistical evaluation of dose expansion cohorts in phase I clinical trials.
abstract: BACKGROUND
  Phase I trials often include a dose expansion cohort (DEC), in which additional patients are treated at the estimated maximum tolerated dose (MTD) after dose escalation, with the goal of ensuring that data are available from more than six patients at a single dose level. However, protocols do not always detail how, or even if, the additional toxicity data will be used to reanalyze the MTD or whether observed toxicity in the DEC will warrant changing the assigned dose. A DEC strategy has not been statistically justified.
  
  
  METHODS
  We conducted a simulation study of two phase I designs: the "3+3" and the Continual Reassessment Method (CRM). We quantified how many patients are assigned the true MTD using a 10 to 20 patient DEC and how a sensible reanalysis using the DEC changes the probability of selecting the true MTD. We compared these results with those from an equivalently sized larger CRM that does not include a DEC.
  
  
  RESULTS
  With either the 3+3 or CRM, reanalysis with the DEC increased the probability of identifying the true MTD. However, a large CRM without a DEC was more likely to identify the true MTD while still treating 10 or 15 patients at this dose level.
  
  
  CONCLUSIONS
  Where feasible, a CRM design with no explicit DEC is preferred to designs that fix a dose for all patients in a DEC.
authors.affiliation: Departments of Biostatistics (PSB, JS, JMGT, TMB, KAG, SD, MJS), Internal Medicine (GPK), Radiation Oncology (JMGT, TSL, MJS), University of Michigan. philb@umich.edu.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Boonstra
authors.affiliation: Departments of Biostatistics (PSB, JS, JMGT, TMB, KAG, SD, MJS), Internal Medicine (GPK), Radiation Oncology (JMGT, TSL, MJS), University of Michigan.
authors.forename: Jincheng
authors.initials: J
authors.lastname: Shen
authors.affiliation: Departments of Biostatistics (PSB, JS, JMGT, TMB, KAG, SD, MJS), Internal Medicine (GPK), Radiation Oncology (JMGT, TSL, MJS), University of Michigan.
authors.forename: Jeremy M G
authors.initials: JM
authors.lastname: Taylor
authors.affiliation: Departments of Biostatistics (PSB, JS, JMGT, TMB, KAG, SD, MJS), Internal Medicine (GPK), Radiation Oncology (JMGT, TSL, MJS), University of Michigan.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Braun
authors.affiliation: Departments of Biostatistics (PSB, JS, JMGT, TMB, KAG, SD, MJS), Internal Medicine (GPK), Radiation Oncology (JMGT, TSL, MJS), University of Michigan.
authors.forename: Kent A
authors.initials: KA
authors.lastname: Griffith
authors.affiliation: Departments of Biostatistics (PSB, JS, JMGT, TMB, KAG, SD, MJS), Internal Medicine (GPK), Radiation Oncology (JMGT, TSL, MJS), University of Michigan.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Daignault
authors.affiliation: Departments of Biostatistics (PSB, JS, JMGT, TMB, KAG, SD, MJS), Internal Medicine (GPK), Radiation Oncology (JMGT, TSL, MJS), University of Michigan.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Kalemkerian
authors.affiliation: Departments of Biostatistics (PSB, JS, JMGT, TMB, KAG, SD, MJS), Internal Medicine (GPK), Radiation Oncology (JMGT, TSL, MJS), University of Michigan.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.affiliation: Departments of Biostatistics (PSB, JS, JMGT, TMB, KAG, SD, MJS), Internal Medicine (GPK), Radiation Oncology (JMGT, TSL, MJS), University of Michigan.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schipper
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020714:Maximum Tolerated Dose; D012107:Research Design
chemical_list: D000970:Antineoplastic Agents