title: Impact of disease progression date determination on progression-free survival estimates in advanced lung cancer.
abstract: BACKGROUND
  In patients with advanced lung cancer, overall survival is largely influenced by progression status. Because progression-free survival (PFS)-based endpoints are controversial, the authors evaluated the impact of the progression date (PD) determination approach on PFS estimates.
  
  
  METHODS
  Individual patient data from 21 trials (14 North Central Cancer Treatment Group trials and 7 Southwest Oncology Group trials) were used. The reported PD (RPD) was defined as either the radiographic scan date or the clinical deterioration date. PD was determined using Method 1 (M1), the RPD; M2, 1 day after the last progression-free scan; M3, midpoint between the last progression-free scan and the RPD; and M4, an interval-censoring approach. PFS was estimated using Kaplan-Meier (M1-M3), and maximum-likelihood (M4) methods. Simulation studies were performed to understand the impact of the length of time elapsed between the last progression-free scan and the PD on time-to-progression estimates.
  
  
  RESULTS
  PFS estimates using the RPD were the highest, and M2 was the most conservative. M3 and M4 were similar because the majority of progressions occurred during treatment (ie, frequent disease assessments). M3 was influenced less by the length of the assessment schedules (percentage difference from the true time-to-progression, <1.5%) compared with M1 (11% to 30%) and M2 (-8% to -29%). The overall study conclusion was unaffected by the method used for randomized trials.
  
  
  CONCLUSIONS
  The magnitude of difference in the PFS estimates was large enough to alter trial conclusions in patients with advanced lung cancer. The results indicate that standards for PD determination, the use of sensitivity analyses, and randomized trials are critical when designing trials and reporting efficacy using PFS-based endpoints.
authors.affiliation: Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Qi
authors.forename: Katie L
authors.initials: KL
authors.lastname: Allen Ziegler
authors.forename: Shauna L
authors.initials: SL
authors.lastname: Hillman
authors.forename: Mary W
authors.initials: MW
authors.lastname: Redman
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schild
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
mesh_terms: D017322:Clinical Trials, Phase II as Topic; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality*; D016032:Randomized Controlled Trials as Topic