title: Evaluation of three definitions of progression-free survival in preoperative cancer therapy (JCOG0801-A).
abstract: OBJECTIVE
  Progression-free survival is an often-used endpoint in clinical trials comparing preoperative therapy and surgery-first therapy. Because the surgery date is always later in the preoperative arm than in the surgery-first arm, it is difficult to define progression-free survival optimally. We evaluated three progression-free survival definitions that used different methods to handle incomplete resection.
  
  
  METHODS
  The three definitions specify the event date of incomplete resection (IR) as follows: 'IR = event' method, date of surgery; 'IR not event' method, date of radiological or clinical progression after incomplete resection; landmark method, landmark time. According to these definitions, the theoretical strengths and weaknesses of the three definitions are investigated. Three patterns of progression-free survival and overall survival were estimated using the data of the Japan Clinical Oncology Group studies.
  
  
  RESULTS
  Theoretically, 'IR = event' inflates alpha error while 'IR not event' method and landmark method reduce the statistical power under the alternative hypothesis. In JCOG9907, hazard ratios for the three definitions were: 'IR = event', 0.80 (95% confidence interval, 0.59-1.07; P = 0.13); 'IR not event', 0.81 (95% confidence interval, 0.60-1.09; P = 0.16); landmark, 0.80 (95% confidence interval, 0.59-1.07; P = 0.15). No P value of any methods corresponded with the positive result for overall survival (P = 0.03). In the preoperative arms of the four studies, maximum differences in median and percentage of 1 year progression-free survival among the three definitions were 0-6.4 months and 1.2-5.2%.
  
  
  CONCLUSIONS
  Progression-free survival sometimes fails as a surrogate of overall survival, and differences among results obtained with various progression-free survival definitions can be large. Overall survival should be used as primary endpoint in studies evaluating preoperative therapy.
authors: Multi-institutional Clinical Trial Support Center, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan. kennakam@ncc.go.jp
authors: Kenichi
authors: K
authors: Nakamura
authors: Taro
authors: T
authors: Shibata
authors: Atsuo
authors: A
authors: Takashima
authors: Seiichiro
authors: S
authors: Yamamoto
authors: Haruhiko
authors: H
authors: Fukuda
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D006801:Humans; D007564:Japan; D009367:Neoplasm Staging; D009369:Neoplasms / Q000401:mortality* / Q000628:therapy*; D011300:Preoperative Care; D016032:Randomized Controlled Trials as Topic; D015996:Survival Rate