title: Progression-free survival and overall survival in phase III trials of molecular-targeted agents in advanced non-small-cell lung cancer.
abstract: BACKGROUND
  We examined how crossover therapy might affect the association between progression-free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC).
  
  
  METHODS
  We extracted PFS- and OS-hazard ratios (HRs) in phase III trials of molecular-targeted agents for advanced NSCLC. Their relationship was modeled in a linear function with the coefficient of determination (R-squared) to assess the correlation between PFS and OS.
  
  
  RESULTS
  Thirty-four trials with 35 pairs for the investigational and reference arms were identified (24,158 patients). Overall, there was little correlation between PFS- and OS-HRs (R-squared = 0.14), suggesting PFS-HR could account only for 14% of variation in OS-HR. The median proportion of crossover therapy per trial was 20%. If patients seldom crossed over (none or <1%), the association between PFS- and OS-HRs was strong (R-squared = 0.69). When the proportion of crossover was ≥1%, however, R-squared declined considerably (≥1% to <20% crossover, R-squared = 0.27; ≥20% to <40%, R-squared = 0.06; and ≥40%, R-squared = 0.27).
  
  
  CONCLUSIONS
  A PFS advantage seldom is associated with an OS advantage any longer. Our analysis suggests this is due to a high level of crossover now that an increasing number of active agents are available for NSCLC.
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan. khotta@md.okayama-u.ac.jp
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hotta
authors.forename: Etsuji
authors.initials: E
authors.lastname: Suzuki
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maio
authors.forename: Paolo
authors.initials: P
authors.lastname: Chiodini
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
authors.forename: Eiki
authors.initials: E
authors.lastname: Ichihara
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.forename: Christian
authors.initials: C
authors.lastname: Manegold
authors.forename: Lothar
authors.initials: L
authors.lastname: Pilz
authors.forename: Akiko
authors.initials: A
authors.lastname: Hisamoto-Sato
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tabata
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D016032:Randomized Controlled Trials as Topic