title: Association between incremental gains in the objective response rate and survival improvement in phase III trials of first-line chemotherapy for extensive disease small-cell lung cancer.
abstract: BACKGROUND
  The duration of, resources required for and cost of clinical trials could be reduced if a surrogate end point was to be used in place of survival. We assessed the extent to which the objective response rate (ORR) is predictive of mortality, how much difference in the ORR is needed to predict an obvious survival difference and what factors could affect the association between the two parameters during the first-line treatment of extensive disease (ED)-small-cell lung cancer (SCLC).
  
  
  METHODS
  We used the ORRs and median survival times (MSTs) from 48 phase III trials of first-line chemotherapy involving 8779 randomised patients with ED-SCLC in a linear regression analysis. The MST difference was calculated as the difference in MST between the investigational and reference arms; the ORR difference was similarly defined.
  
  
  RESULTS
  ORR difference between the treatment arms was modestly associated with the MST difference in the overall trials (R(2) = 0.3314). In contrast, the relationship was stronger among only trials in which prophylactic cranial irradiation was given to those having an objective response to the initial chemotherapy (R(2) = 0.6279). In this trial setting, large differences in ORR were needed to predict a survival advantage (1.2-day survival advantage per 2% increase in ORR).
  
  
  CONCLUSIONS
  In the first-line treatment of ED-SCLC, a favourable relationship was detected between the two parameters in the selected trial setting. Large ORR differences were needed to predict a survival benefit, clearly suggesting the need for new chemotherapeutic agents.
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan. khotta@md.okayama-u.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Hotta
authors.forename: K
authors.initials: K
authors.lastname: Kiura
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: N
authors.initials: N
authors.lastname: Takigawa
authors.forename: I
authors.initials: I
authors.lastname: Oze
authors.forename: N
authors.initials: N
authors.lastname: Ochi
authors.forename: M
authors.initials: M
authors.lastname: Tabata
authors.forename: M
authors.initials: M
authors.lastname: Tanimoto
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D016371:Cranial Irradiation; D006801:Humans; D016014:Linear Models; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D018714:Radiotherapy, Adjuvant; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome