title: Inter-institutional heterogeneity in outcomes of chemotherapy for metastatic gastric cancer: correlative study in the JCOG9912 phase III trial.
abstract: BACKGROUND
  The standard chemotherapy regimen for gastric cancer has been established by several phase III trials. However, few studies have evaluated inter-institutional heterogeneity in randomised trials; such research may assure the generalisability of the results and also the reliability of the study group itself.
  
  
  METHODS
  The Japan Clinical Oncology Group (JCOG)9912 phase III trial compared irinotecan plus cisplatin and S-1 alone with fluorouracil alone for metastatic gastric cancer, and finally demonstrated the non-inferiority of S-1 alone with respect to overall survival (OS). Mixed effects models were used to evaluate outcomes of 658 patients from 22 hospitals. After adjustment for nine background factors, the heterogeneity in OS, progression-free survival (PFS), and incidences of grade 3-4 adverse events among hospitals was estimated. We also estimated the correlation between outcomes and either hospital volume or medical oncology clinical experience.
  
  
  RESULTS
  A large degree of heterogeneity in median OS was observed for fluorouracil alone (range, 8.3-13.3 months), while the difference in median PFS between hospitals was small (range, 2.4-3.4 months). Although some heterogeneity in the treatment effect of irinotecan plus cisplatin or S-1 alone was observed in OS and PFS, the HRs did not exceed 1.00 in any hospital for either regimen. There was minimal heterogeneity in the incidences of grade 3-4 adverse events. There was a trend towards correlation between greater medical oncology clinical experience and both better OS after fluorouracil alone and a lower HR for OS after irinotecan plus cisplatin, but it was not statistically significant.
  
  
  CONCLUSIONS
  Large inter-institutional heterogeneity was observed in OS, but not in PFS, after the standard regimen, but there was little heterogeneity in the treatment effects of irinotecan plus cisplatin or S-1 alone, indicating that the final results of the JCOG9912 trial can be generalised to the target population.
  
  
  BACKGROUND
  NCT00142350.
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address: ykurokawa@gesurg.med.osaka-u.ac.jp.
authors.forename: Y
authors.initials: Y
authors.lastname: Kurokawa
authors.affiliation: Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Boku
authors.affiliation: Division of Biostatistics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ohtsu
authors.affiliation: Japan Clinical Oncology Group Data Center, National Cancer Center, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Mizusawa
authors.affiliation: Japan Clinical Oncology Group Data Center, National Cancer Center, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Japan Clinical Oncology Group Data Center, National Cancer Center, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Fukuda
keywords: S-1; fluorouracil; gastric cancer; heterogeneity; irinotecan plus cisplatin