title: Progression-free survival as a surrogate for overall survival in first-line chemotherapy for advanced pancreatic cancer.
abstract: Overall survival (OS), as the primary end-point in first-line chemotherapy trials, requires a prolonged follow-up time and may be confounded by subsequent regimens. This study aimed to evaluate the correlation between OS and surrogate end-points (progression-free survival [PFS], response rate and disease control rate), and to identify a potential surrogate for OS in advanced pancreatic cancer.
  
  
  
  Based on an electronic search, we identified randomized controlled phase II and III trials of first-line chemotherapy for advanced pancreatic cancer. Correlation analyses were performed between surrogate end-points and OS, and between improvements in surrogates and those in OS.
  
  
  
  Fifty trials (II/II-III/III, 17/2/31) with 111 treatment arms were identified, and 15,906 patients were analysed. PFS was most strongly correlated with OS (correlation coefficient, 0.76). Weighted linear regression models revealed the greatest determinant coefficient of 0.84 between the hazard ratio (HR) of the experimental arms compared with the control arms of PFS and that of OS. The approximate equation was log HROS = 0.01 + 0.77 × log HRPFS, indicating that risk reduction of OS via chemotherapy would translate into a 77% risk reduction of PFS. The surrogacy of PFS for OS was robust throughout our subgroup analyses: e.g., biologic versus non-biologic regimens, locally advanced versus metastatic disease.
  
  
  
  The surrogacy of PFS for OS in pancreatic cancer was validated. Therefore, the use of PFS as the primary end-point in clinical trials could facilitate the early introduction of new effective chemotherapy regimens into clinical practice.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: hamada-tky@umin.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hamada
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: ynakai-tky@umin.ac.jp.
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Nakai
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: isayama-tky@umin.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Isayama
authors.affiliation: Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan. Electronic address: yasunagah-tky@umin.ac.jp.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasunaga
authors.affiliation: Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan. Electronic address: ptmatsui-tky@umin.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: naminatsu.takahara@gmail.com.
authors.forename: Naminatsu
authors.initials: N
authors.lastname: Takahara
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: smizuno-tky@umin.ac.jp.
authors.forename: Suguru
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: kogureh-tky@umin.ac.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kogure
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: sab-tky@umin.net.
authors.forename: Saburo
authors.initials: S
authors.lastname: Matsubara
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: natsuyoy-gi@umin.ac.jp.
authors.forename: Natsuyo
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: mtada-tky@umin.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tada
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: kkoike-tky@umin.ac.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015415:Biomarkers; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D010190:Pancreatic Neoplasms / Q000628:therapy*; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic
chemical_list: D015415:Biomarkers
keywords: Drug therapy; End-point determination; Pancreatic neoplasms; Survival; Treatment outcome