title: Surrogate end points for overall survival and local control in neoadjuvant rectal cancer trials: statistical evaluation based on the FFCD 9203 trial.
abstract: BACKGROUND
  In resectable rectal cancer trials, pathological parameters are early preoperative treatment efficacy measures. Their validation as surrogate end points for long-term clinical outcomes would allow to reduce trial duration. The aim was to evaluate potential surrogates for overall survival (OS) and local control (LC) in preoperative T3/T4 rectal cancer trials. Candidate variables included ypT and ypN stages, T downstaging, tumor regression grade (TRG), and circumferential resection margin (CRM) status.
  
  
  METHODS
  In the Fédération Francophone de Cancérologie Digestive (FFCD) 9203 trial, 742 eligible patients were randomly assigned to receive preoperative radiotherapy with or without concurrent chemotherapy. Surrogacy was evaluated using Prentice criteria and the proportion of treatment effect (PTE) explained by each potential surrogate.
  
  
  RESULTS
  None of the candidate surrogates fulfilled all Prentice criteria. Data analyses did not provide interpretable PTE measures for OS. Regarding LC, the highest PTE was reached by TRG, which explained 12% of the effect on local recurrence. This proportion may not exceed 41% [95% confidence interval (CI) -1% to 41%]. PTE explained by the CRM status was associated with a wide uncertainty (95% CI -81% to 105%), which does not exclude a potentially high degree of surrogacy.
  
  
  CONCLUSIONS
  In the FFCD 9203 trial, pathological parameters were not surrogate for OS or LC.
authors.affiliation: Fédération Francophone de Cancérologie Digestive, Inserm U866 Faculté de Médecine, Dijon; University of Burgundy, Dijon. Electronic address: nicolas.methy@u-bourgogne.fr.
authors.forename: N
authors.initials: N
authors.lastname: Methy
authors.affiliation: Fédération Francophone de Cancérologie Digestive, Inserm U866 Faculté de Médecine, Dijon; University of Burgundy, Dijon; Department of Gastroenterology, University Hospital Le Bocage, Dijon.
authors.forename: L
authors.initials: L
authors.lastname: Bedenne
authors.affiliation: Department of Medical Oncology, Centre Alexis Vautrin, Vandoeuvre-lès-Nancy.
authors.forename: T
authors.initials: T
authors.lastname: Conroy
authors.affiliation: Department of Gastroenterology, University Hospital Robert Debre, Reims.
authors.forename: O
authors.initials: O
authors.lastname: Bouché
authors.affiliation: Department of Radiotherapy, University Hospital Pierre Benite, Lyon.
authors.forename: O
authors.initials: O
authors.lastname: Chapet
authors.affiliation: Department of Digestive Oncology, Gustave Roussy Institute, Villejuif.
authors.forename: M
authors.initials: M
authors.lastname: Ducreux
authors.affiliation: Department of Radiotherapy, Centre Antoine Lacassagne, Nice, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Gérard
authors.affiliation: Fédération Francophone de Cancérologie Digestive, Inserm U866 Faculté de Médecine, Dijon.
authors.forename: F
authors.initials: F
authors.lastname: Bonnetain
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D016032:Randomized Controlled Trials as Topic; D012004:Rectal Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers