title: Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus.
abstract: BACKGROUND
  The outcome of patients with locally advanced gastroesophageal adenocarcinoma (adenocarcinoma of the esophagus, gastroesophageal (GE) junction, and stomach) is poor. There is conflicting evidence regarding the effects of perioperative chemotherapy on survival and other outcomes.
  
  
  OBJECTIVE
  To assess the effect of perioperative chemotherapy for gastroesophageal adenocarcinoma on survival and other clinically relevant outcomes in the overall population of participants in randomized controlled trials (RCTs) and in prespecified subgroups.
  
  
  METHODS
  We performed computerized searches in the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Review of Effectiveness (DARE), the Cochrane Database of Systematic Reviews (CDSR) from The Cochrane Library, MEDLINE (1966 to May 2011), EMBASE (1980 to May 2011), and LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud), combining the Cochrane highly sensitive search strategy with specific search terms. Moreover, we handsearched several online databases, conference proceedings, and reference lists of retrieved papers.
  
  
  METHODS
  We included RCTs which randomized patients with gastroesophageal adenocarcinoma, in the absence of distant metastases, to receive either chemotherapy with or without radiotherapy followed by surgery, or surgery alone.
  
  
  METHODS
  Two independent review authors identified eligible trials. We solicited individual patient data (IPD) from all selected trials. We performed meta-analyses based on intention-to-treat populations using the two-stage method to combine IPD with aggregate data from RCTs for which IPD were unavailable. We combined data from all trials providing IPD in a Cox proportional hazards model to assess the effect of several covariables on overall survival.
  
  
  RESULTS
  We identified 14 RCTs with 2422 eligible patients. For eight RCTs with 1049 patients (43.3%), we were able to obtain IPD. Perioperative chemotherapy was associated with significantly longer overall survival (hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.73 to 0.89). This corresponds to a relative survival increase of 19% or an absolute survival increase of 9% at five years. This survival advantage was consistent across most subgroups. There was a trend towards a more pronounced treatment effect for tumors of the GE junction compared to other sites, and for combined chemoradiotherapy as compared to chemotherapy in tumors of the esophagus and GE junction. Resection with negative margins was a strong predictor of survival. Multivariable analysis showed that tumor site, performance status, and age have an independent significant effect on survival. Moreover, there was a significant interaction of the effect of perioperative chemotherapy with age (larger treatment effect in younger patients). Perioperative chemotherapy also showed a significant effect on several secondary outcomes. It was associated with longer disease-free survival, higher rates of R0 resection, and more favorable tumor stage upon resection, while there was no association with perioperative morbidity and mortality.
  
  
  CONCLUSIONS
  Perioperative chemotherapy for resectable gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should thus be offered to all eligible patients. There is a trend to a larger survival advantage for tumors of the GE junction as compared to other sites and for chemoradiotherapy as compared to chemotherapy in esophageal and GE junction tumors. Likewise, there is an interaction between age and treatment effect, with younger patients having a larger survival advantage, and no survival advantage for elderly patients.
authors.affiliation: Department of Surgery, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany. ulrich.ronellenfitsch@umm.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Ronellenfitsch
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwarzbach
authors.forename: Ralf
authors.initials: R
authors.lastname: Hofheinz
authors.forename: Peter
authors.initials: P
authors.lastname: Kienle
authors.forename: Meinhard
authors.initials: M
authors.lastname: Kieser
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Slanger
authors.forename: Katrin
authors.initials: K
authors.lastname: Jensen
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000628:therapy*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000628:therapy; D059248:Chemoradiotherapy / Q000379:methods; D003131:Combined Modality Therapy / Q000379:methods; D004938:Esophageal Neoplasms / Q000401:mortality / Q000628:therapy*; D004943:Esophagogastric Junction / Q000601:surgery; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D013274:Stomach Neoplasms / Q000401:mortality / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents