title: Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.
abstract: BACKGROUND
  Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years.
  
  
  METHODS
  Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2-3N0-1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m(2) of body-surface area] for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed.
  
  
  RESULTS
  Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84·1 months (range 61·1-116·8, IQR 70·7-96·6), median overall survival was 48·6 months (95% CI 32·1-65·1) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months (14·2-33·7) in the surgery alone group (HR 0·68 [95% CI 0·53-0·88]; log-rank p=0·003). Median overall survival for patients with squamous cell carcinomas was 81·6 months (95% CI 47·2-116·0) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months (15·4-26·7) in the surgery alone group (HR 0·48 [95% CI 0·28-0·83]; log-rank p=0·008); for patients with adenocarcinomas, it was 43·2 months (24·9-61·4) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months (13·0-41·2) in the surgery alone group (HR 0·73 [95% CI 0·55-0·98]; log-rank p=0·038).
  
  
  CONCLUSIONS
  Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer.
  
  
  BACKGROUND
  Dutch Cancer Foundation (KWF Kankerbestrijding).
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands. Electronic address: j.shapiro@erasmusmc.nl.
authors.forename: Joel
authors.initials: J
authors.lastname: Shapiro
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands; Department of Surgery, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: J Jan B
authors.initials: JJB
authors.lastname: van Lanschot
authors.affiliation: Department of Radiation Oncology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Maarten C C M
authors.initials: MCCM
authors.lastname: Hulshof
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: van Hagen
authors.affiliation: Department of Surgery, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Mark I
authors.initials: MI
authors.lastname: van Berge Henegouwen
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands.
authors.forename: Bas P L
authors.initials: BPL
authors.lastname: Wijnhoven
authors.affiliation: Department of Medical Oncology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Hanneke W M
authors.initials: HWM
authors.lastname: van Laarhoven
authors.affiliation: Department of Surgery, Catharina Hospital, Eindhoven, Netherlands.
authors.forename: Grard A P
authors.initials: GAP
authors.lastname: Nieuwenhuijzen
authors.affiliation: Department of Medical Oncology, University Medical Centre Groningen, Groningen, Netherlands.
authors.forename: Geke A P
authors.initials: GAP
authors.lastname: Hospers
authors.affiliation: Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors.forename: Johannes J
authors.initials: JJ
authors.lastname: Bonenkamp
authors.affiliation: Department of Surgery, VU Medical Centre, Amsterdam, Netherlands.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Cuesta
authors.affiliation: Department of Medical Oncology, Rijnstate Hospital, Arnhem, Netherlands.
authors.forename: Reinoud J B
authors.initials: RJB
authors.lastname: Blaisse
authors.affiliation: Department of Radiation Oncology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Olivier R C
authors.initials: ORC
authors.lastname: Busch
authors.affiliation: Department of Pathology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands; Department of Pathology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Fiebo J W
authors.initials: FJW
authors.lastname: Ten Kate
authors.affiliation: Department of Medical Oncology, Catharina Hospital, Eindhoven, Netherlands.
authors.forename: Geert-Jan M
authors.initials: GM
authors.lastname: Creemers
authors.affiliation: Department of Medical Oncology, Academic Medical Centre, Amsterdam, Netherlands; Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors.forename: Cornelis J A
authors.initials: CJA
authors.lastname: Punt
authors.affiliation: Department of Surgery, University Medical Centre Groningen, Groningen, Netherlands.
authors.forename: John Th M
authors.initials: JTM
authors.lastname: Plukker
authors.affiliation: Department of Medical Oncology, VU Medical Centre, Amsterdam, Netherlands.
authors.forename: Henk M W
authors.initials: HMW
authors.lastname: Verheul
authors.affiliation: Department of Surgery, Rijnstate Hospital, Arnhem, Netherlands.
authors.forename: Ernst J Spillenaar
authors.initials: EJS
authors.lastname: Bilgen
authors.affiliation: Department of Pathology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands; Department of Pathology, St Lucas Andreas Hospital, Amsterdam, Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: van Dekken
authors.affiliation: Department of Radiation Oncology, Catharina Hospital, Eindhoven, Netherlands.
authors.forename: Maurice J C
authors.initials: MJC
authors.lastname: van der Sangen
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands; Verbeeten Institute, Tilburg, Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Rozema
authors.affiliation: Department of Pathology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands.
authors.forename: Katharina
authors.initials: K
authors.lastname: Biermann
authors.affiliation: Department of Radiation Oncology, University Medical Centre Groningen, Groningen, Netherlands.
authors.forename: Jannet C
authors.initials: JC
authors.lastname: Beukema
authors.affiliation: Department of Radiation Oncology, VU Medical Centre, Amsterdam, Netherlands.
authors.forename: Anna H M
authors.initials: AHM
authors.lastname: Piet
authors.affiliation: Department of Radiation Oncology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: van Rij
authors.affiliation: Arnhem Radiotherapeutic Institute ARTI, Arnhem, Netherlands.
authors.forename: Janny G
authors.initials: JG
authors.lastname: Reinders
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands.
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Tilanus
authors.affiliation: Department of Public Health, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands.
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
authors.affiliation: Department of Medical Oncology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, Netherlands.
authors.forename: Ate
authors.initials: A
authors.lastname: van der Gaast
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin / Q000008:administration & dosage; D059248:Chemoradiotherapy; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery*; D004943:Esophagogastric Junction / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects / Q000601:surgery*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage
chemical_list: D016190:Carboplatin; D017239:Paclitaxel; D005472:Fluorouracil