title: Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus.
abstract: OBJECTIVE
  To assess tumour regression grade (TRG) and lymph node downstaging to help define patients who benefit from neoadjuvant chemotherapy.
  
  
  METHODS
  Two hundred and eighteen consecutive patients with adenocarcinoma of the esophagus or gastro-esophageal junction treated with surgery alone or neoadjuvant chemotherapy and surgery between 2005 and 2011 at a single institution were reviewed. Triplet neoadjuvant chemotherapy consisting of platinum, fluoropyrimidine and anthracycline was considered for operable patients (World Health Organization performance status ≤ 2) with clinical stage T2-4 N0-1. Response to neoadjuvant chemotherapy (NAC) was assessed using TRG, as described by Mandard et al. In addition lymph node downstaging was also assessed. Lymph node downstaging was defined by cN1 at diagnosis: assessed radiologically (computed tomography, positron emission tomography, endoscopic ultrasonography), then pathologically recorded as N0 after surgery; ypN0 if NAC given prior to surgery, or pN0 if surgery alone. Patients were followed up for 5 years post surgery. Recurrence was defined radiologically, with or without pathological confirmation. An association was examined between t TRG and lymph node downstaging with disease free survival (DFS) and a comprehensive range of clinicopathological characteristics.
  
  
  RESULTS
  Two hundred and eighteen patients underwent esophageal resection during the study interval with a mean follow up of 3 years (median follow up: 2.552, 95%CI: 2.022-3.081). There was a 1.8% (n = 4) inpatient mortality rate. One hundred and thirty-six (62.4%) patients received NAC, with 74.3% (n = 101) of patients demonstrating some signs of pathological tumour regression (TRG 1-4) and 5.9% (n = 8) having a complete pathological response. Forty four point one percent (n = 60) had downstaging of their nodal disease (cN1 to ypN0), compared to only 15.9% (n = 13) that underwent surgery alone (pre-operatively overstaged: cN1 to pN0), (P < 0.0001). Response to NAC was associated with significantly increased DFS (mean DFS; TRG 1-2: 5.1 years, 95%CI: 4.6-5.6 vs TRG 3-5: 2.8 years, 95%CI: 2.2-3.3, P < 0.0001). Nodal down-staging conferred a significant DFS advantage for those patients with a poor primary tumour response to NAC (median DFS; TRG 3-5 and nodal down-staging: 5.533 years, 95%CI: 3.558-7.531 vs TRG 3-5 and no nodal down-staging: 1.114 years, 95%CI: 0.961-1.267, P < 0.0001).
  
  
  CONCLUSIONS
  Response to NAC in the primary tumour and in the lymph nodes are both independently associated with improved DFS.
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Fergus
authors.initials: F
authors.lastname: Noble
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Luke
authors.initials: L
authors.lastname: Nolan
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Bateman
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: James P
authors.initials: JP
authors.lastname: Byrne
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Jamie J
authors.initials: JJ
authors.lastname: Kelly
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Bailey
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Sharland
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Charlotte N
authors.initials: CN
authors.lastname: Rees
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Iveson
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Underwood
authors.affiliation: Fergus Noble, Luke Nolan, Tim J Underwood, Andrew R Bateman, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Bateman
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D019160:Endosonography; D004739:England; D015251:Epirubicin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D016629:Esophagectomy / Q000009:adverse effects / Q000401:mortality; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D017052:Hospital Mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000187:drug effects* / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D015251:Epirubicin; D002945:Cisplatin; D005472:Fluorouracil
keywords: Esophageal cancer; Gastro-esophageal cancer; Neoadjuvant; Regression