title: Accuracy of Detecting Residual Disease After Cross Neoadjuvant Chemoradiotherapy for Esophageal Cancer (preSANO Trial): Rationale and Protocol.
abstract: BACKGROUND
  Results from the recent CROSS trial showed that neoadjuvant chemoradiotherapy (nCRT) significantly increased survival as compared to surgery alone in patients with potentially curable esophageal cancer. Furthermore, in the nCRT arm 49% of patients with a squamous cell carcinoma (SCC) and 23% of patients with an adenocarcinoma (AC) had a pathologically complete response in the resection specimen. These results provide a rationale to reconsider and study the timing and necessity of esophagectomy in (all) patients after application of the CROSS regimen.
  
  
  OBJECTIVE
  We propose a "surgery as needed" approach after completion of nCRT. In this approach, patients will undergo active surveillance after completion of nCRT. Surgical resection would be offered only to those patients in whom residual disease or a locoregional recurrence is highly suspected or proven. However, before a surgery as needed approach in oesophageal cancer patients (SANO) can be tested in a randomized controlled trial, we aim to determine the accuracy of detecting the presence or absence of residual disease after nCRT (preSANO trial).
  
  
  METHODS
  This study is set up as a prospective, single arm, multicenter, diagnostic trial. Operable patients with potentially curable SCC or AC of the esophagus or esophagogastric junction will be included. Approximately 4-6 weeks after completion of nCRT all included patients will undergo a first clinical response evaluation (CRE-I) including endoscopy with (random) conventional mucosal biopsies of the primary tumor site and of any other suspected lesions in the esophagus and radial endo-ultrasonography (EUS) for measurement of tumor thickness and area. Patients in whom no locoregional or disseminated disease can be proven by cytohistology will be offered a postponed surgical resection 6-8 weeks after CRE-I (ie, approximately 12-14 weeks after completion of nCRT). In the week preceding the postponed surgical resection, a second clinical response evaluation (CRE-II) will be planned that will include a whole body PET-CT, followed again by endoscopy with (random) conventional mucosal biopsies of the primary tumor site and any other suspected lesions in the esophagus, radial EUS for measurement of tumor thickness and area, and linear EUS plus fine needle aspiration of PET-positive lesions and/or suspected lymph nodes. The main study parameter is the correlation between the clinical response assessment during CRE-I and CRE-II and the final pathological response in the resection specimen.
  
  
  RESULTS
  The first patient was enrolled on July 23, 2013, and results are expected in January 2016.
  
  
  CONCLUSIONS
  If this preSANO trial shows that the presence or absence of residual tumor can be predicted reliably 6 or 12 weeks after completion of nCRT, a randomized trial comparing nCRT plus standard surgery versus chemoradiotherapy plus "surgery as needed" will be conducted (SANO trial).
  
  
  BACKGROUND
  Netherlands Trial Register: NTR4834; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4834 (archived by Webcite at http://www.webcitation.org/6Ze7mn67B).
authors.affiliation: Erasmus MC - University Medical Center Rotterdam, Department of Surgery, Rotterdam, Netherlands. b.noordman@erasmusmc.nl.
authors.forename: Bo Jan
authors.identifier: http://orcid.org/0000-0002-3405-5339
authors.initials: BJ
authors.lastname: Noordman
authors.forename: Joel
authors.identifier: http://orcid.org/0000-0002-6552-4281
authors.initials: J
authors.lastname: Shapiro
authors.forename: Manon Cw
authors.identifier: http://orcid.org/0000-0002-9103-9757
authors.initials: MC
authors.lastname: Spaander
authors.forename: Kausilia K
authors.identifier: http://orcid.org/0000-0003-4907-3318
authors.initials: KK
authors.lastname: Krishnadath
authors.forename: Hanneke Wm
authors.identifier: http://orcid.org/0000-0003-3546-9709
authors.initials: HW
authors.lastname: van Laarhoven
authors.forename: Mark I
authors.identifier: http://orcid.org/0000-0001-8689-3134
authors.initials: MI
authors.lastname: van Berge Henegouwen
authors.forename: Grard Ap
authors.identifier: http://orcid.org/0000-0002-5837-5513
authors.initials: GA
authors.lastname: Nieuwenhuijzen
authors.forename: Richard
authors.identifier: http://orcid.org/0000-0002-7134-261X
authors.initials: R
authors.lastname: van Hillegersberg
authors.forename: Meindert N
authors.identifier: http://orcid.org/0000-0002-4848-138X
authors.initials: MN
authors.lastname: Sosef
authors.forename: Ewout W
authors.identifier: http://orcid.org/0000-0002-7787-0122
authors.initials: EW
authors.lastname: Steyerberg
authors.forename: Bas Pl
authors.identifier: http://orcid.org/0000-0003-4738-3697
authors.initials: BP
authors.lastname: Wijnhoven
authors.forename: J Jan B
authors.identifier: http://orcid.org/0000-0001-7642-2021
authors.initials: JJ
authors.lastname: van Lanschot
keywords: active surveillance policy; esophageal cancer; esophagectomy; neoadjuvant chemoradiotherapy; surgery as needed