title: Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC trial): study protocol for a multicentre randomized controlled trial.
abstract: BACKGROUND
  Pancreatic cancer is the fourth largest cause of cancer death in the United States and Europe with over 100,000 deaths per year in Europe alone. The overall 5-year survival ranges from 2-7 % and has hardly improved over the last two decades. Approximately 15 % of all patients have resectable disease at diagnosis, and of those, only a subgroup has a resectable tumour at surgical exploration. Data from cohort studies have suggested that outcome can be improved by preoperative radiochemotherapy, but data from well-designed randomized studies are lacking. Our PREOPANC phase III trial aims to test the hypothesis that median overall survival of patients with resectable or borderline resectable pancreatic cancer can be improved with preoperative radiochemotherapy.
  
  
  METHODS
  The PREOPANC trial is a randomized, controlled, multicentric superiority trial, initiated by the Dutch Pancreatic Cancer Group. Patients with (borderline) resectable pancreatic cancer are randomized to A: direct explorative laparotomy or B: after negative diagnostic laparoscopy, preoperative radiochemotherapy, followed by explorative laparotomy. A hypofractionated radiation scheme of 15 fractions of 2.4 gray (Gy) is combined with a course of gemcitabine, 1,000 mg/m(2)/dose on days 1, 8 and 15, preceded and followed by a modified course of gemcitabine. The target volumes of radiation are delineated on a 4D CT scan, where at least 95 % of the prescribed dose of 36 Gy in 15 fractions should cover 98 % of the planning target volume. Standard adjuvant chemotherapy is administered in both treatment arms after resection (six cycles in arm A and four in arm B). In total, 244 patients will be randomized in 17 hospitals in the Netherlands. The primary endpoint is overall survival by intention to treat. Secondary endpoints are (R0) resection rate, disease-free survival, time to locoregional recurrence or distant metastases and perioperative complications. Secondary endpoints for the experimental arm are toxicity and radiologic and pathologic response.
  
  
  CONCLUSIONS
  The PREOPANC trial is designed to investigate whether preoperative radiochemotherapy improves overall survival by means of increased (R0) resection rates in patients with resectable or borderline resectable pancreatic cancer.
  
  
  BACKGROUND
  Trial open for accrual: 3 April 2013 The Netherlands National Trial Register - NTR3709 (8 November 2012) EU Clinical Trials Register - 2012-003181-40 (11 December 2012).
authors.affiliation: Department of Radiation Oncology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. e.versteijne@amc.uva.nl.
authors.forename: Eva
authors.initials: E
authors.lastname: Versteijne
authors.affiliation: Department of Surgery, Erasmus Medical Center, Postbus 2040, 3000 CA, Rotterdam, The Netherlands. c.vaneijck@erasmusmc.nl.
authors.forename: Casper H J
authors.initials: CH
authors.lastname: van Eijck
authors.affiliation: Department of Medical Oncology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. c.punt@amc.uva.nl.
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.affiliation: Department of Surgery, Erasmus Medical Center, Postbus 2040, 3000 CA, Rotterdam, The Netherlands. m.suker@erasmusmc.nl.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Suker
authors.affiliation: Department of Clinical Epidemiologic Biostatics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. a.h.zwinderman@amc.uva.nl.
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.affiliation: Clinical Research Department, Comprehensive Cancer Organisation the Netherlands (IKNL), Postbus 1281, 6501 BG, Nijmegen, The Netherlands. miriam.dohmen@radboudumc.nl.
authors.forename: Miriam A C
authors.initials: MA
authors.lastname: Dohmen
authors.affiliation: Clinical Research Department, Comprehensive Cancer Organisation the Netherlands (IKNL), Postbus 1281, 6501 BG, Nijmegen, The Netherlands. k.groothuis@iknl.nl.
authors.forename: Karin B C
authors.initials: KB
authors.lastname: Groothuis
authors.affiliation: Department of Surgery, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. o.r.busch@amc.uva.nl.
authors.forename: Oliver R C
authors.initials: OR
authors.lastname: Busch
authors.affiliation: Department of Surgery, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. m.g.besselink@amc.uva.nl.
authors.forename: Marc G H
authors.initials: MG
authors.lastname: Besselink
authors.affiliation: Department of Surgery, Catharina Hospital, Postbus 1350, 5602 ZA, Eindhoven, The Netherlands. Ignace.d.Hingh@catharinaziekenhuis.nl.
authors.forename: Ignace H J T
authors.initials: IH
authors.lastname: de Hingh
authors.affiliation: Department of Medical Oncology, Amphia Hospital, Postbus 90158, 4800 RK, Breda, The Netherlands. AtenTije@amphia.nl.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Ten Tije
authors.affiliation: Department of Surgery, Isala Clinics, Postbus 10400, 8000 GK, Zwolle, The Netherlands. g.a.patijn@isala.nl.
authors.forename: Gijs A
authors.initials: GA
authors.lastname: Patijn
authors.affiliation: Department of Surgery, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, The Netherlands. b.a.bonsing@lumc.nl.
authors.forename: Bert A
authors.initials: BA
authors.lastname: Bonsing
authors.affiliation: Department of Medical Oncology, Maastricht University Medical Center, Postbus 3035, 6202 NA, Maastricht, The Netherlands. Judith.de.vos@mumc.nl.
authors.forename: Judith
authors.initials: J
authors.lastname: de Vos-Geelen
authors.affiliation: Department of Surgery, Medical Spectrum Twente, Postbus 50 000, 7500 KA, Enschede, The Netherlands. j.klaase@mst.nl.
authors.forename: Joost M
authors.initials: JM
authors.lastname: Klaase
authors.affiliation: Department of Surgery, Onze Lieve Vrouwe Gasthuis, Postbus 95500, 1090 HM, Amsterdam, The Netherlands. S.Festen@olvg.nl.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Festen
authors.affiliation: Department of Surgery, Sint Antonius Hospital, Postbus 2500, 3430 EM, Nieuwegein, The Netherlands. d.boerma@antoniusziekenhuis.nl.
authors.forename: Djamila
authors.initials: D
authors.lastname: Boerma
authors.affiliation: Department of Surgery, University Medical Center Groningen, Postbus 30.001, 9700 RB, Groningen, The Netherlands. j.i.erdmann@umcg.nl.
authors.forename: Joris I
authors.initials: JI
authors.lastname: Erdmann
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Postbus 85500, 3508 GA, Utrecht, The Netherlands. i.q.molenaar@umcutrecht.nl.
authors.forename: I Quintus
authors.initials: IQ
authors.lastname: Molenaar
authors.affiliation: Department of Surgery, Maasstad Hospital, Maasstadweg 21, 3079 DZ, Rotterdam, The Netherlands. HarstE@maasstadziekenhuis.nl.
authors.forename: Erwin
authors.initials: E
authors.lastname: van der Harst
authors.affiliation: Department of Surgery, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands. marion.vanderkolk@radboudumc.nl.
authors.forename: Marion B
authors.initials: MB
authors.lastname: van der Kolk
authors.affiliation: Department of Radiation Oncology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. c.r.rasch@amc.uva.nl.
authors.forename: Coen R N
authors.initials: CR
authors.lastname: Rasch
authors.affiliation: Department of Radiation Oncology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. g.vantienhoven@amc.uva.nl.
authors.forename: Geertjan
authors.initials: G
authors.lastname: van Tienhoven
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D059186:Chemoradiotherapy, Adjuvant / Q000009:adverse effects / Q000401:mortality; D002985:Clinical Protocols; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D006801:Humans; D053208:Kaplan-Meier Estimate; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000401:mortality; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009426:Netherlands; D010180:Pancreatectomy / Q000009:adverse effects / Q000401:mortality; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000069473:Radiation Dose Hypofractionation; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine