title: Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial.
abstract: BACKGROUND
  Despite complete resection, disease-free survival (DFS) of patients with cholangiocarcinoma (CCA) is less than 65 % after one year and not more than 35 % after three years. For muscle invasive gallbladder carcinoma (GBCA), prognosis is even worse, with an overall survival (OS) of only 30 % after three years. Thus, evaluation of adjuvant chemotherapy in biliary tract cancer in a large randomized trial is warranted.
  
  
  METHODS
  ACTICCA-1 is a randomized, multidisciplinary, multinational phase III investigator initiated trial. With respect to data obtained in the ABC-02 trial, we selected the combination of gemcitabine and cisplatin for 24 weeks as investigational treatment. Based on adjuvant trials in pancreatic cancer with comparable postoperative recovery time, inclusion of patients within a maximum interval of 16 weeks between surgery and start of chemotherapy was stipulated. Due to the different prognosis and treatment susceptibility of muscle invasive carcinoma, two separate cohorts (CCA and GBCA) were included to capture the potentially different treatment effects. Randomization is stratified for lymph node status for both cohorts and localization for CCA. The primary endpoint is DFS and secondary endpoints include OS, safety and tolerability of chemotherapy, quality of life, and patterns of disease recurrence. For CCA, adjuvant chemotherapy should increase DFS 24 months post-surgery from 40 to 55 % to be considered relevant. With a power of 80 % and a significance level of 5 %, 271 evaluable study patients have to be followed for 24-28 months to observe 166 events. For GBCA, chemotherapy should increase DFS 24 months post-surgery from 35 to 55 % to be of relevance; thus, 154 evaluable study patients have to be monitored for 24-28 months to observe 90 events. In both cohorts, randomization will be 1:1 with chemotherapy for 24 weeks and imaging every twelve weeks. In 2014, the study was initiated in Germany and in The Netherlands (funded by the Deutsche Krebshilfe, the Dutch Cancer Society, and supported by medac GmbH). Sites in Australia, Denmark, and the United Kingdom (funded by Cancer Research UK) are joining 2015.
  
  
  BACKGROUND
  The study is registered with ClinicalTrials.gov ( NCT02170090 ) and the European Clinical Trials Database (2012-005078-70). Registration date is 06/18/2014.
authors.affiliation: University Medical Center Hamburg-Eppendorf, and University Cancer Center Hamburg, Hamburg, Germany. a.stein@uke.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Stein
authors.affiliation: Tumor Biology Center, Clinic for Medical Oncology, Freiburg im Breisgau, Germany. arnold@tumorbio.uni-freiburg.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Arnold
authors.affiliation: University College London Cancer Institute, London, UK. j.bridgewater@ucl.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Bridgewater
authors.affiliation: University of New South Wales, Sydney, Australia. d.goldstein@unsw.edu.au.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Vejle Hospital, Vejle, Denmark. lars.henrik.jensen@rsyd.dk.
authors.forename: Lars Henrik
authors.initials: LH
authors.lastname: Jensen
authors.affiliation: Academic Medical Center, Amsterdam, The Netherlands. h.klumpen@amc.uva.nl.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Klümpen
authors.affiliation: University Medical Center Hamburg-Eppendorf, and University Cancer Center Hamburg, Hamburg, Germany. a.lohse@uke.de.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: University Medical Center Hamburg-Eppendorf, and University Cancer Center Hamburg, Hamburg, Germany. nashan@uke.de.
authors.forename: Björn
authors.initials: B
authors.lastname: Nashan
authors.affiliation: Southampton General Hospital, Southampton, United Kingdom. j.n.primrose@soton.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Primrose
authors.affiliation: CTC North GmbH & Co. KG at the University Medical Center Hamburg-Eppendorf, Hamburg, Germany. s.schrum@ctc-north.com.
authors.forename: Silke
authors.initials: S
authors.lastname: Schrum
authors.affiliation: University of Sydney, Sydney, Australia. jenny.shannon@swahs.health.nsw.gov.au.
authors.forename: Jenny
authors.initials: J
authors.lastname: Shannon
authors.affiliation: University Medical Center Hamburg-Eppendorf, and University Cancer Center Hamburg, Hamburg, Germany. e.vettorazzi@uke.de.
authors.forename: Eik
authors.initials: E
authors.lastname: Vettorazzi
authors.affiliation: University Medical Center Hamburg-Eppendorf, and University Cancer Center Hamburg, Hamburg, Germany. hwege@uke.de.
authors.forename: Henning
authors.initials: H
authors.lastname: Wege
mesh_terms: D001315:Australia; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000601:surgery; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects / Q000379:methods*; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000601:surgery; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D003718:Denmark; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000601:surgery; D005858:Germany; D006801:Humans; D009426:Netherlands; D011379:Prognosis; D016896:Treatment Outcome; D006113:United Kingdom; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine