title: Neo-adjuvant chemotherapy followed by surgery versus surgery alone in high-risk patients with resectable colorectal liver metastases: the CHARISMA randomized multicenter clinical trial.
abstract: BACKGROUND
  Efforts to improve the outcome of liver surgery by combining curative resection with chemotherapy have failed to demonstrate definite overall survival benefit. This may partly be due to the fact that these studies often involve strict inclusion criteria. Consequently, patients with a high risk profile as characterized by Fong's Clinical Risk Score (CRS) are often underrepresented in these studies. Conceptually, this group of patients might benefit the most from chemotherapy. The present study evaluates the impact of neo-adjuvant chemotherapy in high-risk patients with primary resectable colorectal liver metastases, without extrahepatic disease. Our hypothesis is that adding neo-adjuvant chemotherapy to surgery will provide an improvement in overall survival (OS) in patients with a high-risk profile.
  
  
  METHODS
  CHARISMA is a multicenter, randomized, phase III clinical trial. Patients will be randomized to either surgery alone (standard treatment, arm A) or to 6 cycles of neo-adjuvant oxaliplatin-based chemotherapy, followed by surgery (arm B). Patients must be ≥ 18 years of age with liver metastases of histologically confirmed primary colorectal carcinoma. Patients with extrahepatic metastases are excluded. Liver metastases must be deemed primarily resectable. Only patients with a CRS of 3-5 are eligible. The primary study endpoint is OS. Secondary endpoints are progression free survival (PFS), quality of life, morbidity of resection, treatment response on neo-adjuvant chemotherapy, and whether CEA levels can predict treatment response.
  
  
  CONCLUSIONS
  CHARISMA is a multicenter, randomized, phase III clinical trial that will provide an answer to the question if adding neo-adjuvant chemotherapy to surgery will improve OS in a well-defined high-risk patient group with colorectal liver metastases.
  
  
  BACKGROUND
  The CHARISMA is registered at European Union Clinical Trials Register (EudraCT), number: 2013-004952-39 , and in the "Netherlands national Trial Register (NTR), number: 4893.
authors.affiliation: Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. n.ayez@erasmusmc.nl.
authors.forename: Ninos
authors.initials: N
authors.lastname: Ayez
authors.affiliation: Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. e.vanderstok@erasmusmc.nl.
authors.forename: Eric P
authors.initials: EP
authors.lastname: van der Stok
authors.affiliation: Department of Surgical Oncology, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands. hans.dewilt@radboudumc.nl.
authors.forename: Hans
authors.initials: H
authors.lastname: de Wilt
authors.affiliation: Department of Medical Oncology, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands. sandra.radema@radboudumc.nl.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Radema
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. r.vanhillegersberg@umcutrecht.nl.
authors.forename: Richard
authors.initials: R
authors.lastname: van Hillegersberg
authors.affiliation: Department of Surgery, Máxima Medical Center, Veldhoven, The Netherlands. r.roumen@mmc.nl.
authors.forename: Rudi M
authors.initials: RM
authors.lastname: Roumen
authors.affiliation: Department of Medical Oncology, Máxima Medical Center, Veldhoven, The Netherlands. g.vreugdenhil@mmc.nl.
authors.forename: Gerard
authors.initials: G
authors.lastname: Vreugdenhil
authors.affiliation: Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. p.j.tanis@amc.nl.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Tanis
authors.affiliation: Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands. c.punt@amc.uva.nl.
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Punt
authors.affiliation: Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands. chc.dejong@mumc.nl.
authors.forename: Cornelis H
authors.initials: CH
authors.lastname: Dejong
authors.affiliation: Department of Medical Oncology, Maastricht University Medical Center, Maastricht, The Netherlands. rob.jansen@mumc.nl.
authors.forename: Rob L
authors.initials: RL
authors.lastname: Jansen
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. h.verheul@vumc.nl.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Verheul
authors.affiliation: Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. k.p.de.jong@umcg.nl.
authors.forename: Koert P
authors.initials: KP
authors.lastname: de Jong
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands. g.a.p.hospers@umcg.nl.
authors.forename: Geke A
authors.initials: GA
authors.lastname: Hospers
authors.affiliation: Department of Surgery, Medisch Spectrum Twente, Enschede, The Netherlands. j.klaase@mst.nl.
authors.forename: Joost M
authors.initials: JM
authors.lastname: Klaase
authors.affiliation: Department of Internal Medicine, Medisch Spectrum Twente, Enschede, The Netherlands. m.legdeur@mst.nl.
authors.forename: Marie-Cecile
authors.initials: MC
authors.lastname: Legdeur
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. e.vanmeerten@erasmusmc.nl.
authors.forename: Esther
authors.initials: E
authors.lastname: van Meerten
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. f.eskens@erasmusmc.nl.
authors.forename: Ferry A
authors.initials: FA
authors.lastname: Eskens
authors.affiliation: Clinical Trial Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. n.vandermeer@erasmusmc.nl.
authors.forename: Nelly
authors.initials: N
authors.lastname: van der Meer
authors.affiliation: Clinical Trial Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. b.vanderholt@erasmusmc.nl.
authors.forename: Bruno
authors.initials: B
authors.lastname: van der Holt
authors.affiliation: Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. c.verhoef@erasmusmc.nl.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Verhoef
authors.affiliation: Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. d.grunhagen@erasmusmc.nl.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Grünhagen
mesh_terms: D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D013505:Digestive System Surgical Procedures; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D012307:Risk Factors
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin