title: Phase II/III multicentre randomised controlled trial evaluating a strategy of primary surgery and adjuvant chemotherapy versus peri-operative chemotherapy for resectable gastric signet ring cell adenocarcinomas - PRODIGE 19 - FFCD1103 - ADCI002.
abstract: BACKGROUND
  A dramatic increase in the incidence of the diffuse form of gastric adenocarcinomas and particularly signet ring cell carcinomas has been observed in Western countries. Evidence is accruing that signet ring cell carcinomas may have inherent chemo resistance leaving many clinicians unsure of the benefits of delaying surgery to pursue a neoadjuvant approach.
  
  
  METHODS
  PRODIGE-19-FFCD1103-ADCI002 is a prospective multicentre controlled randomised phase II/III trial comparing current standard of care of perioperative chemotherapy (2x3 cycles of Epirubicin, cisplatin, 5-fluorouracil) with a strategy of primary surgery followed by adjuvant chemotherapy (6 cycles of Epirubicin, cisplatin, 5-fluorouracil) in patients with a stage IB-III gastric signet ring cell tumour. The principal objective of the phase II study (84 patients) is to determine if the experimental arm (primary surgery followed by adjuvant chemotherapy) has sufficient interest in terms of percentage of living patients at 24 months to be evaluated in a phase III trial. If 7 or less patients in the experimental arm are alive at 24 months, phase III will not be initiated. The primary objective of phase III (230 additional patients) is to demonstrate superiority of the experimental arm in terms of overall survival. Secondary endpoints include overall survival at 36 months, disease free survival at 24 and 36 months, R0 resection rates, treatment tolerance, postoperative mortality and morbidity evaluated by Clavien-Dindo severity index, the prognostic impact of positive peritoneal cytology and the assessment of quality of life. An ancillary study will assess the emotional and cognitive impact of surgery and perioperative chemotherapy for both the patient and their partner.
  
  
  CONCLUSIONS
  As inherent chemo resistance of signet ring cell tumours and delay in definitive surgery may favour tumour progression we hypothesise that a policy of primary surgery followed by adjuvant chemotherapy will improve overall survival compared to a standard perioperative chemotherapeutic strategy. This randomised phase II/III trial is the first dedicated to this histological subtype. Whilst the development of new biomarkers and targeted therapies are awaited, the results of this trial should further help in devising individualised protocols of patient care in a tumour group whose diversity increasingly demands assessment of alternative strategies.
  
  
  BACKGROUND
  ClinicalTrials.gov, NCT01717924.
authors.affiliation: Department of Digestive and Oncological Surgery, University Hospital of Lille, F-59037 Lille, France. guillaume.piessen@chru-lille.fr
authors.forename: Guillaume
authors.initials: G
authors.lastname: Piessen
authors.forename: Mathieu
authors.initials: M
authors.lastname: Messager
authors.forename: Karine
authors.initials: K
authors.lastname: Le Malicot
authors.forename: William B
authors.initials: WB
authors.lastname: Robb
authors.forename: Frédéric
authors.initials: F
authors.lastname: Di Fiore
authors.forename: Marie
authors.initials: M
authors.lastname: Guilbert
authors.forename: Marie
authors.initials: M
authors.lastname: Moreau
authors.forename: Véronique
authors.initials: V
authors.lastname: Christophe
authors.forename: Antoine
authors.initials: A
authors.lastname: Adenis
authors.forename: Christophe
authors.initials: C
authors.lastname: Mariette
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018279:Carcinoma, Signet Ring Cell / Q000188:drug therapy* / Q000601:surgery*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D013505:Digestive System Surgical Procedures; D015251:Epirubicin / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D012107:Research Design; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000601:surgery*
chemical_list: D015251:Epirubicin; D002945:Cisplatin; D005472:Fluorouracil