title: Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer.
abstract: BACKGROUND
  This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS).
  
  
  METHODS
  Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m2followed by oxaliplatin 130 mg/m2(maximum 8 cycles) and then S-1 [20 mg/m2(cohort 1) or 25 mg/m2(cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2-14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer.
  
  
  RESULTS
  DLT was reported for two of the five patients in cohort 2, defining 20 mg/m2twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m2twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations.
  
  
  CONCLUSIONS
  The promising activity of EOS (S-1 dose level, 25 mg/m2twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany. markus.moehler@unimedizin-mainz.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Moehler
authors.affiliation: Mutterhaus Der Borromaerinnen, Trier, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Mahlberg
authors.affiliation: Department of Medical Oncology, Klinikum Grosshadern, University of Munich, Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: Clinic of Comprehensive Cancer Care, MOU, Brno, Czech Republic.
authors.forename: Radka
authors.initials: R
authors.lastname: Obermannová
authors.affiliation: Faculty Hospital Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Eugen
authors.initials: E
authors.lastname: Kubala
authors.affiliation: Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors.forename: Bohuslav
authors.initials: B
authors.lastname: Melichar
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Weinmann
authors.affiliation: Pharmaceutical Research Consulting, Berlin, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Scigalla
authors.affiliation: Prague Clinical Services, Prague, Czech Republic.
authors.forename: Marietta
authors.initials: M
authors.lastname: Tesařová
authors.affiliation: Prague Clinical Services, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Janda
authors.affiliation: Nordic Group, Paris, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Hédouin-Biville
authors.affiliation: The Christie Hospital NHS Foundation Trust, Manchester, UK.
authors.forename: Wasat
authors.initials: W
authors.lastname: Mansoor
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004338:Drug Combinations; D015251:Epirubicin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000556:secondary; D004943:Esophagogastric Junction / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010094:Oxonic Acid / Q000008:administration & dosage; D011379:Prognosis; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000556:secondary; D015996:Survival Rate; D005641:Tegafur / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C079198:S 1 (combination); D005641:Tegafur; D015251:Epirubicin; D010094:Oxonic Acid
keywords: Advanced gastric cancer; Epirubicin; First-line chemotherapy; Oxaliplatin; S-1