title: A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer.
abstract: BACKGROUND
  We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC).
  
  
  METHODS
  Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS).
  
  
  RESULTS
  Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37-0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54-1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47-1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group.
  
  
  CONCLUSIONS
  The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting.
  
  
  BACKGROUND
  Japan Pharmaceutical Information Center: JapicCTI-111554.
authors.affiliation: Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama uenom@kcch.jp.
authors.forename: M
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo.
authors.forename: T
authors.initials: T
authors.lastname: Okusaka
authors.affiliation: Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo.
authors.forename: Y
authors.initials: Y
authors.lastname: Omuro
authors.affiliation: Department of Gastroenterology, The University of Tokyo, Graduate School of Medicine, Tokyo.
authors.forename: H
authors.initials: H
authors.lastname: Isayama
authors.affiliation: Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka.
authors.forename: A
authors.initials: A
authors.lastname: Fukutomi
authors.affiliation: Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa.
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya.
authors.forename: N
authors.initials: N
authors.lastname: Mizuno
authors.affiliation: Department of Surgery, Oita Red Cross Hospital, Oita.
authors.forename: K
authors.initials: K
authors.lastname: Fukuzawa
authors.affiliation: Department of Gastroenterology, National Kyushu Cancer Center, Fukuoka.
authors.forename: M
authors.initials: M
authors.lastname: Furukawa
authors.affiliation: Department of Gastroenterology, National Hospital Organization Shikoku Cancer Center, Matsuyama.
authors.forename: H
authors.initials: H
authors.lastname: Iguchi
authors.affiliation: Gastroenterological Center, Yokohama City University Medical Center, Yokohama.
authors.forename: K
authors.initials: K
authors.lastname: Sugimori
authors.affiliation: Department of Medical Oncology, Kyorin University School of Medicine, Tokyo.
authors.forename: J
authors.initials: J
authors.lastname: Furuse
authors.affiliation: Department of Medical Oncology, Saitama Medical University International Medical Center, Saitama.
authors.forename: K
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka.
authors.forename: T
authors.initials: T
authors.lastname: Ioka
authors.affiliation: Hepato-biliary-pancreatic Surgery, National Hospital Organization Osaka National Hospital, Osaka.
authors.forename: S
authors.initials: S
authors.lastname: Nakamori
authors.affiliation: Department of Gastroenterological Surgery, Kumamoto University, Kumamoto.
authors.forename: H
authors.initials: H
authors.lastname: Baba
authors.affiliation: Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo.
authors.forename: Y
authors.initials: Y
authors.lastname: Komatsu
authors.affiliation: Department of Clinical Medicine (Biostatistics and Pharmaceutical Medicine), Kitasato University School of Pharmacy, Tokyo.
authors.forename: M
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: Division of Gastroenterology, University of Tsukuba, Tsukuba.
authors.forename: I
authors.initials: I
authors.lastname: Hyodo
authors.affiliation: Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Boku
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007564:Japan; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000009:adverse effects / Q000627:therapeutic use*; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D005641:Tegafur / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D003841:Deoxycytidine; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D002955:Leucovorin; D000093542:Gemcitabine
keywords: S-1; albumin; gemcitabine-refractory pancreatic cancer; leucovorin; pancreatic resection; phase II study